NDC 0006-3026 Keytruda

Pembrolizumab

NDC Product Code 0006-3026

NDC 0006-3026-02

Package Description: 1 VIAL in 1 CARTON > 10 mL in 1 VIAL (0006-3026-01)

NDC 0006-3026-04

Package Description: 2 VIAL in 1 CARTON > 10 mL in 1 VIAL (0006-3026-01)

NDC Product Information

Keytruda with NDC 0006-3026 is a a human prescription drug product labeled by Merck Sharp & Dohme Corp.. The generic name of Keytruda is pembrolizumab. The product's dosage form is injection, solution and is administered via intravenous form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1657746, 1657749, 1657750 and 1657751.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Keytruda Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • HISTIDINE (UNII: 4QD397987E)
  • SUCROSE (UNII: C151H8M554)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • HISTIDINE (UNII: 4QD397987E)
  • SUCROSE (UNII: C151H8M554)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Programmed Death Receptor-1 Blocking Antibody - [EPC] (Established Pharmacologic Class)
  • Programmed Death Receptor-1-directed Antibody Interactions - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Merck Sharp & Dohme Corp.
Labeler Code: 0006
FDA Application Number: BLA125514 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-15-2015 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2023 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Pembrolizumab Injection

Pembrolizumab Injection is pronounced as (pem'' broe liz' ue mab)

Why is pembrolizumab injection medication prescribed?
Pembrolizumab injection is used to treat melanoma (a type of skin cancer) that cannot be treated with surgery or that has spread to other parts of the body. Pembrolizumab...
[Read More]

* Please review the disclaimer below.

Keytruda Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Melanoma

KEYTRUDA® is indicated for the treatment of patients with unresectable or metastatic melanoma.KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

1.2 Non-Small Cell Lung Cancer

  • KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations, and is:
  • Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
  • Metastatic.
  • KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

1.3 Head And Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test [see Dosage and Administration (2.1)].KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

1.4 Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

1.5 Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

1.6 Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)], or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14.6)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

1.7 Microsatellite Instability-High Or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.7)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

1.8 Microsatellite Instability-High Or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

1.9 Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.These indications are approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.9)]. Continued approval of these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.10 Esophageal Cancer

  • KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:in combination with platinum- and fluoropyrimidine-based chemotherapy, oras a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)].

1.11 Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)].This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.11)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.12 Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.12)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.13 Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.13)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.14 Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

1.15 Endometrial Carcinoma

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.15)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.16 Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test [see Dosage and Administration (2.1)], that have progressed following prior treatment and who have no satisfactory alternative treatment options.This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.16)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

1.17 Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

1.18 Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)].This indication is approved under accelerated approval based on progression-free survival [see Clinical Studies (14.18)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.19 Adult Indications: Additional Dosing Regimen Of 400 Mg Every 6 Weeks

KEYTRUDA is indicated for use at an additional recommended dosage of 400 mg every 6 weeks for all approved adult indications [see Indications and Usage (1.1-1.18) and Dosage and Administration (2.2)]. This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety [see Clinical Pharmacology (12.2) and Clinical Studies (14.19)]. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials.

2.1 Patient Selection For Nsclc, Hnscc, Urothelial Carcinoma, Gastric Cancer, Esophageal Cancer, Cervical Cancer, Msi-H Or Dmmr Cancer, Msi-H Or Dmmr Crc, Tmb-H Cancer, Or Tnbc

  • Select patients for treatment with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression in:stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.2)]. metastatic NSCLC [see Clinical Studies (14.2)].first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.3)].metastatic urothelial carcinoma [see Clinical Studies (14.6)].metastatic gastric cancer [see Clinical Studies (14.9)]. If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing.previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.10)].recurrent or metastatic cervical cancer [see Clinical Studies (14.11)].For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.7, 14.8)].For the TMB-H indication, select patients for treatment with KEYTRUDA as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.16)].Because the effect of prior chemotherapy on test results for tumor mutation burden (TMB-H), MSI-H, or dMMR in patients with high-grade gliomas is unclear, it is recommended to test for these markers in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.Select patients for treatment with KEYTRUDA in combination with chemotherapy based on the presence of positive PD-L1 expression in:locally recurrent unresectable or metastatic TNBC [see Clinical Studies (14.18)].Information on FDA-approved tests for the detection of PD-L1 expression and TMB status is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved test for the detection of MSI-H or dMMR is not currently available.

Table 1: Recommended DosageIndicationRecommended Dosage of KEYTRUDA
Duration/Timing of Treatment  Monotherapy  Adult patients with unresectable or   metastatic melanoma200 mg every 3 weeks30-minute intravenous infusionor400 mg every 6 weeks  Until disease progression or   unacceptable toxicity  Adjuvant treatment of adult patients   with melanoma200 mg every 3 weeksor400 mg every 6 weeks  Until disease recurrence, unacceptable   toxicity, or up to 12 months  Adult patients with NSCLC,  HNSCC, cHL, PMBCL, locally  advanced or metastatic Urothelial  Carcinoma, MSI-H or dMMR Cancer,  MSI-H or dMMR CRC, Gastric Cancer,  Esophageal Cancer, Cervical Cancer,  HCC, MCC, TMB-H Cancer, or cSCC200 mg every 3 weeksor400 mg every 6 weeks  Until disease progression, unacceptable   toxicity, or up to 24 months  Adult patients with high-risk BCG-  unresponsive NMIBC200 mg every 3 weeksor400 mg every 6 weeks  Until persistent or recurrent high-risk   NMIBC, disease progression,   unacceptable toxicity, or up to   24 months  Pediatric patients with cHL, PMBCL,   MSI-H Cancer, MCC, or TMB-H   Cancer2 mg/kg every 3 weeks (up to amaximum of 200 mg)  Until disease progression, unacceptable  toxicity, or up to 24 months  Combination TherapyRefer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.  Adult patients with NSCLC, HNSCC, or   Esophageal Cancer200 mg every 3 weeksor400 mg every 6 weeksAdminister KEYTRUDA prior to chemotherapy when given on the same day.  Until disease progression, unacceptable  toxicity, or up to 24 months  Adult patients with Gastric Cancer200 mg every 3 weeksor400 mg every 6 weeksAdminister KEYTRUDA prior to trastuzumab and chemotherapy when given on the same day.  Until disease progression, unacceptable   toxicity, or up to 24 months  Adult patients with RCC200 mg every 3 weeksor400 mg every 6 weeksAdminister KEYTRUDA in combination with axitinib 5 mg orally twice daily.When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer.  Until disease progression, unacceptable   toxicity, or for KEYTRUDA, up to   24 months  Adult patients with Endometrial   Carcinoma200 mg every 3 weeksor400 mg every 6 weeksAdminister KEYTRUDA in combination with lenvatinib 20 mg orally once daily.  Until disease progression, unacceptable  toxicity, or for KEYTRUDA, up to  24 months  Adult patients with locally recurrent   unresectable or metastatic TNBC200 mg every 3 weeksor400 mg every 6 weeksAdminister KEYTRUDA prior to chemotherapy when given on the same day.  Until disease progression, unacceptable   toxicity, or up to 24 months

2.3 Dose Modifications

No dose reduction for KEYTRUDA is recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA for Life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.Dosage modifications for KEYTRUDA for adverse reactions that require management different from these general guidelines are summarized in Table 2.Table 2: Recommended Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityBased on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0Dosage ModificationALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normalImmune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]PneumonitisGrade 2WithholdResume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. Grade 3 or 4 Permanently discontinueColitisGrade 2 or 3WithholdGrade 4Permanently discontinueHepatitis with no tumor involvement of the liverAST or ALT increases to more than 3 and up to 8 times ULNorTotal bilirubin increases to more than 1.5 and up to 3 times ULNWithholdFor liver enzyme elevations in patients treated with combination therapy with axitinib, see Table 3.AST or ALT increases to more than 8 times ULN orTotal bilirubin increases to more than 3 times ULNPermanently discontinueHepatitis with tumor involvement of the liverIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on recommendations for hepatitis with no liver involvement.Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULNWithholdALT or AST increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULNPermanently discontinueEndocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severityNephritis with Renal DysfunctionGrade 2 or 3 increased blood creatinine WithholdGrade 4 increased blood creatinine Permanently discontinueExfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS WithholdConfirmed SJS, TEN, or DRESSPermanently discontinueMyocarditis Grade 2, 3, or 4 Permanently discontinueNeurological Toxicities Grade 2 WithholdGrade 3 or 4 Permanently discontinueHematologic toxicity in patients with cHL or PMBCL Grade 4 Withhold until resolution to Grades 0 or 1Other Adverse ReactionsInfusion-related reactions [see Warnings and Precautions (5.2)]Grade 1 or 2 Interrupt or slow the rate of infusionGrade 3 or 4 Permanently discontinueThe following table represents dosage modifications that are different from those described above for KEYTRUDA or in the Full Prescribing Information for the drug administered in combination.Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for CombinationTreatmentAdverse ReactionSeverityDosage ModificationALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normalKEYTRUDA in combination with axitinibLiver enzyme elevationsConsider corticosteroid therapyALT or AST increases to at least 3 times but less than 10 times ULN without concurrent total bilirubin at least 2 times ULNWithhold both KEYTRUDA and axitinib until resolution to Grades 0 or 1Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information.ALT or AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN or ALT or AST ≥10 times ULNPermanently discontinue bothKEYTRUDA and axitinibWhen administering KEYTRUDA in combination with lenvatinib for the treatment of endometrial carcinoma, interrupt one or both as appropriate. No dose reductions are recommended for KEYTRUDA. Withhold, dose reduce, or discontinue lenvatinib in accordance with the instructions in the lenvatinib prescribing information.

Other

  • AdministrationAdminister diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.Do not co-administer other drugs through the same infusion line.

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Melanoma

Ipilimumab-Naive MelanomaThe safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year.The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 4 and 5 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.Table 4: SelectedAdverse reactions occurring at same or higher incidence than in the ipilimumab arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006  Adverse ReactionKEYTRUDA10 mg/kg every 2 or 3 weeksIpilimumabn=555n=256All GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)General  Fatigue280.9283.1Skin and Subcutaneous Tissue  RashIncludes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash.240.2231.2  VitiligoIncludes skin hypopigmentation13020Musculoskeletal and Connective Tissue  Arthralgia180.4101.2  Back pain120.970.8Respiratory, Thoracic and Mediastinal  Cough17070.4  Dyspnea110.970.8Metabolism and Nutrition  Decreased appetite160.5140.8Nervous System  Headache140.2140.8Other clinically important adverse reactions occurring in ≥10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%).Table 5: SelectedLaboratory abnormalities occurring at same or higher incidence than in ipilimumab arm Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205.KEYTRUDA10 mg/kg every 2 or 3 weeksIpilimumabAll GradesGraded per NCI CTCAE v4.0%Grades 3-4%All Grades%Grades 3-4%Chemistry  Hyperglycemia454.2453.8  Hypertriglyceridemia432.6311.1  Hyponatremia284.6267  Increased AST272.6252.5  Hypercholesterolemia201.2130Hematology  Anemia353.8334.0  Lymphopenia337256Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4).

Ipilimumab-Refractory MelanomaThe safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ≥6 months and 4% were exposed for ≥12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ≥6 months and 6% of patients were exposed to KEYTRUDA for ≥12 months.The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis.In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.Table 6: SelectedAdverse reactions occurring at same or higher incidence than in chemotherapy arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-002  Adverse ReactionKEYTRUDA2 mg/kg or 10 mg/kg every 3 weeksChemotherapyChemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatinn=357n=171All GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Skin and Subcutaneous Tissue  Pruritus28080  RashIncludes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic240.680Gastrointestinal  Constipation220.3202.3  Diarrhea200.8202.3  Abdominal pain131.781.2Respiratory, Thoracic and Mediastinal  Cough180160General  Pyrexia140.390.6  Asthenia102.091.8Musculoskeletal and Connective Tissue  Arthralgia140.6101.2Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).Table 7: SelectedLaboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA n=247 and chemotherapy n=116; decreased bicarbonate: KEYTRUDA n=263 and chemotherapy n=123.KEYTRUDA2 mg/kg or 10 mg/kg every 3 weeksChemotherapyAll GradesGraded per NCI CTCAE v4.0%Grades 3-4%All Grades%Grades 3-4%Chemistry  Hyperglycemia496446  Hypoalbuminemia371.9330.6  Hyponatremia377243.8  Hypertriglyceridemia330320.9  Increased alkaline phosphatase263.1181.9  Increased AST242.2160.6  Decreased bicarbonate220.4130  Hypocalcemia 210.3181.9  Increased ALT211.8160.6Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).

Adjuvant Treatment of Resected MelanomaThe safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes).Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054.Table 8: SelectedAdverse reactions occurring at same or higher incidence than in placebo arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-054  Adverse ReactionKEYTRUDA200 mg every 3 weeksn=509Placebon=502All GradesGraded per NCI CTCAE v4.03(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Gastrointestinal  Diarrhea281.2261.2  Nausea170.2150Skin and Subcutaneous Tissue  Pruritus190120  Rash130.290Musculoskeletal and Connective Tissue  Arthralgia161.2140Endocrine  Hypothyroidism1502.80  Hyperthyroidism100.21.20Respiratory, Thoracic and Mediastinal  Cough140110General  Asthenia110.280  Influenza like illness11080Investigations  Weight loss11080Table 9: SelectedLaboratory abnormalities occurring at same or higher incidence than placebo. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 503 to 507 patients) and placebo (range: 492 to 498 patients).KEYTRUDA200 mg every 3 weeksPlaceboAll GradesGraded per NCI CTCAE v4.03%Grades 3-4%All Grades%Grades 3-4%Chemistry  Increased ALT272.4160.2  Increased AST241.8150.4Hematology  Lymphopenia241161.2

NSCLC

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapyThe safety of KEYTRUDA in combination with pemetrexed and investigator's choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Seventy-two percent of patients received carboplatin.The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline.KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-189.Table 10: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189  Adverse ReactionKEYTRUDA 200 mg every 3 weeksPemetrexed Platinum Chemotherapyn=405PlaceboPemetrexedPlatinum Chemotherapyn=202All GradesGraded per NCI CTCAE v4.03(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Gastrointestinal  Nausea563.5523.5  Constipation351.0320.5  Diarrhea315213.0  Vomiting243.7233.0General  FatigueIncludes asthenia and fatigue5612586  Pyrexia200.2150Metabolism and Nutrition  Decreased appetite281.5300.5Skin and Subcutaneous Tissue  RashIncludes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.252.0172.5Respiratory, Thoracic and Mediastinal  Cough210280  Dyspnea213.7265Table 11: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients).KEYTRUDA 200 mg every 3 weeksPemetrexed Platinum ChemotherapyPlacebo Pemetrexed Platinum ChemotherapyAll GradesGraded per NCI CTCAE v4.03%Grades 3-4%All Grades%Grades 3-4%Hematology  Anemia85178118  Lymphopenia64226425  Neutropenia48204119  Thrombocytopenia3012298Chemistry  Hyperglycemia639607  Increased ALT 473.8422.6  Increased AST472.8401.0  Hypoalbuminemia392.8391.1  Increased creatinine 374.2251.0  Hyponatremia327236  Hypophosphatemia30102814  Increased alkaline phosphatase 261.8292.1  Hypocalcemia242.8170.5  Hyperkalemia242.8193.1  Hypokalemia215205

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapyThe safety of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin.The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases.KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%). The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

Previously Untreated NSCLCThe safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator's choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (stage IV), 13% had stage III disease (2% stage IIIA and 11% stage IIIB), and 5% had treated brain metastases at baseline.KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%).Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042.Table 12: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042  Adverse ReactionKEYTRUDA200 mg every 3 weeksn=636Chemotherapyn=615All GradesGraded per NCI CTCAE v4.03(%)Grades 3-5(%)All Grades(%)Grades 3-5(%)General  FatigueIncludes fatigue and asthenia253.1333.9  Pyrexia100.380Metabolism and Nutrition  Decreased appetite171.7211.5Respiratory, Thoracic and Mediastinal  Dyspnea172.0110.8  Cough160.2110.3Skin and Subcutaneous Tissue  RashIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.151.380.2Gastrointestinal  Constipation120210.2  Diarrhea120.8120.5  Nausea120.5321.1Endocrine  Hypothyroidism120.21.50Infections  Pneumonia12796Investigations  Weight loss100.970.2Table 13: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173.KEYTRUDA200 mg every 3 weeksChemotherapyAll GradesGraded per NCI CTCAE v4.03%Grades 3-4%All Grades%Grades 3-4%Chemistry  Hyperglycemia524.7515  Increased ALT334.8342.9  Hypoalbuminemia332.2291.0  Increased AST313.6321.7  Hyponatremia319328  Increased alkaline phosphatase292.3290.3  Hypocalcemia252.5190.7  Hyperkalemia233.0202.2  Increased prothrombin INR212.0152.9Hematology  Anemia434.47919  Lymphopenia3074113

Previously Treated NSCLCThe safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months.The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease.In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010.Table 14: SelectedAdverse reactions occurring at same or higher incidence than in docetaxel arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-010  Adverse ReactionKEYTRUDA2 or 10 mg/kg every 3 weeksn=682Docetaxel75 mg/m2 every 3 weeksn=309All GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Metabolism and Nutrition  Decreased appetite251.5232.6Respiratory, Thoracic and Mediastinal  Dyspnea233.7202.6  Cough190.6140Gastrointestinal  Nausea201.3180.6  Constipation150.6120.6  Vomiting130.9100.6Skin and Subcutaneous Tissue  RashIncludes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic170.480  Pruritus11030.3Musculoskeletal and Connective Tissue  Arthralgia111.090.3  Back pain111.580.3Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).Table 15: SelectedLaboratory abnormalities occurring at same or higher incidence than in docetaxel arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients).KEYTRUDA2 or 10 mg/kg every 3 weeksDocetaxel75 mg/m2 every 3 weeksAll GradesGraded per NCI CTCAE v4.0%Grades 3-4%All Grades%Grades 3-4%Chemistry  Hyponatremia328272.9  Increased alkaline phosphatase283.0160.7  Increased AST261.6120.7  Increased ALT222.790.4Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4).

HNSCC

First-line treatment of metastatic or unresectable, recurrent HNSCCThe safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.3)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab.The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for ≥12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin.KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%).KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048.Table 16: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-048 KEYTRUDA 200 mg every 3 weeksKEYTRUDA 200 mg every 3 weeks Platinum FUCetuximab Platinum FUAdverse Reactionn=300n=276n=287 All GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)General  FatigueIncludes fatigue, asthenia3344911488  Pyrexia130.7160.7120  Mucosal inflammation4.31.33110285Gastrointestinal  Constipation200.3370331.4  Nausea170516516  DiarrheaIncludes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis160.7293.3353.1  Vomiting110.3323.6282.8  Dysphagia82.3122.9102.1  Stomatitis30268283.5Skin  RashIncludes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis202.3170.7708  Pruritus11080100.3Respiratory, Thoracic and Mediastinal  CoughIncludes cough, productive cough180.3220150  DyspneaIncludes dyspnea, exertional dyspnea142.0101.881.0Endocrine  Hypothyroidism18015060Metabolism and Nutrition  Decreased appetite151.0294.7303.5  Weight loss152162.9211.4Infections  PneumoniaIncludes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal1271911136Nervous System  Headache120.3110.780.3  Dizziness50.3100.4130.3  Peripheral sensory neuropathyIncludes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia10141.171Musculoskeletal  MyalgiaIncludes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia121.0130.4110.3  Neck pain60.7101.170.7Psychiatric  Insomnia70.710080Table 17: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-048 KEYTRUDA 200 mg every 3 weeksKEYTRUDA 200 mg every 3 weeks Platinum FUCetuximab Platinum FULaboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/chemotherapy (range: 235 to 266 patients), KEYTRUDA (range: 241 to 288 patients), cetuximab/chemotherapy (range: 249 to 282 patients).All GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Hematology  Lymphopenia542569357445  Anemia52789287819  Thrombocytopenia123.873187618  Neutropenia71.467357142Chemistry  Hyperglycemia473.8556664.7  Hyponatremia461756205920  Hypoalbuminemia443.2474.0491.1  Increased AST283.1242.0373.6  Increased ALT252.1221.6381.8  Increased alkaline phosphatase252.1271.2331.1  Hypercalcemia224.6164.3132.6  Hypocalcemia221.1324587  Hyperkalemia212.8274.3294.3  Hypophosphatemia20535124819  Hypokalemia19534124715  Increased creatinine181.1362.3272.2  Hypomagnesemia160.4421.7766

Previously treated recurrent or metastatic HNSCCAmong the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.3)], the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012.The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.1)].

Relapsed or Refractory cHL KEYNOTE-204The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.4)]. Adults with relapsed or refractory cHL received KEYTRUDA 200 mg intravenously every 3 weeks (n=148) or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC ≥1000/µL, platelet count ≥75,000/µL, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment. Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia.Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Table 18 summarizes adverse reactions in KEYNOTE-204.Table 18: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-204      Adverse ReactionKEYTRUDA200 mg every 3 weeksN=148Brentuximab Vedotin1.8 mg/kg every 3 weeksN=152All GradesGraded per NCI CTCAE v4.0(%)Grades 3- 4(%)All Grades(%)Grades 3- 4Adverse reactions in BV arm were Grade 3 only.(%)Infections   Upper respiratory tract infectionIncludes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection411.4240  Urinary tract infection11 0 3 0.7Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity32 0 29 1.3Gastrointestinal  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis22 2.7 17 1.3  Nausea 14 0 24 0.7  Vomiting 14 1.4 20 0  Abdominal painIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper11 0.7 13 1.3General  Pyrexia 20 0.7 13 0.7  FatigueIncludes fatigue, asthenia20 0 22 0.7Skin and Subcutaneous Tissue  RashIncludes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular‚ rash maculo-papular, rash papular, rash pruritic, toxic skin eruption20 0 19 0.7  Pruritus 18 0 12 0Respiratory, Thoracic and Mediastinal  CoughIncludes cough, productive cough20 0.7 14 0.7  PneumonitisIncludes pneumonitis, interstitial lung disease11 5 3 1.3  DyspneaIncludes dyspnea, dyspnea exertional, wheezing11 0.7 7 0.7Endocrine   Hypothyroidism 19 0 3 0Nervous System  Peripheral neuropathyIncludes dysaesthesia, hypoaesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy11 0.7 43 7  HeadacheIncludes headache, migraine, tension headache11 0 11 0Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare. Table 19 summarizes laboratory abnormalities in KEYNOTE-204.Table 19: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 143 to 148 patients) and BV (range: 146 to 152 patients); hypomagnesemia: KEYTRUDA n=53 and BV n=50.KEYTRUDA200 mg every 3 weeksBrentuximab Vedotin1.8 mg/kg every 3 weeksAll GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Chemistry   Hyperglycemia 46 4.1 36 2.0  Increased AST 39 5 41 3.9  Increased ALT 34 6 45 5  Hypophosphatemia 31 5 18 2.7  Increased creatinine 28 3.4 14 2.6  Hypomagnesemia 25 0 12 0  Hyponatremia 24 4.1 20 3.3  Hypocalcemia 22 2.0 16 0  Increased alkaline phosphatase 21 2.1 22 2.6  Hyperbilirubinemia 16 2.0 9 1.3  Hypoalbuminemia 16 0.7 19 0.7  Hyperkalemia 15 1.4 8 0Hematology  Lymphopenia 35 9 32 13  Thrombocytopenia 34 10 26 5  Neutropenia 28 8 43 17  Anemia 24 5 33 8KEYNOTE-087Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.4)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.Table 20: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-087  Adverse ReactionKEYTRUDA200 mg every 3 weeksN=210All GradesGraded per NCI CTCAE v4.0(%)Grade 3(%)General  FatigueIncludes fatigue, asthenia261.0  Pyrexia241.0Respiratory, Thoracic and Mediastinal  CoughIncludes cough, productive cough240.5  DyspneaIncludes dyspnea, dyspnea exertional, wheezing111.0Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 211.0  Arthralgia100.5Gastrointestinal  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis201.4  Vomiting150  Nausea130Skin and Subcutaneous Tissue  Rash Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrhoeic dermatitis, dermatitis psoriasiform 200.5  Pruritus110Endocrine  Hypothyroidism140.5Infections  Upper respiratory tract infection130Nervous System  Headache110.5  Peripheral neuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy100Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).Table 21: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL who Received KEYTRUDA in KEYNOTE-087  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 208 to 209 patients)KEYTRUDA200 mg every 3 weeksAll GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)Chemistry   HypertransaminasemiaIncludes elevation of AST or ALT342  Increased alkaline phosphatase170  Increased creatinine150.5Hematology  Anemia306  Thrombocytopenia274  Neutropenia247Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).

PMBCLAmong the 53 patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions that occurred in >2% of patients included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170.Table 22: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170  Adverse ReactionKEYTRUDA200 mg every 3 weeksN=53All GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain300Infections  Upper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection280General  Pyrexia280  FatigueIncludes fatigue, asthenia 232Respiratory, Thoracic and Mediastinal  CoughIncludes allergic cough, cough, productive cough262  Dyspnea2111Gastrointestinal  DiarrheaIncludes diarrhea, gastroenteritis132  Abdominal pain Includes abdominal pain, abdominal pain upper130  Nausea110Cardiac  Arrhythmia Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia114Nervous System  Headache110Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).Table 23: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 44 to 48 patients)KEYTRUDA200 mg every 3 weeksAll GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)Hematology  Anemia470  Leukopenia359  Lymphopenia3218  Neutropenia3011Chemistry   Hyperglycemia384  Hypophosphatemia2910  HypertransaminasemiaIncludes elevation of AST or ALT274  Hypoglycemia190  Increased alkaline phosphatase170  Increased creatinine170  Hypocalcemia154  Hypokalemia154

Urothelial Carcinoma

Cisplatin Ineligible Patients with Urothelial Carcinoma The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.6)]. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression.The median duration of exposure to KEYTRUDA was 2.8 months (range: 1 day to 15.8 months).KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone equivalent.Table 24 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.Table 24: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-052Adverse ReactionKEYTRUDA200 mg every 3 weeksN=370All GradesGraded per NCI CTCAE v4.0(%)Grades 3–4(%)GeneralFatigueIncludes fatigue, asthenia386Pyrexia110.5Weight loss100Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain244.9  Arthralgia101.1Metabolism and NutritionDecreased appetite221.6Hyponatremia104.1Gastrointestinal  Constipation211.1  DiarrheaIncludes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements202.4  Nausea181.1  Abdominal painIncludes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper182.7  Elevated LFTsIncludes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, increased transaminases, hyperbilirubinemia, increased blood bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, increased hepatic enzymes, increased liver function tests133.5  Vomiting120Skin and Subcutaneous Tissue  RashIncludes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneiform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized210.5  Pruritus 190.3  Edema peripheralIncludes edema peripheral, peripheral swelling141.1Infections  Urinary tract infection199Blood and Lymphatic System  Anemia177Respiratory, Thoracic, and Mediastinal  Cough140  Dyspnea 110.5Renal and UrinaryIncreased blood creatinine111.1Hematuria 133.0

Previously Treated Urothelial CarcinomaThe safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator's choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.6)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible.The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.Table 25: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-045  Adverse ReactionKEYTRUDA200 mg every 3 weeksChemotherapyChemotherapy: paclitaxel, docetaxel, or vinflunine n=266n=255All GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)General  FatigueIncludes asthenia, fatigue, malaise, lethargy384.55611  Pyrexia140.8131.2Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain323.0272.0Skin and Subcutaneous Tissue  Pruritus23060.4  RashIncludes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrheic keratosis, lichenoid keratosis 200.4130.4Gastrointestinal  Nausea211.1291.6  Constipation191.1323.1  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 182.3191.6  Vomiting150.4130.4  Abdominal pain131.1132.7Infections  Urinary tract infection154.9144.3Metabolism and Nutrition  Decreased appetite213.8211.2Respiratory, Thoracic and Mediastinal  CoughIncludes cough, productive cough 150.490  DyspneaIncludes dyspnea, dyspnea exertional, wheezing141.9121.2Renal and Urinary  Hematuria Includes blood urine present, hematuria, chromaturia 122.381.6Table 26: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: KEYTRUDA n=232 and chemotherapy n=222.KEYTRUDA200 mg every 3 weeksChemotherapyAll GradesGraded per NCI CTCAE v4.0%Grades 3-4%All Grades%Grades 3-4%Chemistry  Hyperglycemia528607  Anemia52136818  Lymphopenia45155325  Hypoalbuminemia431.7503.8  Hyponatremia3794713  Increased alkaline phosphatase377334.9  Increased creatinine354.4282.9  Hypophosphatemia2983414  Increased AST284.1202.5  Hyperkalemia280.8276  Hypocalcemia261.6342.1

BCG-unresponsive High-risk NMIBCThe safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression.The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months).KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057.Table 27: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-057    Adverse ReactionKEYTRUDA200 mg every 3 weeksN=148All GradesGraded per NCI CTCAE v4.03(%)Grades 3–4(%)General  FatigueIncludes asthenia, fatigue, malaise290.7  Peripheral edemaIncludes edema peripheral, peripheral swelling110Gastrointestinal  DiarrheaIncludes diarrhea, gastroenteritis, colitis242.0  Nausea130  Constipation120Skin and Subcutaneous Tissue  RashIncludes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis240.7  Pruritus190.7Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, neck pain190  Arthralgia141.4Renal and Urinary  Hematuria191.4Respiratory, Thoracic, and Mediastinal  CoughIncludes cough, productive cough190Infections  Urinary tract infection122.0  Nasopharyngitis100Endocrine  Hypothyroidism110Table 28: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 124 to 147 patients)KEYTRUDA200 mg every 3 weeksAll GradesGraded per NCI CTCAE v4.03(%)Grades 3-4(%)Chemistry  Hyperglycemia598  Increased ALT253.4  Hyponatremia247  Hypophosphatemia246  Hypoalbuminemia242.1  Hyperkalemia231.4  Hypocalcemia220.7  Increased AST203.4  Increased creatinine200.7Hematology  Anemia351.4  Lymphopenia291.6Microsatellite Instability-High or Mismatch Repair Deficient Colorectal CancerAmong the 153 patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies (14.8)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Gastric CancerFirst-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric Cancer with Trastuzumab and ChemotherapyThe safety analysis of Study KEYNOTE-811 included 217 patients with HER2-positive gastric cancer who received KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3 weeks, compared to 216 patients who received placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3 weeks [see Clinical Studies (14.9)].The median duration of exposure to KEYTRUDA was 5.8 months (range: 1 day to 17.7 months). The study population characteristics were: median age of 63 years (range: 19 to 84), 43% age 65 or older; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1.KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%).In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%), and nausea (49% vs 44%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.There was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for increased ALT (34% vs 29%), and increased creatinine (20% vs 10%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.Previously Treated Gastric CancerAmong the 259 patients with gastric cancer enrolled in KEYNOTE-059 [see Clinical Studies (14.9)], the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 21.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Adverse reactions occurring in patients with gastric cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Esophageal CancerFirst-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal JunctionThe safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.10)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU.The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm.KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%).Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590.Table 29: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-590  Adverse ReactionKEYTRUDA200 mg every 3 weeksCisplatin FUn=370PlaceboCisplatinFUn=370All GradesGraded per NCI CTCAE v4.03(%)Grades 3-4One fatal event of diarrhea was reported in each arm.(%)All Grades(%)Grades 3-4(%)Gastrointestinal  Nausea677637  Constipation400400  Diarrhea364.1333  Vomiting347325  Stomatitis276 26 3.8General  FatigueIncludes asthenia, fatigue5712469Metabolism and Nutrition  Decreased appetite444.1385Investigations  Weight loss243.0245Table 30: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Esophageal Cancer Patients Receiving KEYTRUDA in KEYNOTE-590  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/cisplatin/FU (range: 345 to 365 patients) and placebo/cisplatin/FU (range: 330 to 358 patients)KEYTRUDA200 mg every 3 weeksCisplatin FU Chemotherapy(Cisplatin and FU)All GradesGraded per NCI CTCAE v4.03%Grades 3-4%All Grades%Grades 3-4%Hematology  Anemia83 21 86 24  Neutropenia 74 43 71 41  Leukopenia 72 21 73 17  Lymphopenia 55 22 53 18  Thrombocytopenia 43 5 46 8Chemistry  Hyperglycemia 56 7 55 6  Hyponatremia 53 19 54 19  Hypoalbuminemia 52 2.8 52 2.3  Increased creatinine 45 2.5 42 2.5  Hypocalcemia 44 3.9 38 2  Hypophosphatemia 37 9 31 10  Hypokalemia 30 12 34 15  Increased alkaline phosphatase29 1.9 29 1.7  Hyperkalemia 28 3.6 27 2.6  Increased AST 25 4.4 22 2.8  Increased ALT 23 3.6 18 1.7Previously Treated Recurrent Locally Advanced or Metastatic Esophageal CancerAmong the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.10)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Cervical CancerAmong the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.11)], the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.Table 31: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158  Adverse ReactionKEYTRUDA200 mg every 3 weeksN=98All GradesGraded per NCI CTCAE v4.0(%)Grades 3–4(%)General  FatigueIncludes asthenia, fatigue, lethargy, malaise435  PainIncludes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache222.0  Pyrexia191.0  Edema peripheralIncludes edema peripheral, peripheral swelling152.0Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity275Gastrointestinal  DiarrheaIncludes colitis, diarrhea, gastroenteritis232.0  Abdominal painIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper223.1  Nausea190  Vomiting191.0  Constipation140Metabolism and Nutrition  Decreased appetite210Vascular  HemorrhageIncludes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage195Infections  UTIIncludes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis186  Infection (except UTI)Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis164.1Skin and Subcutaneous Tissue  RashIncludes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular172.0Endocrine  Hypothyroidism110Nervous System  Headache112.0Respiratory, Thoracic and Mediastinal  Dyspnea101.0Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 76 to 79 patients)KEYTRUDA200 mg every 3 weeksAll GradesGraded per NCI CTCAE v4.0(%)Grades 3-4(%)Hematology  Anemia5424  Lymphopenia479Chemistry  Hypoalbuminemia445  Increased alkaline phosphatase422.6  Hyponatremia3813  Hyperglycemia381.3  Increased AST343.9  Increased creatinine325  Hypocalcemia270  Increased ALT213.9  Hypokalemia206Other laboratory abnormalities occurring in ≥10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (19% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (14% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4).

HCCAmong the 104 patients with HCC who received KEYTRUDA in KEYNOTE-224 [see Clinical Studies (14.12)], the median duration of exposure to KEYTRUDA was 4.2 months (range: 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

MCCAmong the 50 patients with MCC enrolled in KEYNOTE-017 [see Clinical Studies (14.13)], the median duration of exposure to KEYTRUDA was 6.6 months (range 1 day to 23.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

RCCThe safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.14)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren's syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months).The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80.Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%).Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA in combination with axitinib. This includes interruption of KEYTRUDA in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).The most common adverse reactions (≥20%) in patients receiving KEYTRUDA and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.Twenty-seven percent (27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction.Tables 33 and 34 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.Table 33: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426  Adverse ReactionKEYTRUDA 200 mg every 3 weeks and Axitinibn=429Sunitinibn=425All GradesGraded per NCI CTCAE v4.03(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Gastrointestinal  DiarrheaIncludes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic5611455  Nausea280.9320.9  Constipation210150.2General  Fatigue/Asthenia5255110Vascular  HypertensionIncludes hypertension, blood pressure increased, hypertensive crisis, labile hypertension48244820Hepatobiliary  HepatotoxicityIncludes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased3920254.9Endocrine  Hypothyroidism350.2320.2Metabolism and Nutrition  Decreased appetite302.8290.7Skin and Subcutaneous Tissue  Palmar-plantar erythrodysesthesia syndrome285403.8  Stomatitis/Mucosal inflammation271.6414  RashIncludes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrhoeric dermatitis, skin discoloration, skin exfoliation, perineal rash251.4210.7Respiratory, Thoracic and Mediastinal  Dysphonia250.23.30  Cough210.2140.5Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 422 patients).KEYTRUDA 200 mg every 3 weeks and AxitinibSunitinibAll GradesGraded per NCI CTCAE v4.03%Grades 3-4%All Grades%Grades 3-4%Chemistry  Hyperglycemia629543.2  Increased ALT6020445  Increased AST5713565  Increased creatinine434.3402.4  Hyponatremia358298  Hyperkalemia346221.7  Hypoalbuminemia320.5341.7  Hypercalcemia270.7151.9  Hypophosphatemia2664917  Increased alkaline phosphatase261.7302.7  HypocalcemiaCorrected for albumin220.2290.7  Blood bilirubin increased222.1211.9  Activated partial thromboplastin time prolongedTwo patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity.221.2140Hematology  Lymphopenia3311468  Anemia292.1658  Thrombocytopenia271.47814

Endometrial CarcinomaThe safety of KEYTRUDA in combination with lenvatinib (20 mg orally once daily) was investigated in KEYNOTE-146, a single-arm, multicenter, open-label trial in 94 patients with endometrial carcinoma whose tumors had progressed following one line of systemic therapy and were not MSI-H or dMMR [see Clinical Studies (14.15)]. The median duration of study treatment was 7 months (range: 0.03 to 37.8 months). The median duration of exposure to KEYTRUDA was 6 months (range: 0.03 to 23.8 months). KEYTRUDA was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Fatal adverse reactions occurred in 3% of patients receiving KEYTRUDA and lenvatinib, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome (RPLS) with intraventricular hemorrhage, and intracranial hemorrhage.Serious adverse reactions occurred in 52% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).KEYTRUDA was discontinued for adverse reactions (Grade 1-4) in 19% of patients, regardless of action taken with lenvatinib. The most common adverse reactions (≥ 2%) leading to discontinuation of KEYTRUDA were adrenal insufficiency (2%), colitis (2%), pancreatitis (2%), and muscular weakness (2%). Adverse reactions leading to interruption of KEYTRUDA occurred in 49% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were: fatigue (14%), diarrhea (6%), decreased appetite (6%), rash (5%), renal impairment (4%), vomiting (4%), increased lipase (4%), weight loss (4%), nausea (3%), increased blood alkaline phosphatase (3%), skin ulcer (3%), adrenal insufficiency (2%), increased amylase (2%), hypocalcemia (2%), hypomagnesemia (2%), hyponatremia (2%), peripheral edema (2%), musculoskeletal pain (2%), pancreatitis (2%), and syncope (2%).Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib.Table 35: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-146  Adverse ReactionKEYTRUDA200 mg every 3 weeks with LenvatinibN=94All Grades(%)Grades 3-4(%)General  FatigueIncludes asthenia, fatigue, and malaise6517Musculoskeletal and Connective Tissue  Musculoskeletal painIncludes arthralgia, arthritis, back pain, breast pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity653Vascular  HypertensionIncludes essential hypertension, hypertension, and hypertensive encephalopathy6538  Hemorrhagic eventsIncludes catheter site bruise, contusion, epistaxis, gastrointestinal hemorrhage, hematemesis, hematuria, hemorrhage intracranial, injection site hemorrhage, intraventricular hemorrhage, large intestinal hemorrhage, metrorrhagia, mouth hemorrhage, uterine hemorrhage, and vaginal hemorrhage284Gastrointestinal  DiarrheaIncludes diarrhea, gastroenteritis, gastrointestinal viral infection, and viral diarrhea644  Nausea485  StomatitisIncludes glossitis, mouth ulceration, oral discomfort, oral mucosal blistering, oropharyngeal pain, and stomatitis430  Vomiting390  Abdominal painIncludes abdominal discomfort, abdominal pain, lower abdominal pain, and upper abdominal pain336  Constipation320Metabolism  Decreased appetiteIncludes decreased appetite and early satiety520  Hypomagnesemia273Endocrine  HypothyroidismIncludes increased blood thyroid stimulating hormone and hypothyroidism511Investigations  Weight loss363Nervous System  Headache331Infections  Urinary tract infectionIncludes cystitis and urinary tract infection 314Respiratory, Thoracic and Mediastinal  Dysphonia290  DyspneaIncludes dyspnea and exertional dyspnea242  Cough210Skin and Subcutaneous Tissue  Palmar-plantar erythrodysesthesia syndrome 263  RashIncludes rash, rash generalized, rash macular, and rash maculo-papular213Table 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-146Laboratory TestWith at least 1 grade increase from baselineKEYTRUDA200 mg every 3 weeks with LenvatinibAll Grades%Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter (range: 71 to 92 patients).Grade 3-4%Chemistry  Increased creatinine807  Hypertriglyceridemia584  Hyperglycemia531  Hypercholesteremia496  Hypoalbuminemia480  Hypomagnesemia472  Increased aspartate aminotransferase434  Hyponatremia4213  Increased lipase4218  Increased alanine aminotransferase353  Increased alkaline phosphatase321  Hypokalemia275  Increased amylase 196  Hypocalcemia143  Hypermagnesemia43Hematology  Thrombocytopenia480  Leukopenia382  Lymphopenia367  Anemia351  Increased INR 213  Neutropenia123TMB-H CancerThe safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.16)]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. cSCCAmong the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.17)], the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).TNBCThe safety of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies (14.18)]. A total of 596 patients (including 34 patients from a safety run-in) received KEYTRUDA 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin.The median duration of exposure to KEYTRUDA was 5.7 months (range: 1 day to 33.0 months).Fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%).Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. Serious adverse reactions in ≥2% of patients were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).KEYTRUDA was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 50% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%), leukopenia (5%), increased AST (5%), decreased white blood cell count (3.9%), and diarrhea (2%).Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355.Table 37: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355      Adverse ReactionKEYTRUDA200 mg every 3 weekswith chemotherapyn=596Placebo every 3 weekswith chemotherapyn=281All GradesGraded per NCI CTCAE v4.03(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)General  FatigueIncludes fatigue and asthenia485494.3Gastrointestinal  Nausea44 1.7 47 1.8  Diarrhea 28 1.8 23 1.8  Constipation 28 0.5 27 0.4  Vomiting 26 2.7 22 3.2Skin and Subcutaneous Tissue  Alopecia 34 0.8 35 1.1  RashIncludes rash, rash maculo-papular, rash pruritic, rash pustular, rash macular, rash papular, butterfly rash, rash erythematous, eyelid rash26 2 16 0Respiratory, Thoracic and Mediastinal  CoughIncludes cough, productive cough, upper-airway cough syndrome23 0 20 0.4Metabolism and Nutrition  Decreased appetite 21 0.8 14 0.4Nervous System  HeadacheIncludes headache, migraine, tension headache20 0.7 23 0.7Table 38: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355      Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients).KEYTRUDA 200 mg every 3 weekswith chemotherapyPlacebo every 3 weekswith chemotherapyAll GradesGraded per NCI CTCAE v4.03%Grades 3-4%All Grades%Grades 3-4%Hematology  Anemia90208519  Leukopenia 85 39 86 39  Neutropenia 76 49 77 52  Lymphopenia 70 26 70 19  Thrombocytopenia 54 19 53 21Chemistry  Increased ALT 60 11 58 8  Increased AST 57 9 55 6  Hyperglycemia 52 4.4 51 2.2  Hypoalbuminemia 37 2.2 32 2.2  Increased alkaline phosphatase 35 3.9 39 2.2  Hypocalcemia 29 3.3 27 1.8  Hyponatremia 28 5 26 6  Hypophosphatemia 21 7 18 4.8  Hypokalemia 20 4.4 18 4.0

Risk SummaryBased on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal DataAnimal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects of the PD-1 pathway on reproduction demonstrated that a central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.

Risk SummaryThere are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose.

Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use in Specific Populations (8.1)].

ContraceptionKEYTRUDA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for at least 4 months following the final dose.

DistributionThe geometric mean value (CV%) for volume of distribution at steady state is 6.0 L (20%).

EliminationPembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)]; this decrease in clearance with time is not considered clinically important. The terminal half-life (t1/2) is 22 days (32%).

Specific PopulationsThe following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR ≥ 15 mL/min/1.73 m2), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or tumor burden. The impact of moderate or severe hepatic impairment on the pharmacokinetics of pembrolizumab is unknown.

Pediatric Patients: Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (10 months to 17 years) are comparable to those of adults at the same dose.

Ipilimumab-Naive MelanomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at a dose of 10 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review [BICR] using Response Evaluation Criteria in Solid Tumors [RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ]). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DoR).The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 66% had no prior systemic therapy for metastatic disease; 69% ECOG PS of 0; 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay; 65% had M1c stage disease; 68% with normal LDH; 36% with reported BRAF mutation-positive melanoma; and 9% with a history of brain metastases. Among patients with BRAF mutation-positive melanoma, 139 (46%) were previously treated with a BRAF inhibitor.The study demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA as compared to ipilimumab. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Efficacy results are summarized in Table 39 and Figure 1.Table 39: Efficacy Results in KEYNOTE-006EndpointKEYTRUDA10 mg/kg every 3 weeksn=277KEYTRUDA10 mg/kg every 2 weeksn=279Ipilimumab3 mg/kg every 3 weeksn=278OS  Deaths (%)92 (33%)85 (30%)112 (40%)  Hazard ratioHazard ratio (KEYTRUDA compared to ipilimumab) based on the stratified Cox proportional hazard model (95% CI) 0.69 (0.52, 0.90)0.63 (0.47, 0.83)---  p-Value (stratified log-rank)0.004<0.001---PFS by BICR  Events (%)157 (57%)157 (56%)188 (68%)  Median in months (95% CI)4.1 (2.9, 6.9)5.5 (3.4, 6.9)2.8 (2.8, 2.9)  Hazard ratio (95% CI)0.58 (0.47, 0.72)0.58 (0.46, 0.72)---  p-Value (stratified log-rank)<0.001<0.001---Best objective response by BICR  ORR (95% CI)33% (27, 39)34% (28, 40)12% (8, 16)    Complete response rate6%5%1%    Partial response rate27%29%10%Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006Based on the final analysis with an additional follow-up of 9 months (total of 383 deaths as pre-specified in the protocol)

Ipilimumab-Refractory MelanomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-002 (NCT01704287), a multicenter, randomized (1:1:1), active-controlled trial in 540 patients randomized to receive one of two doses of KEYTRUDA in a blinded fashion or investigator's choice chemotherapy. The treatment arms consisted of KEYTRUDA 2 mg/kg or 10 mg/kg intravenously every 3 weeks or investigator's choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m2 intravenously every 3 weeks (26%), temozolomide 200 mg/m2 orally once daily for 5 days every 28 days (25%), carboplatin AUC 6 mg/mL/min intravenously plus paclitaxel 225 mg/m2 intravenously every 3 weeks for four cycles then carboplatin AUC of 5 mg/mL/min plus paclitaxel 175 mg/m2 every 3 weeks (25%), paclitaxel 175 mg/m2 intravenously every 3 weeks (16%), or carboplatin AUC 5 or 6 mg/mL/min intravenously every 3 weeks (8%). Randomization was stratified by ECOG PS (0 vs. 1), LDH levels (normal vs. elevated [≥110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received KEYTRUDA until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging; withdrawal of consent; or physician's decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. The major efficacy outcomes were PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Additional efficacy outcome measures were confirmed ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR.The study population characteristics were: median age of 62 years (range: 15 to 89), 43% age 65 or older; 61% male; 98% White; and 55% ECOG PS of 0 and 45% ECOG PS of 1. Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease.The study demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA as compared to control arm. There was no statistically significant difference between KEYTRUDA 2 mg/kg and chemotherapy or between KEYTRUDA 10 mg/kg and chemotherapy in the OS analysis in which 55% of the patients who had been randomized to receive chemotherapy had crossed over to receive KEYTRUDA. Among the 38 patients randomized to KEYTRUDA 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 40.Table 40: Efficacy Results in KEYNOTE-002EndpointKEYTRUDA2 mg/kg every 3 weeksKEYTRUDA10 mg/kg every 3 weeksChemotherapyn=180n=181n=179PFS  Number of Events, n (%)129 (72%)126 (70%)155 (87%)  Progression, n (%)105 (58%)107 (59%)134 (75%)  Death, n (%)24 (13%)19 (10%)21 (12%)  Median in months (95% CI)2.9 (2.8, 3.8)2.9 (2.8, 4.7)2.7 (2.5, 2.8)  p-Value (stratified log-rank)<0.001<0.001---  Hazard ratioHazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model (95% CI) 0.57 (0.45, 0.73)0.50 (0.39, 0.64)---OSWith additional follow-up of 18 months after the PFS analysis  Deaths (%)123 (68%)117 (65%)128 (72%)  Hazard ratio (95% CI)0.86 (0.67, 1.10)0.74 (0.57, 0.96)---  p-Value (stratified log-rank)0.1170.011Not statistically significant compared to multiplicity adjusted significance level of 0.01---  Median in months (95% CI)13.4 (11.0, 16.4)14.7 (11.3, 19.5)11.0 (8.9, 13.8)Objective Response Rate  ORR (95% CI)21% (15, 28)25% (19, 32)4% (2, 9)    Complete response rate2%3%0%    Partial response rate19%23%4%Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002

Adjuvant Treatment of Resected MelanomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-054 (NCT02362594), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma. Patients were randomized to KEYTRUDA 200 mg intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first two years, then every 6 months from year 3 to 5, and then annually.The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD-L1 positive melanoma with TPS ≥1% according to an IUO assay.The trial demonstrated a statistically significant improvement in RFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 41 and Figure 3. Table 41: Efficacy Results in KEYNOTE-054EndpointKEYTRUDA200 mg every 3 weeksn=514Placebon=505NR = not reachedRFS  Number (%) of patients with event 135 (26%)216 (43%)  Median in months (95% CI)NR20.4 (16.2, NR)  Hazard ratioBased on the stratified Cox proportional hazard modelStratified by American Joint Committee on Cancer 7th edition (AJCC) stage (95% CI)0.57 (0.46, 0.70)  p-Value (log-rank)<0.001p-Value is compared with 0.008 of the allocated alpha for this interim analysis.For patients with PD-L1 positive tumors, the HR was 0.54 (95% CI: 0.42, 0.69); p<0.001. The RFS benefit for KEYTRUDA compared to placebo was observed regardless of tumor PD-L1 expression.Figure 3: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-054

  • First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapyThe efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:KEYTRUDA 200 mg, pemetrexed 500 mg/m2, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.Placebo, pemetrexed 500 mg/m2, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks.Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG PS of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 42 and Figure 4 summarize the efficacy results for KEYNOTE-189.Table 42: Efficacy Results in KEYNOTE-189EndpointKEYTRUDA200 mg every 3 weeksPemetrexedPlatinum Chemotherapyn=410PlaceboPemetrexed Platinum Chemotherapyn=206NR = not reachedOS  Number (%) of patients with event127 (31%)108 (52%)  Median in months (95% CI)NR(NR, NR)11.3(8.7, 15.1)  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI)0.49 (0.38, 0.64)  p-ValueBased on a stratified log-rank test<0.0001PFS  Number of patients with event (%)245 (60%)166 (81%)  Median in months (95% CI)8.8 (7.6, 9.2)4.9 (4.7, 5.5)  Hazard ratio (95% CI)0.52 (0.43, 0.64)  p-Value<0.0001Objective Response Rate  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI)48% (43, 53)19% (14, 25)    Complete response0.5%0.5%    Partial response47%18%  p-ValueBased on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status<0.0001Duration of Response  Median in months (range)11.2 (1.1+, 18.0+)7.8 (2.1+, 16.4+)At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with pemetrexed and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69).Figure 4: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189Based on the protocol-specified final OS analysis

  • First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapyThe efficacy of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multi-center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.
  • Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. An additional efficacy outcome measure was DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.The study population characteristics were: median age of 65 years (range: 29 to 88), 55% age 65 or older; 81% male; 77% White; 71% ECOG PS of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel.The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy. Table 43 and Figure 5 summarize the efficacy results for KEYNOTE-407.Table 43: Efficacy Results in KEYNOTE-407EndpointKEYTRUDA 200 mg every 3 weeksCarboplatin Paclitaxel/Paclitaxel protein-boundn=278Placebo Carboplatin Paclitaxel/Paclitaxel protein-boundn=281NE = not estimableOS  Number of events (%)85 (31%)120 (43%)  Median in months (95% CI)15.9 (13.2, NE)11.3 (9.5, 14.8)  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.64 (0.49, 0.85)  p-ValueBased on a stratified log-rank test0.0017PFS  Number of events (%)152 (55%)197 (70%)  Median in months (95% CI)6.4 (6.2, 8.3)4.8 (4.2, 5.7)  Hazard ratio (95% CI) 0.56 (0.45, 0.70)  p-Value<0.0001n=101n=103Objective Response RateORR primary analysis and DoR analysis were conducted with the first 204 patients enrolled.  ORR (95% CI)58% (48, 68)35% (26, 45)  Difference (95% CI)23.6% (9.9, 36.4)  p-ValueBased on a stratified Miettinen-Nurminen test0.0008Duration of Response  Median duration of response in months (range)7.2 (2.4, 12.4+)4.9 (2.0, 12.4+)At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm was 17.1 months (95% CI: 14.4, 19.9) compared to 11.6 months (95% CI: 10.1, 13.7) in the placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm, with an HR of 0.71 (95% CI: 0.58, 0.88).Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407Based on the protocol-specified final OS analysis

First-line treatment of metastatic NSCLC as a single agent

  • KEYNOTE-042The efficacy of KEYTRUDA was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG PS (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator's choice of either of the following platinum-containing chemotherapy regimens:Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies.Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with KEYTRUDA could be reinitiated at the time of subsequent disease progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG PS of 1; 39% with squamous and 61% with nonsquamous histology; 87% had M1 disease and 13% had Stage IIIA (2%) or Stage IIIB (11%) and who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC.The trial demonstrated a statistically significant improvement in OS for patients (PD-L1 TPS ≥50%, TPS ≥20%, TPS ≥1%) randomized to KEYTRUDA as compared with chemotherapy. Table 44 and Figure 6 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%.Table 44: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042TPS ≥1%TPS ≥50%EndpointKEYTRUDA200 mg every 3 weeksChemotherapyKEYTRUDA200 mg every 3 weeksChemotherapyn=637n=637n=299n=300OS  Number of events (%)371 (58%)438 (69%)157 (53%)199 (66%)  Median in months (95% CI)16.7 (13.9, 19.7)12.1 (11.3, 13.3)20.0 (15.4, 24.9)12.2 (10.4, 14.2)  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI)0.81 (0.71, 0.93)0.69 (0.56, 0.85)  p-ValueBased on a stratified log-rank test; compared to a p-Value boundary of 0.02910.00360.0006PFS  Number of events (%)507 (80%)506 (79%)221 (74%)233 (78%)  Median in months (95% CI)5.4 (4.3, 6.2)6.5 (6.3, 7.0)6.9 (5.9, 9.0)6.4 (6.1, 6.9)  Hazard ratio, Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints (95% CI)1.07(0.94, 1.21)0.82(0.68, 0.99)  p-Value-NSNot significant compared to a p-Value boundary of 0.0291Objective Response Rate  ORR (95% CI)27% (24, 31)27% (23, 30)39% (33.9, 45.3)32% (26.8, 37.6)    Complete response rate0.5%0.5%0.7%0.3%    Partial response rate27%26%39%32%Duration of Response  % with duration ≥12 monthsBased on observed duration of response47%16%42%17%  % with duration ≥18 months26%6%25%5%The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥1% and those with PD-L1 TPS ≥50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11).Figure 6: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%)

  • KEYNOTE-024The efficacy of KEYTRUDA was also investigated in KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-controlled trial in 305 previously untreated patients with metastatic NSCLC. The study design was similar to that of KEYNOTE-042, except that only patients whose tumors had high PD-L1 expression (TPS of 50% or greater) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit were eligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator's choice of any of the following platinum-containing chemotherapy regimens:Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;Pemetrexed 500 mg/m2 every 3 weeks and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles;Gemcitabine 1250 mg/m2 on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles;Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for nonsquamous histologies).Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression.The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were OS and ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% White and 15% Asian; 65% with ECOG PS of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received KEYTRUDA at the time of disease progression.The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to KEYTRUDA as compared with chemotherapy. Table 45 and Figure 7 summarize the efficacy results for KEYNOTE-024.Table 45: Efficacy Results in KEYNOTE-024EndpointKEYTRUDA200 mg every 3 weeksChemotherapyn=154n=151NR = not reachedPFS  Number (%) of patients with event73 (47%)116 (77%)  Median in months (95% CI)10.3 (6.7, NR)6.0 (4.2, 6.2)  Hazard ratioBased on the stratified Cox proportional hazard model for the interim analysis (95% CI)0.50 (0.37, 0.68)  p-Value (stratified log-rank)<0.001OS  Number (%) of patients with event44 (29%)64 (42%)  Median in months (95% CI)Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.30.0(18.3, NR)14.2(9.8, 19.0)  Hazard ratio (95% CI) 0.60 (0.41, 0.89)  p-Value (stratified log-rank)0.005p-Value is compared with 0.0118 of the allocated alpha for the interim analysisObjective Response Rate  ORR (95% CI)45% (37, 53)28% (21, 36)    Complete response rate4%1%    Partial response rate41%27%  p-Value (Miettinen-Nurminen)0.001  Median duration of response in months (range)NR(1.9+, 14.5+)6.3(2.1+, 12.6+)Figure 7: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.

Previously treated NSCLCThe efficacy of KEYTRUDA was investigated in KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG PS (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive KEYTRUDA 2 mg/kg intravenously every 3 weeks, KEYTRUDA 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and DoR in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%.The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG PS of 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease.Tables 46 and 47 and Figure 8 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively.Table 46: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010EndpointKEYTRUDA2 mg/kg every 3 weeksn=139KEYTRUDA10 mg/kg every 3 weeksn=151Docetaxel75 mg/m2 every 3 weeksn=152NR = not reachedOS  Deaths (%)58 (42%)60 (40%)86 (57%)  Median in months (95% CI)14.9 (10.4, NR)17.3 (11.8, NR)8.2 (6.4, 10.7)  Hazard ratioHazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model (95% CI) 0.54 (0.38, 0.77)0.50 (0.36, 0.70)---  p-Value (stratified log-rank)<0.001<0.001---PFS  Events (%)89 (64%)97 (64%)118 (78%)  Median in months (95% CI)5.2 (4.0, 6.5)5.2 (4.1, 8.1)4.1 (3.6, 4.3)  Hazard ratio (95% CI) 0.58 (0.43, 0.77)0.59 (0.45, 0.78)---  p-Value (stratified log-rank)<0.001<0.001---Objective Response Rate  ORRAll responses were partial responses (95% CI)30% (23, 39)29% (22, 37)8% (4, 13)  p-Value (Miettinen-Nurminen)<0.001<0.001---  Median duration of response in months (range)NR(0.7+, 16.8+)NR(2.1+, 17.8+)8.1(2.1+, 8.8+)Table 47: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010EndpointKEYTRUDA2 mg/kg every 3 weeksn=344KEYTRUDA10 mg/kg every 3 weeksn=346Docetaxel75 mg/m2 every 3 weeksn=343NR = not reachedOS  Deaths (%)172 (50%)156 (45%)193 (56%)  Median in months (95% CI)10.4 (9.4, 11.9)12.7 (10.0, 17.3)8.5 (7.5, 9.8)  Hazard ratioHazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model (95% CI) 0.71 (0.58, 0.88)0.61 (0.49, 0.75)---  p-Value (stratified log-rank)<0.001<0.001---PFS  Events (%)266 (77%)255 (74%)257 (75%)  Median in months (95% CI)3.9 (3.1, 4.1)4.0 (2.6, 4.3)4.0 (3.1, 4.2)  Hazard ratio (95% CI) 0.88 (0.73, 1.04)0.79 (0.66, 0.94)---  p-Value (stratified log-rank)0.0680.005---Objective Response Rate  ORRAll responses were partial responses (95% CI)18% (14, 23)19% (15, 23)9% (7, 13)  p-Value (Miettinen-Nurminen)<0.001<0.001---  Median duration of response in months (range)NR(0.7+, 20.1+)NR(2.1+, 17.8+)6.2(1.4+, 8.8+)Figure 8: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%)

  • First-line treatment of metastatic or unresectable, recurrent HNSCCThe efficacy of KEYTRUDA was investigated in KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor PD-L1 expression (TPS ≥50% or <50%) according to the PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:KEYTRUDA 200 mg intravenously every 3 weeksKEYTRUDA 200 mg intravenously every 3 weeks, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU)Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU)Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months. A retrospective re-classification of patients' tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization.The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1, and the overall population.The study population characteristics were: median age of 61 years (range: 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian and 2.4% Black; 61% had ECOG PS of 1; and 79% were former/current smokers. Twenty-two percent of patients' tumors were HPV-positive, 23% had PD-L1 TPS ≥50%, and 95% had Stage IV disease (Stage IVA 19%, Stage IVB 6%, and Stage IVC 70%). Eighty-five percent of patients' tumors had PD-L1 expression of CPS ≥1 and 43% had CPS ≥20.The trial demonstrated a statistically significant improvement in OS for patients randomized to KEYTRUDA in combination with chemotherapy compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis in the overall population. Table 48 and Figure 9 summarize efficacy results for KEYTRUDA in combination with chemotherapy.Table 48: Efficacy ResultsResults at a pre-specified interim analysis for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048EndpointKEYTRUDA 200 mg every 3 weeks Platinum FUCetuximab Platinum FUn=281n=278OS  Number (%) of patients with event197 (70%)223 (80%)  Median in months (95% CI)13.0 (10.9, 14.7)10.7 (9.3, 11.7)  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI)0.77 (0.63, 0.93)  p-ValueBased on stratified log-rank test0.0067PFS  Number of patients with event (%)244 (87%)253 (91%)  Median in months (95% CI)4.9 (4.7, 6.0)5.1 (4.9, 6.0)  Hazard ratio (95% CI)0.92 (0.77, 1.10)  p-Value0.3394Objective Response Rate  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI)36% (30.0, 41.5)36% (30.7, 42.3)    Complete response rate6%3%    Partial response rate30%33%Duration of Response  Median in months (range)6.7 (1.6+, 30.4+)4.3 (1.2+, 27.9+)At the pre-specified final OS analysis for the ITT population, the hazard ratio was 0.72 (95% CI: 0.60, 0.87). In addition, KEYNOTE-048 demonstrated a statistically significant improvement in OS for the subgroups of patients with PD-L1 CPS ≥1 (HR=0.65, 95% CI: 0.53, 0.80) and CPS ≥20 (HR=0.60, 95% CI: 0.45, 0.82). Figure 9: Kaplan-Meier Curve for Overall Survival for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048At the time of the protocol-specified final analysis.The trial also demonstrated a statistically significant improvement in OS for the subgroup of patients with PD-L1 CPS ≥1 randomized to KEYTRUDA as a single agent compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis. At the time of the interim and final analyses, there was no significant difference in OS between the KEYTRUDA single agent arm and the control arm for the overall population.Table 49 summarizes efficacy results for KEYTRUDA as a single agent in the subgroups of patients with CPS ≥1 HNSCC and CPS ≥20 HNSCC. Figure 10 summarizes the OS results in the subgroup of patients with CPS ≥1 HNSCC.Table 49: Efficacy ResultsResults at a pre-specified interim analysis for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1 and CPS ≥20)EndpointCPS ≥1CPS ≥20KEYTRUDA200 mg every 3 weeksCetuximab Platinum FUKEYTRUDA200 mg every 3 weeksCetuximab Platinum FUn=257n=255n=133n=122OS  Number of events (%)177 (69%)206 (81%)82 (62%)95 (78%)  Median in months (95% CI)12.3 (10.8, 14.9)10.3 (9.0,11.5)14.9 (11.6, 21.5)10.7 (8.8, 12.8)  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI)0.78 (0.64, 0.96)0.61 (0.45, 0.83)  p-ValueBased on a stratified log-rank test0.01710.0015PFS  Number of events (%)225 (88%)231 (91%)113 (85%)111 (91%)  Median in months (95% CI)3.2 (2.2, 3.4)5.0 (4.8, 5.8)3.4 (3.2, 3.8)5.0 (4.8, 6.2)  Hazard ratio (95% CI)1.15 (0.95, 1.38)0.97 (0.74, 1.27)Objective Response Rate  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI)19% (14.5, 24.4)35% (29.1, 41.1)23% (16.4, 31.4)36% (27.6, 45.3)    Complete response rate5%3%8%3%    Partial response rate14%32%16%33%Duration of Response  Median in months (range) 20.9 (1.5+, 34.8+)4.5 (1.2+, 28.6+)20.9 (2.7, 34.8+)4.2 (1.2+, 22.3+)At the pre-specified final OS analysis comparing KEYTRUDA as a single agent to cetuximab in combination with chemotherapy, the hazard ratio for the subgroup of patients with CPS ≥1 was 0.74 (95% CI: 0.61, 0.90) and the hazard ratio for the subgroup of patients with CPS ≥20 was 0.58 (95% CI: 0.44, 0.78).In an exploratory subgroup analysis for patients with CPS 1-19 HNSCC at the time of the pre-specified final OS analysis, the median OS was 10.8 months (95% CI: 9.0, 12.6) for KEYTRUDA as a single agent and 10.1 months (95% CI: 8.7, 12.1) for cetuximab in combination with chemotherapy, with an HR of 0.86 (95% CI: 0.66, 1.12).Figure 10: Kaplan-Meier Curve for Overall Survival for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1)At the time of the protocol-specified final analysis.

Previously treated recurrent or metastatic HNSCCThe efficacy of KEYTRUDA was investigated in KEYNOTE-012 (NCT01848834), a multicenter, non-randomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible.Patients received KEYTRUDA 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.The study population characteristics were median age of 60 years, 32% age 65 or older; 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2.The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median DoR had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and DoR were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.

Cisplatin Ineligible Patients with Urothelial CarcinomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open-label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.The study population characteristics were: median age of 74 years; 77% male; and 89% White. Eighty-seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: 50% with baseline creatinine clearance of <60 mL/min, 32% with ECOG PS of 2, 9% with ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 9% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy.Among the 370 patients, 30% (n = 110) had tumors that expressed PD-L1 with a CPS ≥10. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The study population characteristics of these 110 patients were: median age of 73 years; 68% male; and 87% White. Eighty-two percent had M1 disease, and 18% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 18% of patients had a primary tumor in the upper tract. Seventy-six percent of patients had visceral metastases, including 11% with liver metastases. Reasons for cisplatin ineligibility included: 45% with baseline creatinine clearance of <60 mL/min, 37% with ECOG PS of 2, 10% with ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 8% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy.The median follow-up time for 370 patients treated with KEYTRUDA was 7.8 months (range 0.1 to 20 months). Efficacy results are summarized in Table 53.Table 53: Efficacy Results in KEYNOTE-052EndpointKEYTRUDA200 mg every 3 weeksAll Subjectsn=370PD-L1 CPS <10n=260Includes 9 subjects with unknown PD-L1 statusPD-L1 CPS ≥10n=110+ Denotes ongoing responseNR = not reachedObjective Response Rate  ORR (95% CI)29% (24, 34)21% (16, 26)47% (38, 57)    Complete response rate7%3%15%    Partial response rate22%18%32%Duration of Response  Median in months (range)NR(1.4+, 17.8+)NR(1.4+, 16.3+)NR(1.4+, 17.8+)

Previously Untreated Urothelial CarcinomaKEYNOTE-361 (NCT02853305) is an ongoing, multicenter, randomized study in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy. The study compares KEYTRUDA with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. The trial also enrolled a third arm of monotherapy with KEYTRUDA to compare to platinum-based chemotherapy alone. The independent Data Monitoring Committee (iDMC) for the study conducted a review of early data and found that in patients classified as having low PD-L1 expression (CPS <10), those treated with KEYTRUDA monotherapy had decreased survival compared to those who received platinum-based chemotherapy. The iDMC recommended to stop further accrual of patients with low PD-L1 expression in the monotherapy arm, however, no other changes were recommended, including any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm.

Previously Treated Urothelial CarcinomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-045 (NCT02256436), a multicenter, randomized (1:1), active-controlled trial in 542 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.Patients were randomized to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator's choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=90), docetaxel 75 mg/m2 (n=92), or vinflunine 320 mg/m2 (n=90). Treatment continued until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR.The study population characteristics were: median age of 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG PS of 0 and 56% ECOG PS of 1; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens.The study demonstrated statistically significant improvements in OS and ORR for patients randomized to KEYTRUDA as compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy with respect to PFS. The median follow-up time for this trial was 9.0 months (range: 0.2 to 20.8 months). Table 54 and Figure 12 summarize the efficacy results for KEYNOTE-045.Table 54: Efficacy Results in KEYNOTE-045KEYTRUDA200 mg every 3 weeksChemotherapyn=270n=272+ Denotes ongoing responseNR = not reachedOS  Deaths (%)155 (57%)179 (66%)  Median in months (95% CI)10.3 (8.0, 11.8)7.4 (6.1, 8.3)  Hazard ratioHazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model (95% CI) 0.73 (0.59, 0.91)  p-Value (stratified log-rank) 0.004PFS by BICR  Events (%)218 (81%)219 (81%)  Median in months (95% CI)2.1 (2.0, 2.2)3.3 (2.3, 3.5)  Hazard ratio (95% CI) 0.98 (0.81, 1.19)  p-Value (stratified log-rank)0.833Objective Response Rate  ORR (95% CI)21% (16, 27)11% (8, 16)    Complete response rate7%3%    Partial response rate14%8%    p-Value (Miettinen-Nurminen)0.002    Median duration of response in months (range)NR(1.6+, 15.6+)4.3(1.4+, 15.4+)Figure 12: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045

BCG-unresponsive High-Risk Non-Muscle Invasive Bladder CancerThe efficacy of KEYTRUDA was investigated in KEYNOTE-057 (NCT02625961), a multicenter, open-label, single-arm trial in 96 patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression.Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response.The study population characteristics were: median age of 73 years (range: 44 to 92); 44% age ≥75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumor pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12.The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Efficacy results are summarized in Table 55.Table 55: Efficacy Results in KEYNOTE-057EndpointKEYTRUDA200 mg every 3 weeksn=96Complete Response Rate (95% CI)41% (31, 51)Duration of ResponseBased on patients (n=39) that achieved a complete response; reflects period from the time complete response was achieved  Median in months (range)16.2 (0.0+, 30.4Denotes ongoing response)  % (n) with duration ≥12 months46% (18)

  • First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal/Gastroesophageal Junction CancerKEYNOTE-590The efficacy of KEYTRUDA was investigated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients with active autoimmune disease, a medical condition that required immunosuppression, or who received prior systemic therapy in the locally advanced or metastatic setting were ineligible. Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and ECOG performance status (0 vs. 1).Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:KEYTRUDA 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, CPS ≥10, and in all patients. Additional efficacy outcome measures were ORR and DoR, according to modified RECIST v1.1, as assessed by the investigator. The study population characteristics were: median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% White, 53% Asian, and 1% Black; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27% had adenocarcinoma.The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with chemotherapy, compared to chemotherapy. Table 61 and Figure 14 summarize the efficacy results for KEYNOTE-590 in all patients.Table 61: Efficacy Results in Patients with Locally Advanced Unresectable or Metastatic Esophageal Cancer in KEYNOTE-590EndpointKEYTRUDA200 mg every 3 weeksCisplatin FUn=373PlaceboCisplatinFUn=376OS  Number (%) of events262 (70)309 (82)  Median in months   (95% CI)12.4 (10.5, 14.0)9.8 (8.8, 10.8)  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI)0.73 (0.62, 0.86)  p-ValueBased on a stratified log-rank test <0.0001PFS  Number of events (%)297 (80)333 (89)  Median in months   (95% CI)6.3 (6.2, 6.9)5.8 (5.0, 6.0)  Hazard ratio (95% CI)0.65 (0.55, 0.76)  p-Value<0.0001Objective Response Rate  ORR, %Confirmed complete response or partial response  (95% CI)45 (40, 50)29 (25, 34)    Number (%) of complete responses 24 (6)9 (2.4)    Number (%) of partial responses144 (39)101 (27)    p-ValueBased on the stratified Miettinen and Nurminen method<0.0001Duration of Response  Median in months   (range)8.3 (1.2+, 31.0+)6.0 (1.5+, 25.0+)Figure 14: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590In a pre-specified formal test of OS in patients with PD-L1 CPS ≥ 10 (n=383), the median was 13.5 months (95% CI: 11.1, 15.6) for the KEYTRUDA arm and 9.4 months (95% CI: 8.0, 10.7) for the placebo arm, with a HR of 0.62 (95% CI: 0.49, 0.78; p-Value < 0.0001). In an exploratory analysis, in patients with PD-L1 CPS < 10 (n=347), the median OS was 10.5 months (95% CI: 9.7, 13.5) for the KEYTRUDA arm and 10.6 months (95% CI: 8.8, 12.0) for the placebo arm, with a HR of 0.86 (95% CI: 0.68, 1.10).Previously Treated Recurrent Locally Advanced or Metastatic Esophageal CancerKEYNOTE-181The efficacy of KEYTRUDA was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible.Patients were randomized (1:1) to receive either KEYTRUDA 200 mg every 3 weeks or investigator's choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 4-week cycle, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 180 mg/m2 every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia). Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measure was OS evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional efficacy outcome measures were PFS, ORR, and DoR, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.A total of 628 patients were enrolled and randomized to KEYTRUDA (n=314) or investigator's treatment of choice (n=314). Of these 628 patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS ≥10. Of these 167 patients, 85 patients were randomized to KEYTRUDA and 82 patients to investigator's treatment of choice [paclitaxel (n=50), docetaxel (n=19), or irinotecan (n=13)]. The baseline characteristics of these 167 patients were: median age of 65 years (range: 33 to 80), 51% age 65 or older; 84% male; 32% White and 68% Asian; 38% had an ECOG PS of 0 and 62% had an ECOG PS of 1. Ninety percent had M1 disease and 10% had M0 disease. Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine. Thirty-three percent of patients received prior treatment with a taxane.The observed OS hazard ratio was 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS ≥10, and 0.89 (95% CI: 0.75, 1.05) in all randomized patients. On further examination in patients whose ESCC tumors expressed PD-L1 (CPS ≥10), an improvement in OS was observed among patients randomized to KEYTRUDA as compared with chemotherapy. Table 62 and Figure 15 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS ≥10.Table 62: Efficacy Results in Patients with Recurrent or Metastatic ESCC (CPS ≥10) in KEYNOTE-181EndpointKEYTRUDA 200 mg every 3 weeks n=85Chemotherapy   n=82OS  Number (%) of patients with event68 (80%)72 (88%)  Median in months (95% CI)10.3 (7.0, 13.5)6.7 (4.8, 8.6)  Hazard ratioBased on the Cox regression model stratified by geographic region (Asia vs. ex-Asia) (95% CI)0.64 (0.46, 0.90)PFS  Number (%) of patients with event76 (89%)76 (93%)  Median in months (95% CI)3.2 (2.1, 4.4)2.3 (2.1, 3.4)  Hazard ratio (95% CI) 0.66 (0.48, 0.92)Objective Response Rate  ORR (95% CI)22 (14, 33)7 (3, 15)  Number (%) of complete responses4 (5)1 (1)  Number (%) of partial responses15 (18)5 (6)  Median duration of response in months (range)9.3 (2.1+, 18.8+)7.7 (4.3, 16.8+)Figure 15: Kaplan-Meier Curve for Overall Survival in KEYNOTE-181 (ESCC CPS ≥10)

KEYNOTE-180The efficacy of KEYTRUDA was investigated in KEYNOTE-180 (NCT02559687), a multicenter, non-randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181.The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.Among the 121 patients enrolled, 29% (n=35) had ESCC that expressed PD-L1 CPS ≥10. The baseline characteristics of these 35 patients were: median age of 65 years (range: 47 to 81), 51% age 65 or older; 71% male; 26% White and 69% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. One hundred percent had M1 disease. The ORR in the 35 patients with ESCC expressing PD-L1 was 20% (95% CI: 8, 37). Among the 7 responding patients, the DoR ranged from 4.2 to 25.1+ months, with 5 patients (71%) having responses of 6 months or longer and 3 patients (57%) having responses of 12 months or longer.

  • Immune-Mediated Adverse ReactionsInform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA. These reactions may include:Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)].Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.1)].Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, or Type 1 diabetes mellitus [see Warnings and Precautions (5.1)].
  • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.1)].Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see Warnings and Precautions (5.1)].Other immune-mediated adverse reactions:Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)].Advise patients of the risk of solid organ transplant rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection [see Warnings and Precautions (5.1)].

  • Infusion-Related ReactionsAdvise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].

  • Complications of Allogeneic HSCTAdvise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.3)].

  • Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].

  • LactationAdvise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose [see Use in Specific Populations (8.2)].

  • Laboratory TestsAdvise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions (5.1)].

Manufactured by: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC., Whitehouse Station, NJ 08889, USAU.S. License No. 0002For KEYTRUDA injection, at:MSD Ireland (Carlow)County Carlow, IrelandFor patent information: www.merck.com/product/patent/home.htmlThe trademarks depicted herein are owned by their respective companies.Copyright © 2014-2021 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved.uspi-mk3475-iv-2107r046

3 Dosage Forms And Strengths

  • Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial

4 Contraindications

None.

5.1 Severe And Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions.Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.Immune-Mediated PneumonitisKEYTRUDA can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) of patients and withholding of KEYTRUDA in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients.In clinical studies enrolling 389 adult patients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31 (8%) patients, including Grades 3-4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.Immune-Mediated ColitisKEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) of patients and withholding of KEYTRUDA in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients.Hepatotoxicity and Immune-Mediated HepatitisKEYTRUDA as a Single AgentKEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) of patients and withholding of KEYTRUDA in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients.KEYTRUDA with AxitinibKEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.3)].With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both KEYTRUDA and axitinib. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.Immune-Mediated EndocrinopathiesAdrenal InsufficiencyKEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)].Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.HypophysitisKEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)].Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.Thyroid DisordersKEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)].Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). No patients discontinued KEYTRUDA due to thyroiditis. KEYTRUDA was withheld in <0.1% (1) of patients.Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (2) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement.The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.Type 1 Diabetes Mellitus, which can present with Diabetic KetoacidosisMonitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)].Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. Type 1 diabetes mellitus led to permanent discontinuation in <0.1% (1) of patients and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy.Immune-Mediated Nephritis with Renal DysfunctionKEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) of patients and withholding of KEYTRUDA in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients.Immune-Mediated Dermatologic Adverse ReactionsKEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)].Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of KEYTRUDA in 0.1% (2) of patients and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients.Other Immune-Mediated Adverse ReactionsThe following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.Cardiac/Vascular: Myocarditis, pericarditis, vasculitisNervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathyOcular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitisMusculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumaticaEndocrine: HypoparathyroidismHematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)].

5.4 Increased Mortality In Patients With Multiple Myeloma When Keytruda Is Added To A Thalidomide Analogue And Dexamethasone

In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

  • The following clinically significant adverse reactions are described elsewhere in the labeling.Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)].Infusion-related reactions [see Warnings and Precautions (5.2)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

6.2 Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to pembrolizumab in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, a subset analysis was performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 27 (2.1%) of 1289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies of whom six (0.5%) patients had neutralizing antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic profile or increased infusion reactions with anti-pembrolizumab binding antibody development.

8.4 Pediatric Use

The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with cHL, PMBCL, MCC, MSI-H cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.4, 14.5, 14.7, 14.13, 14.16)].In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive solid tumors received KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (30%), upper respiratory tract infection (29%), and headache (25%). Laboratory abnormalities that occurred at a ≥10% higher rate in pediatric patients when compared to adults were leukopenia (30%), neutropenia (26%), and Grade 3 anemia (17%). The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)].

8.5 Geriatric Use

Of 3781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 48% were 65 years and over and 17% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.Of 389 adult patients with cHL who were treated with KEYTRUDA in clinical studies, 46 (12%) were 65 years and over. Patients aged 65 years and over had a higher incidence of serious adverse reactions (50%) than patients aged younger than 65 years (24%). Clinical studies of KEYTRUDA in cHL did not include sufficient numbers of patients aged 65 years and over to determine whether effectiveness differs from that in younger patients. Of 596 adult patients with TNBC who were treated with KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin in KEYNOTE-355, 137 (23%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

11 Description

Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells.KEYTRUDA (pembrolizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.

12.1 Mechanism Of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

12.2 Pharmacodynamics

Based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data from an interim analysis of 41 patients with melanoma treated with pembrolizumab 400 mg every 6 weeks, there are no anticipated clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks.

12.3 Pharmacokinetics

The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity.Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.

13.2 Animal Toxicology And/Or Pharmacology

In animal models, inhibition of PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus (LCMV). Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.

14.4 Classical Hodgkin Lymphoma

  • KEYNOTE-204The efficacy of KEYTRUDA was investigated in KEYNOTE-204 (NCT02684292), a randomized, open-label, active controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized (1:1) to receive:KEYTRUDA 200 mg intravenously every 3 weeks orBrentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeksTreatment was continued until unacceptable toxicity, disease progression, or a maximum of 35 cycles (up to approximately 2 years). Disease assessment was performed every 12 weeks. Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse <12 months after completion vs. relapse ≥12 months after completion). The main efficacy measure was PFS as assessed by BICR using 2007 revised International Working Group criteria. The study population characteristics were: median age of 35 years (range: 18 to 84); 57% male; 77% White, 9% Asian, 3.9% Black. The median number of prior therapies was 2 (range: 1 to 10) in the KEYTRUDA arm and 3 (range: 1 to 11) in the BV arm, with 18% in both arms having 1 prior line. Forty-two percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy.Efficacy is summarized in Table 50 and Figure 11. Table 50: Efficacy Results in Patients with cHL in KEYNOTE-204Endpoint KEYTRUDA200 mg every 3 weeksn=151Brentuximab Vedotin1.8 mg/kg every 3 weeksn=153+Denotes a censored value.PFS  Number of patients with event (%)81 (54%)88 (58%)  Median in months (95% CI)Based on Kaplan-Meier estimates.13.2 (10.9, 19.4)8.3 (5.7, 8.8)  Hazard ratioBased on the stratified Cox proportional hazard model. (95% CI)0.65 (0.48, 0.88)  p-ValueBased on a stratified log-rank test. One-sided p-value, with a prespecified boundary of 0.0043.0.0027Objective Response Rate  ORRDifference in ORR is not statistically significant. (95% CI)66% (57, 73)54% (46, 62)    Complete response25%24%    Partial response41%30%Duration of Response  Median in months (range)20.7 (0.0+, 33.2+)13.8 (0.0+, 33.9+)Figure 11: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-204KEYNOTE-087The efficacy of KEYTRUDA was investigated in KEYNOTE-087 (NCT02453594), a multicenter, non-randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, Complete Response Rate, and DoR) were assessed by BICR according to the 2007 revised International Working Group (IWG) criteria.The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; and 49% ECOG PS of 0 and 51% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range: 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior autologous HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy. Efficacy results for KEYNOTE-087 are summarized in Table 51.Table 51: Efficacy Results in Patients with cHL in KEYNOTE-087EndpointKEYTRUDA200 mg every 3 weeksn=210Median follow-up time of 9.4 monthsObjective Response Rate  ORR (95% CI)69% (62, 75)    Complete response rate22%    Partial response rate47%Duration of Response  Median in months (range)11.1 (0.0+, 11.1)Based on patients (n=145) with a response by independent review

14.5 Primary Mediastinal Large B-Cell Lymphoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), a multicenter, open-label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by BICR according to the 2007 revised IWG criteria. The efficacy outcome measures were ORR and DoR.The study population characteristics were: median age of 33 years (range: 20 to 61 years); 43% male; 92% White; and 43% ECOG PS of 0 and 57% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy.For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months). Efficacy results for KEYNOTE-170 are summarized in Table 52.Table 52: Efficacy Results in Patients with PMBCL in KEYNOTE-170EndpointKEYTRUDA200 mg every 3 weeksn=53Median follow-up time of 9.7 monthsNR = not reachedObjective Response Rate   ORR (95% CI)45% (32, 60)    Complete response rate11%    Partial response rate34%Duration of Response  Median in months (range)NR (1.1+, 19.2+)Based on patients (n=24) with a response by independent review

14.7 Microsatellite Instability-High Or Mismatch Repair Deficient Cancer

  • The efficacy of KEYTRUDA was investigated in patients with MSI-H or mismatch repair deficient (dMMR), solid tumors enrolled in one of five uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible across the five trials. Patients received either KEYTRUDA 200 mg every 3 weeks or KEYTRUDA 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. A maximum of 24 months of treatment with KEYTRUDA was administered. For the purpose of assessment of anti-tumor activity across these 5 trials, the major efficacy outcome measures were ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR.Table 56: MSI-H TrialsStudyDesign and Patient PopulationNumber of PatientsMSI-H/dMMR TestingDosagePrior TherapyCRC = colorectal cancerPCR = polymerase chain reactionIHC = immunohistochemistryKEYNOTE-016NCT01876511prospective, investigator-initiated6 sitespatients with CRC and other tumors 28 CRC30 non-CRClocal PCR or IHC 10 mg/kg every 2 weeksCRC: ≥ 2 prior regimensNon-CRC: ≥1 prior regimenKEYNOTE-164NCT02460198prospective international multi-center CRC61local PCR or IHC200 mg every 3 weeksPrior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb KEYNOTE-012NCT01848834retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer 6 central PCR10 mg/kg every 2 weeks≥1 prior regimenKEYNOTE-028NCT02054806retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC5central PCR10 mg/kg every 2 weeks≥1 prior regimenKEYNOTE-158NCT02628067prospective international multi-center enrollment of patients with MSI-H/dMMR non-CRCretrospectively identified patients who were enrolled in specific rare tumor non-CRC cohorts19 local PCR or IHC (central PCR for patients in rare tumor non-CRC cohorts)200 mg every 3 weeks≥1 prior regimenTotal149A total of 149 patients with MSI-H or dMMR cancers were identified across the five trials. Among these 149 patients, the baseline characteristics were: median age of 55 years, 36% age 65 or older; 56% male; 77% White, 19% Asian, and 2% Black; and 36% ECOG PS of 0 and 64% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease and 2% had locally advanced, unresectable disease. The median number of prior therapies for metastatic or unresectable disease was two. Eighty-four percent of patients with metastatic CRC and 53% of patients with other solid tumors received two or more prior lines of therapy.The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Fourteen of the 149 patients were retrospectively identified as MSI-H by testing tumor samples from a total of 415 patients using a central laboratory developed PCR test. Forty-seven patients had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 were identified using both tests. Efficacy results are summarized in Tables 57 and 58.Table 57: Efficacy Results for Patients with MSI-H/dMMR CancerEndpointKEYTRUDA n=149NR = not reachedObjective Response Rate  ORR (95% CI)39.6% (31.7, 47.9)    Complete response rate7.4%    Partial response rate32.2%Duration of Response  Median in months (range)NR (1.6+, 22.7+)  % with duration ≥6 months78%Table 58: Response by Tumor TypeObjective Response RateDuration of Response rangeNn (%)95% CI(months)CR = complete responsePR = partial responseSD = stable diseasePD = progressive diseaseNE = not evaluableCRC9032 (36%)(26%, 46%)(1.6+, 22.7+)Non-CRC5927 (46%)(33%, 59%)(1.9+, 22.1+)  Endometrial cancer145 (36%)(13%, 65%)(4.2+, 17.3+)  Biliary cancer113 (27%)(6%, 61%)(11.6+, 19.6+)  Gastric or GE junction cancer95 (56%)(21%, 86%)(5.8+, 22.1+)  Pancreatic cancer65 (83%)(36%, 100%)(2.6+, 9.2+)  Small intestinal cancer83 (38%)(9%, 76%)(1.9+, 9.1+)  Breast cancer2PR, PR(7.6, 15.9)  Prostate cancer2PR, SD9.8+  Bladder cancer1NE  Esophageal cancer1PR18.2+  Sarcoma1PD  Thyroid cancer1NE  Retroperitoneal adenocarcinoma1PR7.5+  Small cell lung cancer1CR8.9+  Renal cell cancer1PD

14.8 Microsatellite Instability-High Or Mismatch Repair Deficient Colorectal Cancer

  • The efficacy of KEYTRUDA was investigated in KEYNOTE-177 (NCT02563002), a multicenter, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR CRC. MSI or MMR tumor status was determined locally using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of the following chemotherapy regimens given intravenously every 2 weeks: mFOLFOX6 (oxaliplatin, leucovorin, and FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.Treatment with KEYTRUDA or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measures were PFS (as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) and OS. Additional efficacy outcome measures were ORR and DoR. A total of 307 patients were enrolled and randomized to KEYTRUDA (n=153) or chemotherapy (n=154). The baseline characteristics of these 307 patients were: median age of 63 years (range: 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an ECOG PS of 0 and 48% had an ECOG PS of 1; and 27% received prior adjuvant or neoadjuvant chemotherapy. Among 154 patients randomized to receive chemotherapy,143 received chemotherapy per the protocol. Of the 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI. The trial demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA compared with chemotherapy. At the time of the PFS analysis, the overall survival data were not mature (66% of the required number of events for the OS final analysis). The median follow-up time was 27.6 months (range: 0.2 to 48.3 months). Table 59 and Figure 13 summarize the key efficacy measures for KEYNOTE-177. Table 59: Efficacy Results in Patients with MSI-H or dMMR CRC in KEYNOTE-177EndpointKEYTRUDA 200 mg every 3 weeks n=153 Chemotherapy   n=154+ Denotes ongoing responseNR = not reached PFS  Number (%) of patients with event82 (54%)113 (73%)  Median in months (95% CI)16.5 (5.4, 32.4)8.2 (6.1, 10.2)  Hazard ratioBased on Cox regression model (95% CI)0.60 (0.45, 0.80)  p-ValueTwo-sided p-value based on log-rank test (compared to a significance level of 0.0234)0.0004Objective Response RateBased on confirmed response by BICR review  ORR (95% CI)44% (35.8, 52.0)33% (25.8, 41.1)     Complete response rate11%4%    Partial response rate33%29%Duration of Response,Based on n=67 patients with a response in the KEYTRUDA arm and n=51 patients with a response in the chemotherapy arm  Median in months (range)NR (2.3+, 41.4+)10.6 (2.8, 37.5+)  % with duration ≥12 monthsBased on observed duration of response75%37%  % with duration ≥24 months43%18%Figure 13: Kaplan-Meier Curve for PFS in KEYNOTE-177

14.9 Gastric Cancer

  • First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction (GEJ) AdenocarcinomaThe efficacy of KEYTRUDA in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that was designed to enroll 692 patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms.KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle.Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX).All study medications, except oral capecitabine, were administered as an intravenous infusion for every 3 week cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. In an interim efficacy analysis, major outcome measures assessed were ORR and DoR by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.At the time of the interim analysis, ORR and DoR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range: 19 to 84), 41% age 65 or older; 82% male; 63% White, 31% Asian, and 0.8% Black; 47% ECOG PS of 0 and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (stage IV) and 3% had locally advanced unresectable disease. Eighty-seven percent had tumors that expressed PD-L1 with a CPS ≥1. Ninety-one percent (n=240) had tumors that were not MSI-H, 1% (n=2) had tumors that were MSI-H, and in 8% (n=22) the status was not known. Eighty-seven percent of patients received CAPOX.A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. Efficacy results are summarized in Table 60.Table 60: Efficacy Results for KEYNOTE-811EndpointKEYTRUDA200 mg every 3 weeksTrastuzumabFluoropyrimidine and Platinum Chemotherapyn=133PlaceboTrastuzumabFluoropyrimidine and Platinum Chemotherapyn=131Objective Response Rate  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI)74% (66, 82)52% (43, 61)    Complete response rate11%3.1%    Partial response rate63%49%  p-Valuep-Value based on stratified Miettinen and Nurminen method (compared to an alpha boundary of 0.002)<0.0001Duration of Responsen=99n=68  Median in months (range)10.6 (1.1+, 16.5+)9.5 (1.4+, 15.4+)  % with duration ≥6 months65%53%Previously Treated Gastric or Gastroesophageal Junction (GEJ) AdenocarcinomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-059 (NCT02335411), a multicenter, non-randomized, open-label multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet. HER2/neu positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.Among the 259 patients, 55% (n = 143) had tumors that expressed PD-L1 with a CPS ≥1 and microsatellite stable (MSS) tumor status or undetermined MSI or MMR status. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The baseline characteristics of these 143 patients were: median age of 64 years, 47% age 65 or older; 77% male; 82% White and 11% Asian; and 43% ECOG PS of 0 and 57% ECOG PS of 1. Eighty-five percent had M1 disease and 7% had M0 disease. Fifty-one percent had two and 49% had three or more prior lines of therapy in the recurrent or metastatic setting.For the 143 patients, the ORR was 13.3% (95% CI: 8.2, 20.0); 1.4% had a complete response and 11.9% had a partial response. Among the 19 responding patients, the DoR ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and 5 patients (26%) having responses of 12 months or longer.Among the 259 patients enrolled in KEYNOTE-059, 7 (3%) had tumors that were determined to be MSI-H. An objective response was observed in 4 patients, including 1 complete response. The DoR ranged from 5.3+ to 14.1+ months.

14.11 Cervical Cancer

The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR.Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx kit. The baseline characteristics of these 77 patients were: median age of 45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting.No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1). Efficacy results are summarized in Table 63 for patients with PD-L1 expression (CPS ≥1).Table 63: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-158EndpointKEYTRUDA200 mg every 3 weeksn=77Median follow-up time of 11.7 months (range 0.6 to 22.7 months)+ Denotes ongoing responseNR = not reachedObjective Response Rate  ORR (95% CI)14.3% (7.4, 24.1)    Complete response rate2.6%    Partial response rate11.7%Duration of Response   Median in months (range)NR (4.1, 18.6+)Based on patients (n=11) with a response by independent review  % with duration ≥6 months91%

14.12 Hepatocellular Carcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-224 (NCT02702414), a single-arm, multicenter trial in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib; had measurable disease; and Child-Pugh class A liver impairment. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity, investigator-assessed confirmed disease progression (based on repeat scan at least 4 weeks from the initial scan showing progression), or completion of 24 months of KEYTRUDA. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.The study population characteristics were: median age of 68 years, 67% age 65 or older; 83% male; 81% White and 14% Asian; and 61% ECOG PS of 0 and 39% ECOG PS of 1. Child-Pugh class and score were A5 for 72%, A6 for 22%, B7 for 5%, and B8 for 1% of patients. Twenty-one percent of the patients were HBV seropositive and 25% HCV seropositive. There were 9 patients (9%) who were seropositive for both HBV and HCV. For these 9 patients, all of the HBV cases and three of the HCV cases were inactive. Sixty-four percent (64%) of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both. Thirty-eight percent (38%) of patients had alpha-fetoprotein (AFP) levels ≥400 mcg/L. All patients received prior sorafenib; of whom 20% were unable to tolerate sorafenib. No patient received more than one prior systemic therapy (sorafenib).Efficacy results are summarized in Table 64.Table 64: Efficacy Results in KEYNOTE-224EndpointKEYTRUDA200 mg every 3 weeksn=104BICR-Assessed Objective Response Rate (RECIST v1.1)  ORR (95% CI)Based on patients (n=18) with a confirmed response by independent review17% (11, 26)    Complete response rate1%    Partial response rate16%BICR-Assessed Duration of Response  % with duration ≥6 months89%  % with duration ≥12 months56%

14.13 Merkel Cell Carcinoma

The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1.The study population characteristics were: median age of 71 years (range: 46 to 91), 80% age 65 or older; 68% male; 90% White; and 48% ECOG PS of 0 and 52% ECOG PS of 1. Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.Efficacy results are summarized in Table 65.Table 65: Efficacy Results in KEYNOTE-017EndpointKEYTRUDA2 mg/kg every 3 weeksn=50+ Denotes ongoing responseObjective Response Rate  ORR (95% CI)56% (41, 70)    Complete response rate (95% CI)24% (13, 38)    Partial response rate (95% CI)32% (20, 47)Duration of Response  Range in monthsThe median duration of response was not reached.5.9, 34.5+  Patients with duration ≥6 months, n (%)27 (96%)  Patients with duration ≥12 months, n (%)15 (54%)

14.14 Renal Cell Carcinoma

  • The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus "Rest of the World").Patients were randomized (1:1) to one of the following treatment arms:KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter.The study population characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate and 13% poor.The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. Table 66 and Figure 16 summarize the efficacy results for KEYNOTE-426. The median follow-up time was 12.8 months (range 0.1 to 22.0 months). Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status.Table 66: Efficacy Results in KEYNOTE-426EndpointKEYTRUDA 200 mg every 3 weeks and AxitinibSunitinibn=432n=429NR = not reachedOS  Number of patients with event (%)59 (14%)97 (23%)  Median in months (95% CI)NR (NR, NR)NR (NR, NR)  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI)0.53 (0.38, 0.74)  p-ValueBased on stratified log-rank test<0.0001p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis).  12-month OS rate90% (86, 92)78% (74, 82)PFS  Number of patients with event (%)183 (42%)213 (50%)  Median in months (95% CI)15.1 (12.6, 17.7)11.0 (8.7, 12.5)  Hazard ratio (95% CI)0.69 (0.56, 0.84)  p-Value0.0001p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis).Objective Response Rate  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI)59% (54, 64)36% (31, 40)    Complete response rate6%2%    Partial response rate53%34%  p-ValueBased on Miettinen and Nurminen method stratified by IMDC risk group and geographic region<0.0001Figure 16: Kaplan-Meier Curve for Overall Survival in KEYNOTE-426

14.15 Endometrial Carcinoma

The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-146 (NCT02501096), a single-arm, multicenter, open-label, multi-cohort trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily until unacceptable toxicity or disease progression as determined by the investigator. The major efficacy outcome measures were ORR and DoR as assessed by BICR using RECIST 1.1.Administration of KEYTRUDA and lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA dosing was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 6 weeks until week 24, followed by every 9 weeks thereafter.Among the 108 patients, 87% (n=94) had tumors that were not MSI-H or dMMR, 10% (n=11) had tumors that were MSI-H or dMMR, and in 3% (n=3) the status was not known. Tumor MSI status was determined using a polymerase chain reaction (PCR) test. Tumor MMR status was determined using an IHC test. The baseline characteristics of the 94 patients with tumors that were not MSI-H or dMMR were: median age of 66 years, 62% age 65 or older; 86% White, 6% Black, 4% Asian, and 3% other races; and ECOG PS of 0 (52%) or 1 (48%). All 94 of these patients received prior systemic therapy for endometrial carcinoma: 51% had one, 38% had two, and 11% had three or more prior systemic therapies.Efficacy results are summarized in Table 67.Table 67: Efficacy Results in KEYNOTE-146EndpointKEYTRUDA 200 mg every 3 weeks with lenvatinibn=94Median follow-up time of 18.7 months+ Denotes ongoing responseNR = not reachedObjective Response Rate  ORR (95% CI)38.3% (29, 49)    Complete response rate10.6%    Partial response rate27.7%Response duration    Median in months (range)NR (1.2+, 33.1+)Based on patients (n=36) with a response by independent review    % with duration ≥6 months69%

14.16 Tumor Mutational Burden-High Cancer

The efficacy of KEYTRUDA was investigated in a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with high tumor mutation burden (TMB-H) who were enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Assessment of tumor status was performed every 9 weeks for the first 12 months and every 12 weeks thereafter.The statistical analysis plan pre-specified ≥10 and ≥13 mutations per megabase using the FoundationOne CDx assay as cutpoints to assess TMB. Testing of TMB was blinded with respect to clinical outcomes. The major efficacy outcome measures were ORR and DoR in patients who received at least one dose of KEYTRUDA as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. In KEYNOTE-158, 1050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥10 mutations per megabase. Among the 102 patients with TMB-H advanced solid tumors, the study population characteristics were: median age of 61 years (range: 27 to 80), 34% age 65 or older; 34% male; 81% White; and 41% ECOG PS of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy. Efficacy results are summarized in Tables 68 and 69. Table 68: Efficacy Results for Patients with TMB-H Cancer in KEYNOTE-158  EndpointKEYTRUDA200 mg every 3 weeksTMB ≥10 mut/Mbn=102Median follow-up time of 11.1 monthsTMB ≥13 mut/Mbn=70+ Denotes ongoing responseNR = not reachedObjective Response Rate  ORR (95% CI)29% (21, 39)37% (26, 50)    Complete response rate4%3%    Partial response rate25%34%Duration of Response n=30 n=26   Median in months (range)From product-limit (Kaplan-Meier) method for censored dataNR (2.2+, 34.8+)NR (2.2+, 34.8+)  % with duration ≥12 months57%58%  % with duration ≥24 months50%50%Table 69: Response by Tumor Type (TMB ≥10 mut/Mb)Objective Response RateDuration of Response rangeNn (%)95% CI(months)CR = complete responsePR = partial responseSD = stable diseasePD = progressive diseaseOverallNo TMB-H patients were identified in the cholangiocarcinoma cohort 10230 (29%)(21%, 39%)(2.2+, 34.8+)  Small cell lung cancer3410 (29%)(15%, 47%)(4.1, 32.5+)  Cervical cancer165 (31%)(11%, 59%)(3.7+, 34.8+)  Endometrial cancer157 (47%)(21%, 73%)(8.4+, 33.9+)  Anal cancer141 (7%)(0.2%, 34%)18.8+  Vulvar cancer122 (17%)(2%, 48%)(8.8, 11.0)  Neuroendocrine cancer52 (40%)(5%, 85%)(2.2+, 32.6+)  Salivary cancer3PR, SD, PD31.3+  Thyroid cancer2CR, CR(8.2, 33.2+)  Mesothelioma cancer1PDIn an exploratory analysis in 32 patients enrolled in KEYNOTE-158 whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI: 4%, 29%), including two complete responses and two partial responses.

14.17 Cutaneous Squamous Cell Carcinoma

The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC or locally advanced cSCC enrolled in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed every 6 weeks during the first year, and every 9 weeks during the second year. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 105 patients with recurrent or metastatic cSCC treated, the study population characteristics were: median age of 72 years (range: 29 to 95), 71% age 65 or older; 76% male; 71% White, 25% race unknown; 34% ECOG PS of 0 and 66% ECOG PS of 1. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC, and 31% had both locally recurrent and metastatic cSCC. Eighty-seven percent received one or more prior lines of therapy; 74% received prior radiation therapy. Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range: 35 to 95), 80% age 65 or older; 72% male; 83% White, 13% race unknown; 41% ECOG PS of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy.Efficacy results are summarized in Table 70. Table 70: Efficacy Results in KEYNOTE-629EndpointKEYTRUDARecurrent or Metastatic cSCCn=105KEYTRUDALocally Advanced cSCCn=54+ Denotes ongoing responseObjective Response Rate  ORR (95% CI)35% (26, 45)50% (36, 64)    Complete response rate11%17%    Partial response rate25%33%Duration of ResponseMedian follow-up time: recurrent or metastatic cSCC: 23.8 months; locally advanced cSCC: 13.4 monthsn=37n=27    Median in months (range)NR (2.7, 30.4+)NR (1.0+, 17.2+)    % with duration ≥6 months76%81%    % with duration ≥12 months68%37%

14.18 Triple-Negative Breast Cancer

  • The efficacy of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by chemotherapy treatment (paclitaxel or paclitaxel protein-bound vs. gemcitabine and carboplatin), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx kit, and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no).Patients were randomized (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:KEYTRUDA 200 mg on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.Placebo on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.Assessment of tumor status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter. The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ tested in the subgroup of patients with CPS ≥10. Additional efficacy outcome measures were OS as well as ORR and DoR as assessed by BICR.The study population characteristics for patients were: median age of 53 years (range: 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian, and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post-menopausal status. Seventy-five percent of patients had tumor PD-L1 expression CPS ≥1 and 38% had tumor PD-L1 expression CPS ≥10.Table 71 and Figure 17 summarize the efficacy results for KEYNOTE-355.Table 71: Efficacy Results in KEYNOTE-355 (CPS ≥10)EndpointKEYTRUDA200 mg every 3 weekswith chemotherapyn=220Placeboevery 3 weekswith chemotherapyn=103PFS  Number of patients with event   (%)136 (62%)79 (77%)  Median in months (95% CI)9.7 (7.6, 11.3)5.6 (5.3, 7.5)  Hazard ratioBased on stratified Cox regression model (95% CI)0.65 (0.49, 0.86)  p-ValueOne-sided p-Value based on stratified log-rank test0.0012ORR  Objective confirmed response   rate (95% CI)53% (46, 60)40% (30, 50)    Complete response rate17%13%    Partial response rate36%27%DoR  Median in months (95% CI)19.3 (9.9, 29.8)7.3 (5.3, 15.8)Figure 17: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-355 (CPS ≥10)

14.19 Adult Indications: Additional Dosing Regimen Of 400 Mg Every 6 Weeks

The efficacy and safety of KEYTRUDA using a dosage of 400 mg every 6 weeks for all approved adult indications was primarily based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma [see Clinical Pharmacology (12.2)].

16 How Supplied/Storage And Handling

KEYTRUDA injection (clear to slightly opalescent, colorless to slightly yellow solution):Carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02)Carton containing two 100 mg/4 mL (25 mg/mL), single-dose vials (NDC 0006-3026-04)

Storage And Handling

Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Spl Medguide

  • This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: July 2021MEDICATION GUIDEKEYTRUDA® (key-true-duh)(pembrolizumab)injectionWhat is the most important information I should know about KEYTRUDA?KEYTRUDA is a medicine that may treat certain cancers by working with your immune system. KEYTRUDA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:Lung problemscoughshortness of breathchest painIntestinal problemsdiarrhea (loose stools) or more frequent bowel movements than usualstools that are black, tarry, sticky, or have blood or mucussevere stomach-area (abdomen) pain or tendernessLiver problemsyellowing of your skin or the whites of your eyessevere nausea or vomitingpain on the right side of your stomach area (abdomen)dark urine (tea colored)bleeding or bruising more easily than normalHormone gland problemsheadaches that will not go away or unusual headacheseye sensitivity to lighteye problemsrapid heartbeatincreased sweatingextreme tirednessweight gain or weight lossfeeling more hungry or thirsty than usualurinating more often than usualhair lossfeeling coldconstipationyour voice gets deeperdizziness or faintingchanges in mood or behavior, such as decreased sex drive, irritability, or forgetfulnessKidney problemsdecrease in your amount of urineblood in your urineswelling of your anklesloss of appetiteSkin problemsrashitchingskin blistering or peelingpainful sores or ulcers in your mouth or in your nose, throat, or genital areafever or flu-like symptomsswollen lymph nodesProblems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with KEYTRUDA. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:chest pain, irregular heartbeat, shortness of breath, swelling of anklesconfusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legsdouble vision, blurry vision, sensitivity to light, eye pain, changes in eyesightpersistent or severe muscle pain or weakness, muscle crampslow red blood cells, bruisingInfusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:chills or shakingitching or rashflushingshortness of breath or wheezingdizzinessfeeling like passing outfeverback painRejection of a transplanted organ. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with KEYTRUDA. Your healthcare provider will monitor you for these complications.Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during treatment with KEYTRUDA. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with KEYTRUDA if you have severe side effects.What is KEYTRUDA?KEYTRUDA is a prescription medicine used to treat:a kind of skin cancer called melanoma. KEYTRUDA may be used:when your melanoma has spread or cannot be removed by surgery (advanced melanoma), orto help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.a kind of lung cancer called non-small cell lung cancer (NSCLC).KEYTRUDA may be used with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your lung cancer:has spread (advanced NSCLC), andis a type called “nonsquamous”, andyour tumor does not have an abnormal “EGFR” or “ALK” gene.KEYTRUDA may be used with the chemotherapy medicines carboplatin and either paclitaxel or paclitaxel protein-bound as your first treatment when your lung cancer:has spread (advanced NSCLC), andis a type called “squamous”.KEYTRUDA may be used alone as your first treatment when your lung cancer:has not spread outside your chest (stage III) and you cannot have surgery or chemotherapy with radiation oryour NSCLC has spread to other areas of your body (advanced NSCLC), andyour tumor tests positive for “PD-L1”, anddoes not have an abnormal “EGFR” or “ALK” gene.KEYTRUDA may also be used alone when:you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, andyour tumor tests positive for “PD-L1”, andif your tumor has an abnormal “EGFR” or “ALK” gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working.a kind of cancer called head and neck squamous cell cancer (HNSCC).KEYTRUDA may be used with the chemotherapy medicines fluorouracil and a platinum as your first treatment when your head and neck cancer has spread or returned and cannot be removed by surgery.KEYTRUDA may be used alone as your first treatment when your head and neck cancer:has spread or returned and cannot be removed by surgery, andyour tumor tests positive for “PD-L1”.KEYTRUDA may be used alone when your head and neck cancer:has spread or returned, andyou have received chemotherapy that contains platinum and it did not work or is no longer working.a kind of cancer called classical Hodgkin lymphoma (cHL):in adults when:your cHL has returned oryou have tried a treatment and it did not work, orin children when:you have tried a treatment and it did not work oryour cHL has returned after you received 2 or more types of treatment.a kind of cancer called primary mediastinal B-cell lymphoma (PMBCL) in adults and children when:you have tried a treatment and it did not work oryour PMBCL has returned after you received 2 or more types of treatment.a kind of bladder and urinary tract cancer called urothelial carcinoma.KEYTRUDA may be used when your cancer has not spread to nearby tissue in the bladder, but is at high-risk for spreading (high-risk non-muscle-invasive bladder cancer [NMIBC]) when:your tumor is a type called “carcinoma in situ” (CIS), andyou have tried treatment with Bacillus Calmette-Guerin (BCG) and it did not work, andyou are not able to or have decided not to have surgery to remove your bladder.KEYTRUDA may be used when your bladder or urinary tract cancer:has spread or cannot be removed by surgery (advanced urothelial cancer) and,you are not able to receive chemotherapy that contains a medicine called cisplatin, and your tumor tests positive for “PD-L1”, oryou are not able to receive a medicine called cisplatin or carboplatin, oryou have received chemotherapy that contains platinum, and it did not work or is no longer working.a kind of cancer that is shown by a laboratory test to be a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor. KEYTRUDA may be used in adults and children to treat:cancer that has spread or cannot be removed by surgery (advanced cancer), andhas progressed following treatment, and you have no satisfactory treatment options.
  • It is not known if KEYTRUDA is safe and effective in children with MSI-H cancers of the brain or spinal cord (central nervous system cancers).a kind of cancer called colon or rectal cancer. KEYTRUDA may be used when your cancer:has spread or cannot be removed by surgery (advanced colon or rectal cancer), andhas been shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).a kind of stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma. KEYTRUDA may be used with the medicine trastuzumab with fluoropyrimidine and platinum chemotherapy as your first treatment when your stomach cancer:is HER2-positive, andhas spread or cannot be removed by surgery (advanced gastric cancer).KEYTRUDA may be used alone when your stomach cancer:
  • Tests positive for “PD L1”, andhas returned or spread (advanced gastric cancer), andyou have received 2 or more types of chemotherapy, including fluoropyrimidine and chemotherapy that contains platinum, and it did not work or is no longer working, andif your tumor is HER2-positive, you also received a HER2-targeted medicine and it did not work or is no longer working.a kind of cancer called esophageal or certain gastroesophageal junction (GEJ) carcinomas that cannot be cured by surgery or a combination of chemotherapy and radiation therapy.KEYTRUDA may be used with platinum- and fluoropyrimidine-based chemotherapy medicines. KEYTRUDA may be used alone when:you have received one or more types of treatment, and it did not work or it is no longer working, andyour tumor is a type called “squamous”, andyour tumor tests positive for “PD-L1”.a kind of cancer called cervical cancer that tests positive for “PD-L1.” KEYTRUDA may be used when your cervical cancer:has returned, or has spread or cannot be removed by surgery (advanced cervical cancer), andyou have received chemotherapy, and it did not work or is no longer working.a kind of liver cancer called hepatocellular carcinoma, after you have received the medicine sorafenib.a kind of skin cancer called Merkel cell carcinoma (MCC) in adults and children. KEYTRUDA may be used to treat your skin cancer when it has spread or returned.a kind of kidney cancer called renal cell carcinoma (RCC). KEYTRUDA may be used with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC).a kind of uterine cancer called endometrial carcinoma. KEYTRUDA may be used with the medicine lenvatinib:when your tumors are not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), andyou have received anti-cancer treatment, and it did not work or is no longer working, andyour cancer cannot be cured by surgery or radiation (advanced endometrial carcinoma).a kind of cancer that is shown by a test to be tumor mutational burden-high (TMB-H). KEYTRUDA may be used in adults and children to treat:solid tumors that have spread or cannot be removed by surgery (advanced cancer), andyou have received anti-cancer treatment, and it did not work or is no longer working, andyou have no satisfactory treatment options.It is not known if KEYTRUDA is safe and effective in children with TMB-H cancers of the brain or spinal cord (central nervous system cancers).a kind of skin cancer called cutaneous squamous cell carcinoma (cSCC). KEYTRUDA may be used when your skin cancer:has returned or spread, andcannot be cured by surgery or radiation.a kind of cancer called triple-negative breast cancer (TNBC). KEYTRUDA may be used with chemotherapy medicines when your breast cancer:has returned and cannot be removed by surgery or has spread, andtests positive for “PD-L1”.Before receiving KEYTRUDA, tell your healthcare provider about all of your medical conditions, including if you:have immune system problems such as Crohn’s disease, ulcerative colitis, or lupushave received an organ transplanthave received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)have received radiation treatment to your chest areahave a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndromeare pregnant or plan to become pregnant. KEYTRUDA can harm your unborn baby.Females who are able to become pregnant:Your healthcare provider will give you a pregnancy test before you start treatment with KEYTRUDA.You should use an effective method of birth control during and for at least 4 months after the final dose of KEYTRUDA. Talk to your healthcare provider about birth control methods that you can use during this time.Tell your healthcare provider right away if you think you may be pregnant or if you become pregnant during treatment with KEYTRUDA.are breastfeeding or plan to breastfeed. It is not known if KEYTRUDA passes into your breast milk. Do not breastfeed during treatment with KEYTRUDA and for 4 months after your final dose of KEYTRUDA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will I receive KEYTRUDA?Your healthcare provider will give you KEYTRUDA into your vein through an intravenous (IV) line over 30 minutes.In adults, KEYTRUDA is usually given every 3 weeks or 6 weeks depending on the dose of KEYTRUDA that you are receiving.In children, KEYTRUDA is usually given every 3 weeks.Your healthcare provider will decide how many treatments you need.Your healthcare provider will do blood tests to check you for side effects.If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of KEYTRUDA?KEYTRUDA can cause serious side effects. See “What is the most important information I should know about KEYTRUDA?”Common side effects of KEYTRUDA when used alone include: feeling tired, pain, including pain in muscles, bones or joints and stomach-area (abdominal) pain, decreased appetite, itching, diarrhea, nausea, rash, fever, cough, shortness of breath, and constipation.
  • Side effects of KEYTRUDA when used alone that are more common in children than in adults include: fever, vomiting, upper respiratory tract infection, headache, and low levels of white blood cells and red blood cells (anemia).Common side effects of KEYTRUDA when given with certain chemotherapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs, swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, mouth sores, headache, and weight loss.Common side effects of KEYTRUDA when given with axitinib include: diarrhea, feeling tired or weak, high blood pressure, liver problems, low levels of thyroid hormone, decreased appetite, blisters or rash on the palms of your hands and soles of your feet, nausea, mouth sores or swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, hoarseness, rash, cough, and constipation.Common side effects of KEYTRUDA when given with lenvatinib include: feeling tired, high blood pressure, joint and muscle pain, diarrhea, decreased appetite, low levels of thyroid hormone, nausea, mouth sores, vomiting, weight loss, stomach-area (abdominal) pain, headache, constipation, urinary tract infection, hoarseness, bleeding, low magnesium level, blisters or rash on the palms of your hands and soles of your feet, shortness of breath, cough, and rash.These are not all the possible side effects of KEYTRUDA.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of KEYTRUDAMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about KEYTRUDA that is written for health professionals.What are the ingredients in KEYTRUDA?Active ingredient: pembrolizumabInactive ingredients: KEYTRUDA injection: L-histidine, polysorbate 80, sucrose, and Water for Injection.Manufactured by: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC., Whitehouse Station, NJ 08889, USAU.S. License No. 0002For patent information: www.merck.com/product/patent/home.htmlCopyright © 2014-2021 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. usmg-mk3475-iv-2107r041For more information, go to www.keytruda.com.

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