Keytruda Qlex Injection, Solution
FDA Label NDC 0006-5083

KEYTRUDA QLEX^™ is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

KEYTRUDA QLEX is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with Stage IIB, IIC, or III melanoma following complete resection.

KEYTRUDA QLEX, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA QLEX, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of adult patients with metastatic squamous NSCLC.

KEYTRUDA QLEX, as a single agent, is indicated for the first-line treatment of adult 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 QLEX, as a single agent, is indicated for the treatment of adult 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 QLEX.

KEYTRUDA QLEX is indicated for the treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA QLEX, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

KEYTRUDA QLEX, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM).

KEYTRUDA QLEX, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of adult patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA QLEX, as a single agent, is indicated for the first-line treatment of adult 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 QLEX, as a single agent, is indicated for the treatment of adult patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

KEYTRUDA QLEX, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer.

KEYTRUDA QLEX, as a single agent, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma:

• who are not eligible for any platinum-containing chemotherapy, or
• who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA QLEX, as a single agent, is indicated for the treatment of adult 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.

KEYTRUDA QLEX is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options [see Dosage and Administration (2.1)].

KEYTRUDA QLEX is indicated for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test [see Dosage and Administration (2.1)].

KEYTRUDA QLEX, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)].

KEYTRUDA QLEX, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA approved test [see Dosage and Administration (2.1)].

KEYTRUDA QLEX is indicated for the treatment of adult 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 for patients with tumors that express PD-L1 (CPS ≥ 1) [see Dosage and Administration (2.1)], or
• as 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)].

KEYTRUDA QLEX, in combination with chemoradiotherapy (CRT), is indicated for the treatment of adult patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III-IVA).

KEYTRUDA QLEX, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)].

KEYTRUDA QLEX, as a single agent, is indicated for the treatment of adult 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)].

KEYTRUDA QLEX is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen.

KEYTRUDA QLEX, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer (BTC).

KEYTRUDA QLEX is indicated for the treatment of adult and pediatric patients 12 years and older with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

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

KEYTRUDA QLEX, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

KEYTRUDA QLEX is indicated for the adjuvant treatment of adult patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions [see Clinical Studies (14.15)].

KEYTRUDA QLEX, in combination with carboplatin and paclitaxel, followed by KEYTRUDA QLEX as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.

KEYTRUDA QLEX, in combination with lenvatinib, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)].

KEYTRUDA QLEX, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)].

KEYTRUDA QLEX is indicated for the treatment of adult and pediatric patients 12 years and older 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 (14.17)]. 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 QLEX in pediatric patients 12 years and older with TMB-H central nervous system cancers have not been established.

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

KEYTRUDA QLEX is indicated for the treatment of adult patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA QLEX, in combination with chemotherapy, is indicated for the treatment of adult patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)].

See information on FDA-approved tests for intravenous pembrolizumab. Information on FDA-approved tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics.

Patient Selection for Single-Agent Treatment

Select patients for treatment with KEYTRUDA QLEX 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 (14.3)].
• metastatic NSCLC [see Clinical Studies (14.3)].
• first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.5)].
• previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.10)].
• recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.11)].

For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA QLEX 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 QLEX as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.17)].

Because subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, and dMMR in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.

Additional Patient Selection Information for MSI-H or dMMR in Patients with non-CRC Solid Tumors

Due to discordance between local tests and FDA-approved tests, confirmation of MSI-H or dMMR status is recommended by an FDA-approved test in patients with MSI-H or dMMR solid tumors, if feasible. If unable to perform confirmatory MSI-H/dMMR testing, the presence of TMB ≥10 mut/Mb, as determined by an FDA-approved test, may be used to select patients for treatment [see Clinical Studies (14.7)].

Patient Selection for Combination Therapy

For use of KEYTRUDA QLEX in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, and esophageal or gastroesophageal junction (GEJ) carcinoma [see Clinical Studies (14.9), (14.10)].

• An FDA-approved test for the detection of PD-L1 for the selection of patients with PD-L1 (CPS ≥1) expression in esophageal carcinoma in combination with platinum- and fluoropyrimidine-based chemotherapy is not available.

For use of KEYTRUDA QLEX in combination with chemotherapy, with or without bevacizumab, select patients based on the presence of positive PD-L1 expression in persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.11)].

For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with KEYTRUDA QLEX in combination with lenvatinib based on MMR or MSI status in tumor specimens [see Clinical Studies (14.16)].

For use of KEYTRUDA QLEX in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression in locally recurrent unresectable or metastatic TNBC [see Clinical Studies (14.19)].

• KEYTRUDA QLEX has different recommended dosage and administration instructions than intravenous pembrolizumab.
  • To reduce the risk of medication errors, check the vial labels to ensure that the drug being prepared and administered is KEYTRUDA QLEX for subcutaneous use and not intravenous pembrolizumab.
  • Do not substitute KEYTRUDA QLEX with intravenous pembrolizumab because they have different recommended dosages and routes of administration.
  • Patients receiving intravenous pembrolizumab can switch to subcutaneous KEYTRUDA QLEX at their next scheduled dose.
  • Patients receiving subcutaneous KEYTRUDA QLEX can switch to intravenous pembrolizumab at their next scheduled dose.
  • Administer KEYTRUDA QLEX as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel.
  • Every 3-week dosing (395 mg/4,800 units): inject 2.4 mL subcutaneously over 1 minute. Treatment duration is provided in Recommended Dosage (Table 1).
  • Every 6-week dosing (790 mg/9,600 units): inject 4.8 mL subcutaneously over 2 minutes. Treatment duration is provided in Recommended Dosage (Table 1).
  • Inject into healthy skin and never into areas where the skin is red, bruised, tender, or hard.
  • Ensure the injection site is at least 2.5 cm from the previous injection site.
  • During treatment with KEYTRUDA QLEX, do not administer other medications for subcutaneous use at the same site as KEYTRUDA QLEX.
  • Do not administer KEYTRUDA QLEX intravenously.
  • KEYTRUDA QLEX must be administered by a healthcare provider.

The recommended dosages of KEYTRUDA QLEX are presented in Table 1.

• Every 3-week dosing (395 mg pembrolizumab and 4,800 units berahyaluronidase alfa): inject 2.4 mL subcutaneously over 1 minute.
• Every 6-week dosing (790 mg pembrolizumab and 9,600 units berahyaluronidase alfa): inject 4.8 mL subcutaneously over 2 minutes.

Table 1: Recommended Dosage

Indication	Recommended Dosage of KEYTRUDA QLEX	Duration/Timing of Treatment
Monotherapy
Adult patients with unresectable or   metastatic melanoma	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks	Until disease progression or unacceptable   toxicity
Adjuvant treatment of adult patients   with melanoma, NSCLC, or RCC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks	Until disease recurrence, unacceptable   toxicity, or up to 12 months
Adult patients with NSCLC, HNSCC,   locally advanced or metastatic   Urothelial Carcinoma, MSI-H or dMMR   Cancer, MSI-H or dMMR CRC, MSI-H   or dMMR Endometrial Carcinoma,   Esophageal Cancer, Cervical Cancer,   HCC, MCC, TMB-H Cancer, or cSCC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks	Until disease progression, unacceptable   toxicity, or up to 24 months
Adult patients with high-risk BCG-   unresponsive NMIBC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks	Until persistent or recurrent high-risk    NMIBC, disease progression,    unacceptable toxicity, or up to 24 months
Pediatric patients The recommended dosage for melanoma, MSI-H or dMMR cancer, MCC and TMB-H cancer has not been established in pediatric patients 12 years and older who weigh 40 kg or less [see Use in Specific Populations (8.4)]. (12 years and older   who weigh greater than 40 kg) with   MSI-H or dMMR Cancer, MCC, or TMB-   H Cancer	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks	Until disease progression, unacceptable   toxicity, or up to 24 months
Pediatric patients (12 years and older   who weigh greater than 40 kg) for    adjuvant treatment of melanoma	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks	Until disease recurrence, unacceptable   toxicity, or up to 12 months
Combination Therapy Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA QLEX for recommended dosing information, as appropriate.
Adult patients with resectable NSCLC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day.	Neoadjuvant treatment in combination with   chemotherapy for 12 weeks or until   disease progression that precludes   definitive surgery or unacceptable toxicity,   followed by adjuvant treatment with   KEYTRUDA QLEX as a single agent after   surgery for 39 weeks or until disease   recurrence or unacceptable toxicity
Adult patients with NSCLC, MPM,   HNSCC, HER2-negative Gastric   Cancer, Esophageal Cancer, or BTC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day.	Until disease progression, unacceptable   toxicity, or up to 24 months
Adult patients with locally advanced or   metastatic urothelial cancer	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX after enfortumab vedotin when given on the same day.	Until disease progression, unacceptable   toxicity, or up to 24 months
Adult patients with HER2-positive   Gastric Cancer	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to trastuzumab and chemotherapy when given on the same day.	Until disease progression, unacceptable   toxicity, or up to 24 months
Adult patients with Cervical Cancer	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemoradiotherapy or prior to chemotherapy with or without bevacizumab when given on the same day.	Until disease progression, unacceptable   toxicity, or for KEYTRUDA QLEX, up to   24 months
Adult patients with RCC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX in combination with axitinib 5 mg orally twice daily When axitinib is used in combination with KEYTRUDA QLEX, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. or Administer KEYTRUDA QLEX in combination with lenvatinib 20 mg orally once daily.	Until disease progression, unacceptable   toxicity, or for KEYTRUDA QLEX, up to   24 months
Adult patients with Endometrial   Carcinoma	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to carboplatin and paclitaxel when given on the same day. or Administer KEYTRUDA QLEX in combination with lenvatinib 20 mg orally once daily.	Until disease progression, unacceptable   toxicity, or for KEYTRUDA QLEX, up to   24 months
Adult patients with high-risk early-stage   TNBC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day.	Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 395 mg/4,800 units every 3 weeks or 4 doses of 790 mg/9,600 units every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA QLEX as a single agent for up to 27 weeks (9 doses of 395 mg/4,800 units every 3 weeks or 5 doses of 790 mg/9,600 units every 6 weeks) or until disease recurrence or unacceptable toxicity Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA QLEX with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA QLEX.
Adult patients with locally recurrent   unresectable or metastatic TNBC	395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day.	Until disease progression, unacceptable   toxicity, or up to 24 months

No dose reduction for KEYTRUDA QLEX is recommended. In general, withhold KEYTRUDA QLEX for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA QLEX 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 QLEX for adverse reactions that require management different from these general guidelines are summarized in Table 2.

The following table represents dosage modifications that are different from those described above for KEYTRUDA QLEX or in the Full Prescribing Information for the drug administered in combination.

Recommended Dose Modifications for Adverse Reactions for KEYTRUDA QLEX in Combination with Lenvatinib

When administering KEYTRUDA QLEX in combination with lenvatinib, modify the dosage of one or both drugs. Withhold or discontinue KEYTRUDA QLEX as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information.

KEYTRUDA QLEX is a clear to slightly opalescent, colorless to slightly yellow solution provided as:

• Injection: 395 mg pembrolizumab and 4,800 units berahyaluronidase alfa per 2.4 mL (165 mg/2,000 units per mL) in a single-dose vial
• Injection: 790 mg pembrolizumab and 9,600 units berahyaluronidase alfa per 4.8 mL (165 mg/2,000 units per mL) in a single-dose vial

KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients.

KEYTRUDA QLEX 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. For patients with TNBC treated with KEYTRUDA QLEX in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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 QLEX depending on severity [see Dosage and Administration (2.4)]. In general, if KEYTRUDA QLEX 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 Pneumonitis

KEYTRUDA QLEX can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving intravenous pembrolizumab, 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 intravenous pembrolizumab in 1.3% (36) of patients and withholding of intravenous pembrolizumab in 0.9% (26) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients.

In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received intravenous pembrolizumab as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of intravenous pembrolizumab in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted intravenous pembrolizumab, 63% discontinued intravenous pembrolizumab, and 71% had resolution.

Immune-Mediated Colitis

KEYTRUDA QLEX 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 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%), and Grade 2 (0.4%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving intravenous pembrolizumab, 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 intravenous pembrolizumab in 0.5% (15) of patients and withholding of intravenous pembrolizumab in 0.5% (13) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA QLEX can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving intravenous pembrolizumab, 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 intravenous pembrolizumab in 0.2% (6) of patients and withholding of intravenous pembrolizumab in 0.3% (9) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients.

In Combination with Axitinib

KEYTRUDA QLEX 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 QLEX 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 QLEX and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.4)].

Intravenous Pembrolizumab in Combination with Axitinib

With the combination of intravenous pembrolizumab 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 intravenous pembrolizumab (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 intravenous pembrolizumab, 16 patients receiving axitinib, and 24 patients receiving both intravenous pembrolizumab and axitinib. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA QLEX 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 QLEX depending on severity [see Dosage and Administration (2.4)].

Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%), and Grade 2 (0.8%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving intravenous pembrolizumab, 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 intravenous pembrolizumab in <0.1% (1) of patients and withholding of intravenous pembrolizumab in 0.3% (8) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement.

Hypophysitis

KEYTRUDA QLEX 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 QLEX depending on severity [see Dosage and Administration (2.4)].

Intravenous Pembrolizumab as a Single Agent

Hypophysitis occurred in 0.6% (17/2799) of patients receiving intravenous pembrolizumab, 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 intravenous pembrolizumab in 0.1% (4) of patients and withholding of intravenous pembrolizumab in 0.3% (7) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement.

Thyroid Disorders

KEYTRUDA QLEX 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 QLEX depending on severity [see Dosage and Administration (2.4)].

Thyroiditis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%). Hyperthyroidism occurred in 8% (20/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (3.2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%).

Intravenous Pembrolizumab as a Single Agent

Thyroiditis occurred in 0.6% (16/2799) of patients receiving intravenous pembrolizumab, including Grade 2 (0.3%). No patients discontinued intravenous pembrolizumab due to thyroiditis. Intravenous pembrolizumab was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of intravenous pembrolizumab in <0.1% (2) of patients and withholding of intravenous pembrolizumab in 0.3% (7) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement.

The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving intravenous pembrolizumab as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.2%) hyperthyroidism.

Hypothyroidism occurred in 8% (237/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of intravenous pembrolizumab in <0.1% (1) of patients and withholding of intravenous pembrolizumab in 0.5% (14) of patients. All patients who were withheld reinitiated intravenous pembrolizumab 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 intravenous pembrolizumab 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 580 patients with resected NSCLC, occurring in 22% of patients receiving intravenous pembrolizumab as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4)].

Type 1 diabetes mellitus occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy.

Intravenous Pembrolizumab as a Single Agent

Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving intravenous pembrolizumab. Type 1 diabetes mellitus led to permanent discontinuation in <0.1% (1) of patients and withholding of intravenous pembrolizumab in <0.1% (1) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy.

Immune-Mediated Nephritis with Renal Dysfunction

KEYTRUDA QLEX can cause immune-mediated nephritis.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving intravenous pembrolizumab, 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 intravenous pembrolizumab in 0.1% (3) of patients and withholding of intravenous pembrolizumab in 0.1% (3) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA QLEX 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 QLEX depending on severity [see Dosage and Administration (2.4)].

Immune-mediated dermatologic adverse reactions occurred in 1.6% (4/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 4 (0.8%), and Grade 3 (0.8%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving intravenous pembrolizumab, 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 intravenous pembrolizumab in 0.1% (2) of patients and withholding of intravenous pembrolizumab in 0.6% (16) of patients. All patients who were withheld reinitiated intravenous pembrolizumab 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 Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA QLEX, intravenous pembrolizumab, 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, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy

Ocular: 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 (2.8%), duodenitis

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica

Endocrine: Hypoparathyroidism

Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection

KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. In Study MK-3475A-D77, hypersensitivity and administration-related systemic reactions occurred in 3.2% (8/251) of patients receiving KEYTRUDA QLEX, including Grade 2 (2.8%). Monitor patients for signs and symptoms of administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate hypersensitivity and administration-related systemic reactions. For severe or life-threatening hypersensitivity and administration-related systemic reactions, stop injection and permanently discontinue KEYTRUDA QLEX [see Dosage and Administration (2.4)].

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 Melanoma

The safety of intravenous pembrolizumab 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 intravenous pembrolizumab 10 mg/kg every 2 weeks (n=278) or intravenous pembrolizumab 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 (14.2)]. 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 intravenous pembrolizumab and similar in both treatment arms. Fifty-one and 46% of patients received intravenous pembrolizumab 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 intravenous pembrolizumab arms. Adverse reactions leading to permanent discontinuation of intravenous pembrolizumab occurred in 9% of patients. Adverse reactions leading to discontinuation of intravenous pembrolizumab 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 intravenous pembrolizumab occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 6 and 7 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-006.

Other clinically important adverse reactions occurring in ≥10% of patients receiving intravenous pembrolizumab were diarrhea (26%), nausea (21%), and pruritus (17%).

Other laboratory abnormalities occurring in ≥20% of patients receiving intravenous pembrolizumab 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 Melanoma

The safety of intravenous pembrolizumab 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 (intravenous pembrolizumab dose), randomized (1:1:1), active-controlled trial in which 528 patients received intravenous pembrolizumab 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 (14.2)]. 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 intravenous pembrolizumab 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to intravenous pembrolizumab 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the intravenous pembrolizumab 2 mg/kg arm, 36% of patients were exposed to intravenous pembrolizumab for ≥6 months and 4% were exposed for ≥12 months. In the 10 mg/kg arm, 41% of patients were exposed to intravenous pembrolizumab for ≥6 months and 6% of patients were exposed to intravenous pembrolizumab 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 intravenous pembrolizumab arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving intravenous pembrolizumab; 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 intravenous pembrolizumab occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-002.

Other clinically important adverse reactions occurring in patients receiving intravenous pembrolizumab were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).

Other laboratory abnormalities occurring in ≥20% of patients receiving intravenous pembrolizumab were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma

Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.2)] treated with intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent.

Adjuvant Treatment of Stage III Resected Melanoma

The safety of intravenous pembrolizumab 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 intravenous pembrolizumab by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.2)]. 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving intravenous pembrolizumab; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of intravenous pembrolizumab 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 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-054.

NSCLC

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy

The safety of intravenous pembrolizumab 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 (14.3)]. A total of 607 patients received intravenous pembrolizumab 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by intravenous pembrolizumab 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 intravenous pembrolizumab 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab 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.

Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-189.

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy

The safety of intravenous pembrolizumab 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 (14.3)]. Safety data are available for the first 203 patients who received intravenous pembrolizumab 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 intravenous pembrolizumab was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab 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.

Intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

Previously Untreated NSCLC

The safety of intravenous pembrolizumab 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 (14.3)]. Patients received intravenous pembrolizumab 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 intravenous pembrolizumab was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab 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.

Intravenous pembrolizumab was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-042.

Previously Treated NSCLC

The safety of intravenous pembrolizumab 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 (14.3)]. A total of 991 patients received intravenous pembrolizumab 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 intravenous pembrolizumab 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to intravenous pembrolizumab 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to intravenous pembrolizumab 2 mg/kg in 31% of patients exposed to intravenous pembrolizumab for ≥6 months. In the intravenous pembrolizumab 10 mg/kg arm, 34% of patients were exposed to intravenous pembrolizumab 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. The most common adverse events resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.8%). Adverse reactions leading to interruption of intravenous pembrolizumab 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 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-010.

Other clinically important adverse reactions occurring in patients receiving intravenous pembrolizumab were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).

Other laboratory abnormalities occurring in ≥20% of patients receiving intravenous pembrolizumab 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 (32% 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).

Neoadjuvant and Adjuvant Treatment of Resectable NSCLC

The safety of intravenous pembrolizumab in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with intravenous pembrolizumab as a single agent after surgery was investigated in KEYNOTE-671, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition [see Clinical Studies (14.3)]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible.

The median duration of exposure to intravenous pembrolizumab 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino.

Adverse reactions occurring in patients with resectable NSCLC receiving intravenous pembrolizumab in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving intravenous pembrolizumab in combination with chemotherapy.

Neoadjuvant Phase of KEYNOTE-671

A total of 396 patients received at least 1 dose of intravenous pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.

Serious adverse reactions occurred in 34% of patients who received intravenous pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%).

Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received intravenous pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).

Of the 396 intravenous pembrolizumab-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n=25) and 4.3% (n=17), respectively, did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reactions that led to cancellation of surgery in the intravenous pembrolizumab arm was interstitial lung disease (1%).

Of the 325 intravenous pembrolizumab-treated patients who received surgery, 3.1% (n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 2.5% (n=8) experienced delay of surgery due to adverse reactions.

Of the 325 intravenous pembrolizumab-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 3.2% (n=10) did not receive adjuvant treatment due to adverse reactions.

Adjuvant Phase of KEYNOTE-671

A total of 290 patients in the intravenous pembrolizumab arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment.

Of the patients who received single agent intravenous pembrolizumab as adjuvant treatment, 14% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of adjuvant intravenous pembrolizumab due to an adverse reaction occurred in 12% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous pembrolizumab were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%).

Adjuvant Treatment of Resected NSCLC

The safety of intravenous pembrolizumab as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.3)]. A total of 1161 patients received intravenous pembrolizumab 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis.

The median duration of exposure to intravenous pembrolizumab was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months.

The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving intravenous pembrolizumab as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.

Malignant Pleural Mesothelioma (MPM)

First-line treatment of unresectable advanced or metastatic MPM with pemetrexed and platinum chemotherapy

The safety of intravenous pembrolizumab in combination with pemetrexed and platinum chemotherapy (either carboplatin or cisplatin) was investigated in KEYNOTE-483, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with previously untreated, unresectable advanced or metastatic MPM [see Clinical Studies (14.4)]. A total of 473 patients received intravenous pembrolizumab 200 mg, pemetrexed, and platinum every 3 weeks for up to 6 cycles followed by intravenous pembrolizumab (n=241), or pemetrexed and platinum chemotherapy every 3 weeks for up to 6 cycles (n=232). Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible.

The median duration of exposure to intravenous pembrolizumab 200 mg every 3 weeks was 6.9 months (range: 1 day to 25.2 months). Sixty-one percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months.

Adverse reactions occurring in patients with MPM were generally similar to those in other patients receiving intravenous pembrolizumab in combination with pemetrexed and platinum chemotherapy.

HNSCC

First-line treatment of metastatic or unresectable, recurrent HNSCC

The safety of intravenous pembrolizumab, 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 (14.5)]. 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 intravenous pembrolizumab 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 intravenous pembrolizumab, 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 intravenous pembrolizumab was 3.5 months (range: 1 day to 24.2 months) in the intravenous pembrolizumab 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 intravenous pembrolizumab single agent arm and 18% of patients in the combination arm were exposed to intravenous pembrolizumab for ≥12 months. Fifty-seven percent of patients receiving intravenous pembrolizumab in combination with chemotherapy started treatment with carboplatin.

Intravenous pembrolizumab was discontinued for adverse reactions in 12% of patients in the intravenous pembrolizumab single agent arm. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 31% of patients; the most common adverse reactions leading to interruption of intravenous pembrolizumab (≥2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%).

Intravenous pembrolizumab was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 45% of patients; the most common adverse reactions leading to interruption of intravenous pembrolizumab (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).

Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-048.

Previously treated recurrent or metastatic HNSCC

Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.5)], the median duration of exposure to intravenous pembrolizumab 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.

Intravenous pembrolizumab was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. 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 intravenous pembrolizumab 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)].

Urothelial Cancer

Patients with urothelial cancer in combination with enfortumab vedotin

The safety of intravenous pembrolizumab in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14.6)]. A total of 440 patients received intravenous pembrolizumab 200 mg on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. Among patients who received intravenous pembrolizumab and enfortumab vedotin, the median duration of exposure to intravenous pembrolizumab was 8.5 months (range: 9 days to 28.5 months).

Fatal adverse reactions occurred in 3.9% of patients treated with intravenous pembrolizumab in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).

Permanent discontinuation of intravenous pembrolizumab occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis/ILD (4.8%) and rash (3.4%).

Dose interruptions of intravenous pembrolizumab occurred in 61% of patients. The most common adverse reactions (≥2%) resulting in interruption of intravenous pembrolizumab were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%).

Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39.

Clinically relevant adverse reactions (<20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/ILD (10%), hypothyroidism (10%), blurred vision (6%), infusion site extravasation (2%), and myositis (0.5%).

Cisplatin-ineligible patients with urothelial cancer in combination with enfortumab vedotin

The safety of intravenous pembrolizumab in combination with enfortumab vedotin was investigated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial cancer and who are not eligible for cisplatin-based chemotherapy [see Clinical Studies (14.6)]. A total of 121 patients received intravenous pembrolizumab 200 mg on Day 1, and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle. The median duration of exposure to intravenous pembrolizumab was 6.9 months (range 1 day to 29.6 months).

Fatal adverse reactions occurred in 5% of patients treated with intravenous pembrolizumab in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%).

Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab and enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%).

Permanent discontinuation of intravenous pembrolizumab occurred in 32% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%).

Dose interruptions of intravenous pembrolizumab occurred in 69% of patients. The most common adverse reactions (≥2%) resulting in interruption of intravenous pembrolizumab were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), lipase increased (5%), acute kidney injury (3.3%), ALT increased (2.5%), and COVID-19 (2.5%).

Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-869.

Clinically relevant adverse reactions (<20%) include vomiting (19.8%), fever (18%), hypothyroidism (11%), pneumonitis/ILD (10%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%).

Platinum-Ineligible Patients with Urothelial Carcinoma

The safety of intravenous pembrolizumab was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.6)]. Patients received intravenous pembrolizumab 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression.

The median duration of exposure to intravenous pembrolizumab was 2.8 months (range: 1 day to 15.8 months).

Intravenous pembrolizumab 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 intravenous pembrolizumab experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of intravenous pembrolizumab 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 intravenous pembrolizumab in KEYNOTE-052.

Previously Treated Urothelial Carcinoma

The safety of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.

Intravenous pembrolizumab was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.9%). Adverse reactions leading to interruption of intravenous pembrolizumab 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 intravenous pembrolizumab-treated patients. The most frequent serious adverse reactions (≥2%) in intravenous pembrolizumab-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-045.

BCG-unresponsive High-risk NMIBC

The safety of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab was 4.3 months (range: 1 day to 25.6 months).

Intravenous pembrolizumab was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of intravenous pembrolizumab-treated patients. The most frequent serious adverse reactions (≥2%) in intravenous pembrolizumab-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 intravenous pembrolizumab in KEYNOTE-057.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

The safety of intravenous pembrolizumab was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.7)]. The median duration of exposure to intravenous pembrolizumab was 6.2 months (range: 1 day to 53.5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received intravenous pembrolizumab as a single agent.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

Among the 153 patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies (14.8)] treated with intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent.

Gastric Cancer

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma

The safety of intravenous pembrolizumab was evaluated in 696 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 350 patients treated with intravenous pembrolizumab 200 mg, trastuzumab, and CAPOX (n=297) or FP (n=53) every 3 weeks, compared to 346 patients treated with placebo, trastuzumab, and CAPOX (n=298) or FP (n=48) every 3 weeks [see Clinical Studies (14.10)].

The median duration of exposure to intravenous pembrolizumab was 9.2 months (range: 1 day to 33.6 months).

Fatal adverse reactions occurred in 3 patients who received intravenous pembrolizumab in combination with trastuzumab and CAPOX or FP and included pneumonitis in 2 patients and hepatitis in 1 patient.

Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. Adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%).

Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 71% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (7%), pneumonia (5%), anemia (4.9%), COVID-19 (3.1%), hypokalemia (3.1%), fatigue/asthenia (4.9%), decreased appetite (4%), increased AST (3.7%), increased blood bilirubin (4.6%), increased ALT (2.9%), vomiting (2.6%), pneumonitis (2.3%), pyrexia (2.3%), increased blood creatinine (2%), and colitis (2%).

In the intravenous pembrolizumab arm versus placebo, there was a difference of ≥5% incidence between patients treated with intravenous pembrolizumab versus standard of care for diarrhea (53% vs. 47%), rash (35% vs. 28%), hypothyroidism (11% vs. 5%), and pneumonia (11% vs. 5%). 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 intravenous pembrolizumab versus standard of care for decreased leukocytes (60% vs. 54%), decreased calcium (56% vs. 46%), decreased lymphocytes (59% vs. 51%), decreased potassium (41% vs. 36%), increased bilirubin (33% vs. 25%), increased creatinine (28% vs. 18%), and decreased glucose (17% vs. 11%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma

The safety of intravenous pembrolizumab was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with intravenous pembrolizumab 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, compared to 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Clinical Studies (14.9)].

The median duration of exposure to intravenous pembrolizumab was 6.2 months (range: 1 day to 33.7 months).

Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received intravenous pembrolizumab, including infection (2.3%) and thromboembolism (1.3%).

Permanent discontinuation of intravenous pembrolizumab due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab in ≥1% were infections (1.8%) and diarrhea (1.0%).

Dosage interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%).

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-859.

Esophageal Cancer

First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal Junction

The safety of intravenous pembrolizumab, 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 intravenous pembrolizumab 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 intravenous pembrolizumab combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm.

Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 67% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥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 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-590.

Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer

Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.10)] treated with intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent.

Cervical Cancer

FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy

The safety of intravenous pembrolizumab in combination with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18, a placebo-controlled, randomized (1:1), multicenter, double-blind trial including 597 patients with FIGO 2014 Stage III-IVA cervical cancer [see Clinical Studies (14.11)]. Two hundred ninety-four patients received intravenous pembrolizumab in combination with chemoradiotherapy and 303 patients received placebo in combination with chemoradiotherapy.

The median duration of exposure to intravenous pembrolizumab was 20 months (range: 1 day to 32 months).

Fatal adverse reactions occurred in 1.4% of patients receiving intravenous pembrolizumab in combination with chemoradiotherapy, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage.

Serious adverse reactions occurred in 34% of patients receiving intravenous pembrolizumab in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥1% of patients included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%).

Intravenous pembrolizumab was discontinued for adverse reactions in 9% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%).

Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 47% of patients; the most common adverse reactions leading to interruption of intravenous pembrolizumab (≥2%) were anemia (7%), COVID-19 (7%), SARS-CoV-2 test positive (4.8%), diarrhea (4.1%), increased ALT (4.1%), increased AST (3.4%) decreased neutrophil count (3.1%), and urinary tract infection (2.7%).

Table 33 and Table 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-A18.

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of intravenous pembrolizumab in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies (14.11)]. A total of 616 patients, regardless of tumor PD-L1 expression, received intravenous pembrolizumab 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks.

The median duration of exposure to intravenous pembrolizumab was 9.9 months (range: 1 day to 26 months).

Fatal adverse reactions occurred in 4.6% of patients receiving intravenous pembrolizumab in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.

Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%).

Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) was colitis (1%).

Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%).

For patients treated with intravenous pembrolizumab, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

Table 35 and Table 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-826.

Previously Treated Recurrent or Metastatic Cervical Cancer

Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.11)], the median duration of exposure to intravenous pembrolizumab was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Intravenous pembrolizumab was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving intravenous pembrolizumab. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 37 and 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-158.

Other laboratory abnormalities occurring in ≥10% of patients receiving intravenous pembrolizumab were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (17% 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 (10% 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).

HCC

Previously Treated HCC

The safety of intravenous pembrolizumab was investigated in KEYNOTE-394, a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients with previously treated HCC. Patients were randomized (2:1) and received intravenous pembrolizumab 200 mg (n=299) or placebo (n=153) intravenously every 3 weeks for up to 35 cycles [see Clinical Studies (14.12)].

The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the intravenous pembrolizumab arm and 2.2 months (range: 1 day to 15.5 months) in the placebo arm. Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab was ascites (2.3%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%).

Tables 39 and 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-394.

BTC

The safety of intravenous pembrolizumab in combination with gemcitabine and cisplatin, was investigated in KEYNOTE-966, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting [see Clinical Studies (14.13)]. A total of 1063 patients received either intravenous pembrolizumab 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks.

The median duration of exposure to intravenous pembrolizumab was 6 months (range: 1 day to 28 months).

Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) was pneumonitis (1.3%).

Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).

In the intravenous pembrolizumab plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients treated with intravenous pembrolizumab versus placebo for pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of ≥5% incidence in laboratory abnormalities between patients treated with intravenous pembrolizumab plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

MCC

Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.14)], the median duration of exposure to intravenous pembrolizumab was 6.3 months (range 1 day to 28 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 intravenous pembrolizumab as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%).

RCC

In combination with axitinib in the first-line treatment of advanced RCC (KEYNOTE-426)

The safety of intravenous pembrolizumab in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.15)]. 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab or axitinib occurred in 31% of patients; 13% intravenous pembrolizumab only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of intravenous pembrolizumab, 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 intravenous pembrolizumab infusions due to infusion-related reactions, occurred in 76% of patients receiving intravenous pembrolizumab in combination with axitinib. This includes interruption of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with intravenous pembrolizumab and axitinib in KEYNOTE-426.

In combination with lenvatinib in the first-line treatment of advanced RCC (KEYNOTE-581)

The safety of intravenous pembrolizumab was evaluated in KEYNOTE-581 [see Clinical Studies (14.15)]. Patients received intravenous pembrolizumab 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340). The median duration of exposure to the combination therapy of intravenous pembrolizumab and lenvatinib was 17 months (range: 0.1 to 39).

Fatal adverse reactions occurred in 4.3% of patients treated with intravenous pembrolizumab in combination with lenvatinib, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage.

Serious adverse reactions occurred in 51% of patients receiving intravenous pembrolizumab and lenvatinib. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).

Permanent discontinuation of either of intravenous pembrolizumab, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving intravenous pembrolizumab in combination with lenvatinib; 29% intravenous pembrolizumab only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of intravenous pembrolizumab, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Dose interruptions of intravenous pembrolizumab, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving intravenous pembrolizumab in combination with lenvatinib. Intravenous pembrolizumab was interrupted in 55% of patients and both drugs were interrupted in 39% of patients. The most common adverse reactions (≥3%) resulting in interruption of intravenous pembrolizumab were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%).

Fifteen percent (15%) of patients treated with intravenous pembrolizumab in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with intravenous pembrolizumab and lenvatinib in KEYNOTE-581.

Clinically relevant adverse reactions (<20%) that occurred in patients receiving intravenous pembrolizumab with lenvatinib were myocardial infarction (3%) and angina pectoris (1%).

Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both intravenous pembrolizumab and lenvatinib (n=38) and was not observed on rechallenge with intravenous pembrolizumab alone (n=3).

Adjuvant treatment of RCC

The safety of intravenous pembrolizumab as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of intravenous pembrolizumab by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.15)]. The median duration of exposure to intravenous pembrolizumab was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Serious adverse reactions occurred in 20% of these patients receiving intravenous pembrolizumab. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with intravenous pembrolizumab, including one case of pneumonia.

Discontinuation of intravenous pembrolizumab due to an adverse reaction occurred in 21% of patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).

Dose interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 26% of patients; the most common (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each).

Tables 45 and 46 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-564.

Endometrial Carcinoma

Primary Advanced or Recurrent Endometrial Carcinoma

The safety of intravenous pembrolizumab in combination with chemotherapy (paclitaxel and carboplatin) was investigated in KEYNOTE-868, a randomized (1:1), multicenter, double-blind, placebo-controlled trial that enrolled patients with advanced or recurrent endometrial carcinoma [see Clinical Studies (14.16)]. A total of 759 patients received intravenous pembrolizumab 200 mg every 3 weeks and chemotherapy for 6 cycles followed by intravenous pembrolizumab 400 mg every 6 weeks for up to 14 cycles (n=382) or placebo and chemotherapy for 6 cycles followed by placebo for up to 14 cycles (n=377). The median duration of exposure to intravenous pembrolizumab was 5.6 months (range: 1 day to 24.0 months).

Serious adverse reactions occurred in 35% of patients receiving intravenous pembrolizumab in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy.

Fatal adverse reactions occurred in 1.6% of patients receiving intravenous pembrolizumab in combination with chemotherapy, including COVID-19 (0.5%), and cardiac arrest (0.3%).

Intravenous pembrolizumab was discontinued for an adverse reaction in 14% of patients. Chemotherapy dose reduction was required in 29% of patients receiving intravenous pembrolizumab in combination with chemotherapy, compared to 23% of patients receiving placebo in combination with chemotherapy. There were no clinically meaningful differences in chemotherapy discontinuations or interruptions between arms.

Adverse reactions occurring in patients treated with intravenous pembrolizumab and chemotherapy were generally similar to those observed with intravenous pembrolizumab alone or chemotherapy alone with the exception of rash (33% all Grades; 2.9% Grades 3-4).

In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H.

The safety of intravenous pembrolizumab in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.16)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received intravenous pembrolizumab 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325).

For patients with pMMR or not MSI-H tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to intravenous pembrolizumab was 6.8 months (range: 1 day to 25.8 months).

Fatal adverse reactions among these patients occurred in 4.7% of those treated with intravenous pembrolizumab and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.

Serious adverse reactions occurred in 50% of these patients receiving intravenous pembrolizumab and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%).

Discontinuation of intravenous pembrolizumab due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of intravenous pembrolizumab (≥1%) was increased ALT (1.2%).

Dose interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%).

Tables 47 and 48 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with lenvatinib in KEYNOTE-775.

As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma

Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.16)] treated with intravenous pembrolizumab as a single agent, the median duration of exposure to intravenous pembrolizumab was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent.

TMB-H Cancer

The safety of intravenous pembrolizumab was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.17)]. The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent.

cSCC

Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.18)], the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).

TNBC

Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC

The safety of intravenous pembrolizumab in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with intravenous pembrolizumab as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC.

A total of 778 patients on the intravenous pembrolizumab arm received at least 1 dose of intravenous pembrolizumab in combination with neoadjuvant chemotherapy followed by intravenous pembrolizumab as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies (14.19)].

The median duration of exposure to intravenous pembrolizumab 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months).

Fatal adverse reactions occurred in 0.9% of patients receiving intravenous pembrolizumab, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction.

Serious adverse reactions occurred in 44% of patients receiving intravenous pembrolizumab. Serious adverse reactions in ≥2% of patients who received intravenous pembrolizumab included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of intravenous pembrolizumab were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 57% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%).

Tables 49 and 50 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-522.

Locally Recurrent Unresectable or Metastatic TNBC

The safety of intravenous pembrolizumab 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 (14.19)]. A total of 596 patients (including 34 patients from a safety run-in) received intravenous pembrolizumab 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin.

The median duration of exposure to intravenous pembrolizumab was 5.7 months (range: 1 day to 33.0 months).

Fatal adverse reactions occurred in 2.5% of patients receiving intravenous pembrolizumab in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%).

Serious adverse reactions occurred in 30% of patients receiving intravenous pembrolizumab 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%).

Intravenous pembrolizumab was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 50% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥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 51 and 52 summarize the adverse reactions and laboratory abnormalities in patients on intravenous pembrolizumab in KEYNOTE-355.

Risk Summary

Based on its mechanism of action [see Clinical Pharmacology (12.1)], KEYTRUDA QLEX 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 to 4% and 15 to 20%, respectively.

Data

Animal Data

KEYTRUDA QLEX for subcutaneous injection contains pembrolizumab and berahyaluronidase alfa [see Description (11)].

Pembrolizumab:

Animal reproduction studies have not been conducted with pembrolizumab 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 pembrolizumab 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.

Berahyaluronidase alfa:

In an embryo-fetal development study, pregnant rabbits were administered daily subcutaneous injections of 138,600, 403,200, or 1,209,600 U/kg berahyaluronidase alfa during the period of organogenesis (gestation days 6 to 19). Berahyaluronidase alfa caused delayed fetal development at doses ≥403,200 U/kg, which is >2,500 times higher than the human dose (U/kg basis). Increased post-implantation loss and visceral malformations (supernumerary fissure lung lobe) were observed at 1,209,600 U/kg, which is >7,500 times higher than the human dose. In an embryo-fetal development study in rats, there were no adverse embryo-fetal findings in pregnant animals administered daily subcutaneous injections of berahyaluronidase alfa at doses up to 2,520,000 U/kg (>15,000 times higher than the human dose) during the period of organogenesis (gestation days 6 to 17).

In a pre- and post-natal development study in rats, pregnant animals were administered daily subcutaneous injections of 280,000, 840,000, or 2,520,000 U/kg berahyaluronidase alfa from implantation through lactation and weaning (gestation day 6 to lactation day 21). There were no adverse effects on sexual maturation, learning and memory, or fertility of the offspring at doses up to 2,520,000 U/kg, which is >15,000 times higher than the human dose.

Risk Summary

There are no data on the presence of pembrolizumab or berahyaluronidase alfa in either animal or human milk or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk.

The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to KEYTRUDA QLEX are unknown. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA QLEX and for 4 months after the last dose.

Based on its mechanism of action, KEYTRUDA QLEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

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

Contraception

Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA QLEX and for 4 months after the last dose.

Ipilimumab-Naive Melanoma

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab as compared to ipilimumab. Among the 91 patients randomized to intravenous pembrolizumab 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 intravenous pembrolizumab 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 53 and Figure 1.

Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006

Based on the final analysis with an additional follow-up of 9 months (total of 383 deaths as pre-specified in the protocol)

Figure 1 (Keytruda Qlex 01)

Ipilimumab-Refractory Melanoma

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab in a blinded fashion or investigator's choice chemotherapy. The treatment arms consisted of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab. 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 intravenous pembrolizumab as compared to control arm. There was no statistically significant difference between intravenous pembrolizumab 2 mg/kg and chemotherapy or between intravenous pembrolizumab 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 intravenous pembrolizumab. Among the 38 patients randomized to intravenous pembrolizumab 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to intravenous pembrolizumab 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 54 and Figure 2.

Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002

Figure 2 (Keytruda Qlex 02)

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma

The efficacy of intravenous pembrolizumab was investigated in KEYNOTE-716 (NCT03553836), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected Stage IIB or IIC melanoma. Patients were randomized to intravenous pembrolizumab 200 mg or the pediatric (≥12 years old) dose of intravenous pembrolizumab 2 mg/kg intravenously (up to a maximum of 200 mg) every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by AJCC 8^th edition T Stage (>2.0-4.0 mm with ulceration vs. >4.0 mm without ulceration vs. >4.0 mm with ulceration). Patients must not have been previously treated for melanoma beyond complete surgical resection for their melanoma prior to study entry. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) (defined as the time between the date of randomization and the date of first recurrence [local, in-transit or regional lymph nodes or distant recurrence] or death, whichever occurred first). New primary melanomas were excluded from the definition of RFS. Distant metastasis-free survival (DMFS), defined as a spread of tumor to distant organs or distant lymph nodes, was an additional efficacy outcome measure. Patients underwent imaging every six months for one year from randomization, every 6 months from years 2 to 4, and then once in year 5 from randomization or until recurrence, whichever came first.

The study population characteristics were: median age of 61 years (range: 16 to 87), 39% age 65 or older; 60% male; 98% White; and 93% ECOG PS of 0 and 7% ECOG PS of 1. Sixty-four percent had Stage IIB and 35% had Stage IIC.

The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomized to the intravenous pembrolizumab arm compared with placebo. Efficacy results are summarized in Table 55 and Figure 3.

Figure 3: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-716

Figure 3 (Keytruda Qlex 03)

Adjuvant Treatment of Stage III Resected Melanoma

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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 7^th 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. New primary melanomas were excluded from the definition of RFS. DMFS in the whole population and in the population with PD-L1 positive tumors were additional efficacy outcome measures. DMFS was defined as a spread of tumor to distant organs or distant lymph nodes. Patients underwent imaging every 12 weeks after the first dose of intravenous pembrolizumab 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 and DMFS for patients randomized to the intravenous pembrolizumab arm compared with placebo. Efficacy results are summarized in Table 56 and Figure 4.

For patients with PD-L1 positive tumors, the RFS HR was 0.54 (95% CI: 0.42, 0.69); p<0.0001. For patients with PD-L1 positive tumors, the DMFS HR was 0.61 (95% CI: 0.49, 0.76); p<0.0001. The RFS and DMFS benefit for intravenous pembrolizumab compared to placebo was observed regardless of tumor PD-L1 expression.

Figure 4: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-054

Figure 4 (Keytruda Qlex 04)

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy

The efficacy of intravenous pembrolizumab 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:

• Intravenous pembrolizumab 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 intravenous pembrolizumab 200 mg and pemetrexed 500 mg/m² intravenously every 3 weeks.
• 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 57 and Figure 5 summarize the efficacy results for KEYNOTE-189.

Table 57: Efficacy Results in KEYNOTE-189

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=410	Placebo Pemetrexed Platinum Chemotherapy n=206
NR = not reached
OS
Number (%) of patients with event	127 (31%)	108 (52%)
Median in months (95% CI)	NR (NR, NR)	11.3 (8.7, 15.1)
Hazard ratio Based on the stratified Cox proportional hazard model (95% CI)	0.49 (0.38, 0.64)
p-Value Based on a stratified log-rank test	<0.0001
PFS
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	<0.0001
Objective Response Rate
ORR Response: Best objective response as confirmed complete response or partial response (95% CI)	48% (43, 53)	19% (14, 25)
Complete response	0.5%	0.5%
Partial response	47%	18%
p-Value Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status	<0.0001
Duration 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 intravenous pembrolizumab 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 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189

Based on the protocol-specified final OS analysis

Figure 5 (Keytruda Qlex 05)

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy

The efficacy of intravenous pembrolizumab 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:

• Intravenous pembrolizumab 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 intravenous pembrolizumab 200 mg every 3 weeks.
• 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 58 and Figure 6 summarize the efficacy results for KEYNOTE-407.

Table 58: Efficacy Results in KEYNOTE-407

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks Carboplatin Paclitaxel/Paclitaxel protein-bound n=278	Placebo Carboplatin Paclitaxel/Paclitaxel protein-bound n=281
NE = not estimable
OS
Number of events (%)	85 (31%)	120 (43%)
Median in months (95% CI)	15.9 (13.2, NE)	11.3 (9.5, 14.8)
Hazard ratio Based on the stratified Cox proportional hazard model (95% CI)	0.64 (0.49, 0.85)
p-Value Based on a stratified log-rank test	0.0017
PFS
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	<0.0001
	n=101	n=103
Objective Response Rate ORR 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-Value Based on a stratified Miettinen-Nurminen test	0.0008
Duration 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 intravenous pembrolizumab 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 6: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

Based on the protocol-specified final OS analysis

Figure 6 (Keytruda Qlex 06)

First-line treatment of metastatic NSCLC with PD-L1 expression (TPS ≥1%) as a single agent

KEYNOTE-042

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with intravenous pembrolizumab 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 intravenous pembrolizumab as compared with chemotherapy. Table 59 and Figure 7 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%.

Table 59: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042

	TPS ≥1%		TPS ≥50%
Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks	Chemotherapy	Intravenous Pembrolizumab 200 mg every 3 weeks	Chemotherapy
	n=637	n=637	n=299	n=300
OS
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 ratio Based on the stratified Cox proportional hazard model (95% CI)	0.81 (0.71, 0.93)		0.69 (0.56, 0.85)
p-Value Based on a stratified log-rank test; compared to a p-Value boundary of 0.0291	0.0036		0.0006
PFS
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	-		NS Not significant compared to a p-Value boundary of 0.0291
Objective Response Rate
ORR (95% CI)	27% (24, 31)	27% (23, 30)	39% (33.9, 45.3)	32% (26.8, 37.6)
Complete response rate	0.5%	0.5%	0.7%	0.3%
Partial response rate	27%	26%	39%	32%
Duration of Response
% with duration ≥12 months Based on observed duration of response	47%	16%	42%	17%
% with duration ≥18 months	26%	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 7: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%)

Figure 7 (Keytruda Qlex 07)

KEYNOTE-024

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab at the time of disease progression.

The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to intravenous pembrolizumab as compared with chemotherapy. Table 60 and Figure 8 summarize the efficacy results for KEYNOTE-024.

Table 60: Efficacy Results in KEYNOTE-024

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks	Chemotherapy
	n=154	n=151
NR = not reached
PFS
Number (%) of patients with event	73 (47%)	116 (77%)
Median in months (95% CI)	10.3 (6.7, NR)	6.0 (4.2, 6.2)
Hazard ratio Based on the stratified Cox proportional hazard model for the interim analysis (95% CI)	0.50 (0.37, 0.68)
p-Value (stratified log-rank)	<0.001
OS
Number (%) of patients with event	44 (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)	0.005 p-Value is compared with 0.0118 of the allocated alpha for the interim analysis
Objective Response Rate
ORR (95% CI)	45% (37, 53)	28% (21, 36)
Complete response rate	4%	1%
Partial response rate	41%	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 8: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024

Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.

Figure 8 (Keytruda Qlex 08)

Previously treated NSCLC with PD-L1 expression (TPS ≥1%)

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 2 mg/kg intravenously every 3 weeks, intravenous pembrolizumab 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 intravenous pembrolizumab 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 61 and 62 and Figure 9 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively.

Table 61: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010

Endpoint	Intravenous Pembrolizumab 2 mg/kg every 3 weeks n=139	Intravenous Pembrolizumab 10 mg/kg every 3 weeks n=151	Docetaxel 75 mg/m2 every 3 weeks n=152
NR = not reached
OS
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 ratio Hazard ratio (intravenous pembrolizumab 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
ORR All 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 62: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010

Endpoint	Intravenous Pembrolizumab 2 mg/kg every 3 weeks n=344	Intravenous Pembrolizumab 10 mg/kg every 3 weeks n=346	Docetaxel 75 mg/m2 every 3 weeks n=343
NR = not reached
OS
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 ratio Hazard ratio (intravenous pembrolizumab 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)	0.068	0.005	---
Objective Response Rate
ORR All 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 9: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%)

Figure 9 (Keytruda Qlex 09)

Neoadjuvant and adjuvant treatment of resectable NSCLC

The efficacy of intravenous pembrolizumab in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with intravenous pembrolizumab as a single agent was investigated in KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial conducted in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8^th edition. Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or a history of interstitial lung disease or pneumonitis that required steroids were ineligible. Randomization was stratified by stage (II vs. III), tumor PD-L1 expression (TPS ≥50% or <50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia).

Patients were randomized (1:1) to one of the following treatment arms:

• Treatment Arm A: neoadjuvant intravenous pembrolizumab 200 mg on Day 1 in combination with cisplatin 75 mg/m² and either pemetrexed 500 mg/m² on Day 1 or gemcitabine 1000 mg/m² on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, intravenous pembrolizumab 200 mg was administered every 3 weeks for up to 13 cycles.
• Treatment Arm B: neoadjuvant placebo on Day 1 in combination with cisplatin 75 mg/m² and either pemetrexed 500 mg/m² on Day 1 or gemcitabine 1000 mg/m² on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, placebo was administered every 3 weeks for up to 13 cycles.

All study medications were administered via intravenous infusion. Treatment with intravenous pembrolizumab or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumor status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumor status was performed every 16 weeks through the end of Year 3, and then every 6 months thereafter.

The trial was not designed to isolate the effect of intravenous pembrolizumab in each phase (neoadjuvant or adjuvant) of treatment.

The major efficacy outcome measures were OS and investigator-assessed event-free survival (EFS). Additional efficacy outcome measures were pathological complete response (pCR) rate and major pathological response (mPR) rate as assessed by blinded independent pathology review.

The study population characteristics were: median age of 64 years (range: 26 to 83); 45% age 65 or older and 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino; 63% ECOG PS of 0 and 37% ECOG PS of 1. Thirty percent had Stage II and 70% had Stage III disease; 33% had TPS ≥50% and 67% had TPS <50%; 43% had tumors with squamous histology and 57% had tumors with non-squamous histology; 31% were from the East Asian region.

Eighty-one percent of patients in the intravenous pembrolizumab in combination with platinum-containing chemotherapy arm received definitive surgery compared to 76% of patients in the placebo in combination with platinum-containing chemotherapy arm.

The trial demonstrated statistically significant improvements in OS and EFS for patients randomized to intravenous pembrolizumab in combination with platinum-containing chemotherapy followed by intravenous pembrolizumab as a single agent compared with patients randomized to placebo in combination with platinum-containing chemotherapy followed by placebo alone.

Table 63 and Figure 10 summarize the efficacy results for KEYNOTE-671.

Table 63: Efficacy Results in KEYNOTE-671

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy/Intravenous Pembrolizumab n=397	Placebo with chemotherapy/Placebo n=400
NR = not reached
OS
Number of patients with event (%)	110 (28%)	144 (36%)
Median in months Based on Kaplan-Meier estimates (95% CI)	NR (NR, NR)	52.4 (45.7, NR)
Hazard ratio Based on Cox regression model with treatment as a covariate stratified by stage, tumor PD-L1 expression, histology, and geographic region (95% CI)	0.72 (0.56, 0.93)
p-Value Based on stratified log-rank test , Compared to a two-sided p-Value boundary of 0.0109	0.0103
EFS
Number of patients with event (%)	139 (35%)	205 (51%)
Median in months (95% CI)	NR (34.1, NR)	17.0 (14.3, 22.0)
Hazard ratio (95% CI)	0.58 (0.46, 0.72)
p-Value, Compared to a two-sided p-Value boundary of 0.0092	<0.0001

Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-671

Figure 10 (Keytruda Qlex 10)

The trial demonstrated a statistically significant difference in pCR rate (18.1% vs. 4.0%; p<0.0001) and mPR rate (30.2% vs. 11.0%; p<0.0001).

Adjuvant treatment of resected NSCLC

The efficacy of intravenous pembrolizumab was investigated in KEYNOTE-091 (NCT02504372), a multicenter, randomized, triple-blind, placebo-controlled trial conducted in 1177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC by AJCC 7th edition. Patients had not received neoadjuvant radiotherapy or chemotherapy. Adjuvant chemotherapy up to 4 cycles was optional. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. Randomization was stratified by stage (IB vs. II vs. IIIA), receipt of adjuvant chemotherapy (yes vs. no), PD-L1 status (TPS <1% [negative] vs. TPS 1-49% vs. TPS ≥50%), and geographic region (Western Europe vs. Eastern Europe vs. Asia vs. Rest of World). Patients were randomized (1:1) to receive intravenous pembrolizumab 200 mg or placebo intravenously every 3 weeks.

Treatment continued until RECIST v1.1-defined disease recurrence as determined by the investigator, unacceptable toxicity or up to one year. Tumor assessments were conducted every 12 weeks for the first year, then every 6 months for years 2 to 3, and then annually through year 5. After year 5, imaging was performed as per local standard of care. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS). An additional efficacy outcome measure was OS.

Of 1177 patients randomized, 1010 (86%) received adjuvant platinum-based chemotherapy following resection. Among these 1010 patients, the median age was 64 years (range: 35 to 84), 49% age 65 or older; 68% male; 77% White, 18% Asian; 86% current or former smokers; and 39% with ECOG PS of 1. Eleven percent had Stage IB, 57% had Stage II, and 31% had Stage IIIA disease. Thirty-nine percent had PD-L1 TPS <1% [negative], 33% had TPS 1-49%, and 28% had TPS ≥50%. Fifty-two percent were from Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World.

The trial met its primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population for patients randomized to the intravenous pembrolizumab arm compared to patients randomized to the placebo arm. In an exploratory subgroup analysis of the 167 patients (14%) who did not receive adjuvant chemotherapy, the DFS HR was 1.25 (95% CI: 0.76, 2.05). OS results were not mature with only 42% of pre-specified OS events in the overall population.

Table 64 and Figure 11 summarize the efficacy results for KEYNOTE-091 in patients who received adjuvant chemotherapy.

Table 64: Efficacy Results in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks n=506	Placebo n=504
NR = not reached
DFS
Number (%) of patients with event	177 (35%)	231 (46%)
Median in months (95% CI)	58.7 (39.2, NR)	34.9 (28.6, NR)
Hazard ratio Based on the unstratified univariate Cox regression model (95% CI)	0.73 (0.60, 0.89)

Figure 11: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy

Figure 11 (Keytruda Qlex 11)

First-line treatment of metastatic or unresectable, recurrent HNSCC

The efficacy of intravenous pembrolizumab 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:

• Intravenous pembrolizumab 200 mg intravenously every 3 weeks
• Intravenous pembrolizumab 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 intravenous pembrolizumab continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of intravenous pembrolizumab 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 intravenous pembrolizumab 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 66 and Figure 13 summarize efficacy results for intravenous pembrolizumab in combination with chemotherapy.

Table 66: Efficacy Results

Results at a pre-specified interim analysis

for Intravenous Pembrolizumab plus Platinum/Fluorouracil in KEYNOTE-048

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks Platinum FU	Cetuximab Platinum FU
	n=281	n=278
OS
Number (%) of patients with event	197 (70%)	223 (80%)
Median in months (95% CI)	13.0 (10.9, 14.7)	10.7 (9.3, 11.7)
Hazard ratio Based on the stratified Cox proportional hazard model (95% CI)	0.77 (0.63, 0.93)
p-Value Based on stratified log-rank test	0.0067
PFS
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-Value	0.3394
Objective Response Rate
ORR Response: Best objective response as confirmed complete response or partial response (95% CI)	36% (30.0, 41.5)	36% (30.7, 42.3)
Complete response rate	6%	3%
Partial response rate	30%	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 13: Kaplan-Meier Curve for Overall Survival for Intravenous Pembrolizumab plus Platinum/Fluorouracil in KEYNOTE-048

At the time of the protocol-specified final analysis.

Figure 13 (Keytruda Qlex 14)

The trial also demonstrated a statistically significant improvement in OS for the subgroup of patients with PD-L1 CPS ≥1 randomized to intravenous pembrolizumab 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 intravenous pembrolizumab single agent arm and the control arm for the overall population.

Table 67 summarizes efficacy results for intravenous pembrolizumab as a single agent in the subgroups of patients with CPS ≥1 HNSCC and CPS ≥20 HNSCC. Figure 14 summarizes the OS results in the subgroup of patients with CPS ≥1 HNSCC.

Table 67: Efficacy Results

Results at a pre-specified interim analysis

for Intravenous Pembrolizumab as a Single Agent in KEYNOTE-048 (CPS ≥1 and CPS ≥20)

Endpoint	CPS ≥1		CPS ≥20
	Intravenous Pembrolizumab 200 mg every 3 weeks	Cetuximab Platinum FU	Intravenous Pembrolizumab 200 mg every 3 weeks	Cetuximab Platinum FU
	n=257	n=255	n=133	n=122
OS
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 ratio Based on the stratified Cox proportional hazard model (95% CI)	0.78 (0.64, 0.96)		0.61 (0.45, 0.83)
p-Value Based on a stratified log-rank test	0.0171		0.0015
PFS
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
ORR Response: 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 rate	5%	3%	8%	3%
Partial response rate	14%	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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 14: Kaplan-Meier Curve for Overall Survival for Intravenous Pembrolizumab as a Single Agent in KEYNOTE-048 (CPS ≥1)

At the time of the protocol-specified final analysis.

Figure 14 (Keytruda Qlex 15)

Previously treated recurrent or metastatic HNSCC

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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.

In Combination with Enfortumab Vedotin for the Treatment of Patients with Urothelial Cancer

The efficacy of intravenous pembrolizumab in combination with enfortumab vedotin was evaluated in KEYNOTE-A39 (NCT04223856), an open-label, randomized, multicenter trial that enrolled 886 patients with locally advanced or metastatic urothelial cancer who received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded.

Patients were randomized 1:1 to receive either:

• Intravenous pembrolizumab 200 mg over 30 minutes on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle. Intravenous pembrolizumab was given approximately 30 minutes after enfortumab vedotin. Treatment was continued until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, intravenous pembrolizumab was continued for up to 2 years.
• Gemcitabine 1000 mg/m² on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m² or carboplatin (AUC = 4.5 or 5) on Day 1 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity for up to 6 cycles.

Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases.

The median age was 69 years (range: 22 to 91); 77% were male; 67% were White, 22% were Asian, 1% were Black or African American, and 10% were unknown or other; 12% were Hispanic or Latino. Patients had a baseline ECOG performance status of 0 (49%), 1 (47%), or 2 (3%). Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. At baseline, 95% of patients had metastatic urothelial cancer, including 72% with visceral and 22% with liver metastases, and 5% had locally advanced urothelial cancer. Eighty-five percent of patients had urothelial carcinoma (UC) histology including 6% with UC mixed squamous differentiation and 2% with UC mixed other histologic variants. Forty-six percent of patients were considered cisplatin-ineligible and 54% were considered cisplatin-eligible at time of randomization.

The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1. Additional efficacy outcome measures included ORR as assessed by BICR.

The trial demonstrated statistically significant improvements in OS, PFS, and ORR for patients randomized to intravenous pembrolizumab in combination with enfortumab vedotin as compared to platinum-based chemotherapy. Efficacy results were consistent across all stratified patient subgroups.

Table 68 and Figures 15 and 16 summarize the efficacy results for KEYNOTE-A39.

Table 68: Efficacy Results in KEYNOTE-A39

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks in combination with Enfortumab Vedotin n=442	Cisplatin or Carboplatin with Gemcitabine n=444
NR = not reached
OS
Number (%) of patients with event	133 (30%)	226 (51%)
Median in months (95% CI)	31.5 (25.4, NR)	16.1 (13.9, 18.3)
Hazard ratio Based on the stratified Cox proportional hazard regression model (95% CI)	0.47 (0.38, 0.58)
p-Value Two-sided p-Value based on stratified log-rank test	<0.0001
PFS
Number (%) of patients with event	223 (50%)	307 (69%)
Median in months (95% CI)	12.5 (10.4, 16.6)	6.3 (6.2, 6.5)
Hazard ratio (95% CI)	0.45 (0.38, 0.54)
p-Value	<0.0001
Confirmed Objective Response Rate Includes only patients with measurable disease at baseline (n=437 for intravenous pembrolizumab in combination with enfortumab vedotin, n=441 for chemotherapy).
ORR Based on patients with a best overall response as confirmed complete or partial response % (95% CI)	68% (63, 72)	44% (40, 49)
p-Value Two-sided p-Value based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression, cisplatin eligibility and liver metastases	<0.0001
Complete response	29%	12%
Partial response	39%	32%

Figure 15: Kaplan-Meier Curve for Overall Survival in KEYNOTE-A39

Figure 15 (Keytruda Qlex 16)

Figure 16: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A39

Figure 16 (Keytruda Qlex 17)

In Combination with Enfortumab Vedotin for the Treatment of Cisplatin-Ineligible Patients with Urothelial Cancer

The efficacy of intravenous pembrolizumab in combination with enfortumab vedotin was evaluated in KEYNOTE-869 (NCT03288545), an open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) study in patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded from participating in the study.

Patients in the dose escalation cohort (n=5), Cohort A (n=40), and Cohort K (n=76) received enfortumab vedotin 1.25 mg/kg as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by intravenous pembrolizumab 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after enfortumab vedotin. Patients were treated until disease progression or unacceptable toxicity.

A total of 121 patients received intravenous pembrolizumab in combination with enfortumab vedotin. The median age was 71 years (range: 51 to 91); 74% were male; 85% were White, 5% were Black, 4% were Asian and 6% were other, unknown or not reported. Ten percent of patients were Hispanic or Latino. Forty-five percent of patients had an ECOG performance status of 1 and 15% had an ECOG performance status of 2. Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. Reasons for cisplatin-ineligibility included: 60% with baseline creatinine clearance of 30-59 mL/min, 10% with ECOG PS of 2, 13% with Grade 2 or greater hearing loss, and 16% with more than one cisplatin-ineligibility criteria.

At baseline, 97.5% of patients had metastatic urothelial cancer and 2.5% of patients had locally advanced urothelial cancer. Thirty-seven percent of patients had upper tract disease. Eighty-four percent of patients had visceral metastasis at baseline, including 22% with liver metastases. Thirty-nine percent of patients had TCC histology; 13% had TCC with squamous differentiation, and 48% had TCC with other histologic variants.

The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1.

The median follow-up time for the dose escalation cohort + Cohort A was 44.7 months (range 0.7 to 52.4) and for Cohort K was 14.8 months (range: 0.6 to 26.2).

Efficacy results are presented in Table 69 below.

Table 69: Efficacy Results in KEYNOTE-869, Combined Dose Escalation Cohort, Cohort A, and Cohort K

Endpoint	Intravenous Pembrolizumab in combination with Enfortumab Vedotin n=121
Confirmed ORR (95% CI)	68% (58.7, 76.0)
Complete response rate	12%
Partial response rate	55%

The median duration of response for the dose escalation cohort + Cohort A was 22.1 months (range: 1.0+ to 46.3+) and for Cohort K was not reached (range: 1.2 to 24.1+).

Platinum-Ineligible Patients with Urothelial Carcinoma

The efficacy of intravenous pembrolizumab was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open-label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities, including patients who were not eligible for any platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received intravenous pembrolizumab 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. Fifty percent of patients had baseline creatinine clearance of <60 mL/min, 32% had ECOG PS of 2, 9% had ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 9% had one or more of 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 intravenous pembrolizumab was 11.4 months (range 0.1 to 63.8 months). Efficacy results are summarized in Table 70.

Table 70: Efficacy Results in KEYNOTE-052

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks
	All Subjects n=370
+ Denotes ongoing response
Objective Response Rate
ORR (95% CI)	29% (24, 34)
Complete response rate	10%
Partial response rate	20%
Duration of Response
Median in months (range)	33.4 (1.4+, 60.7+)

Platinum-Eligible Patients with Previously Untreated Urothelial Carcinoma

The efficacy of intravenous pembrolizumab for the first-line treatment of platinum-eligible patients with locally advanced or metastatic urothelial carcinoma was investigated in KEYNOTE-361 (NCT02853305), a multicenter, randomized, open-label, active-controlled study in 1010 previously untreated patients. The safety and efficacy of intravenous pembrolizumab in combination with platinum-based chemotherapy for previously untreated patients with locally advanced or metastatic urothelial carcinoma has not been established.

The study compared intravenous pembrolizumab with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. Among the patients receiving intravenous pembrolizumab plus platinum-based chemotherapy, 44% received cisplatin and 56% received carboplatin.

The study did not meet its major efficacy outcome measures of improved PFS or OS in the intravenous pembrolizumab plus chemotherapy arm compared to the chemotherapy-alone arm. Additional efficacy endpoints, including improvement of OS in the intravenous pembrolizumab monotherapy arm, could not be formally tested.

Previously Treated Urothelial Carcinoma

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab as compared to chemotherapy. There was no statistically significant difference between intravenous pembrolizumab 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 71 and Figure 17 summarize the efficacy results for KEYNOTE-045.

Table 71: Efficacy Results in KEYNOTE-045

	Intravenous Pembrolizumab 200 mg every 3 weeks	Chemotherapy
	n=270	n=272
+ Denotes ongoing response NR = not reached
OS
Deaths (%)	155 (57%)	179 (66%)
Median in months (95% CI)	10.3 (8.0, 11.8)	7.4 (6.1, 8.3)
Hazard ratio Hazard ratio (intravenous pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model (95% CI)	0.73 (0.59, 0.91)
p-Value (stratified log-rank)	0.004
PFS 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)	0.833
Objective Response Rate
ORR (95% CI)	21% (16, 27)	11% (8, 16)
Complete response rate	7%	3%
Partial response rate	14%	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 17: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045

Figure 17 (Keytruda Qlex 18)

BCG-unresponsive High-Risk Non-Muscle Invasive Bladder Cancer

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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 72.

Table 72: Efficacy Results in KEYNOTE-057

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks n=96
+ Denotes ongoing response
Complete Response Rate (95% CI)	41% (31, 51)
Duration of Response Based 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+, 30.4+)
% (n) with duration ≥12 months	46% (18)

First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal/Gastroesophageal Junction Cancer for Tumors Expressing PD-L1 (CPS ≥1)

KEYNOTE-590

The efficacy of intravenous pembrolizumab 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:

• Intravenous pembrolizumab 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 intravenous pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with intravenous pembrolizumab 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. Additional analyses of efficacy outcome measures were also conducted based on PD-L1 CPS ≥1.

Among 749 patients, 647 (86%) had tumors expressing PD-L1 CPS ≥ 1. The study population characteristics in patients with PD-L1 CPS ≥ 1 expressing tumors were: median age of 63 years (range: 27 to 89), 41% age 65 or older; 83% male; 36% White, 54% Asian, and 1% Black; 40% had an ECOG PS of 0 and 59% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-four percent had a tumor histology of squamous cell carcinoma, and 26% had adenocarcinoma.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to intravenous pembrolizumab in combination with chemotherapy compared to chemotherapy; however, an exploratory analysis of OS in the PD-L1 CPS <1 population showed an HR of 0.96 (0.59, 1.55), indicating that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 CPS ≥1.

Table 78 and Figures 22 and 23 summarize the efficacy results for KEYNOTE-590 in patients whose tumors expressed PD-L1 CPS ≥1 and CPS ≥10.

Table 78: Efficacy Results in Patients with Locally Advanced Unresectable or Metastatic Esophageal Cancer in KEYNOTE-590

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks Cisplatin FU n=320	Placebo Cisplatin FU n=327	Intravenous Pembrolizumab 200 mg every 3 weeks Cisplatin FU n=186	Placebo Cisplatin FU n=197
	CPS ≥1		CPS ≥10
OS
Number (%) of events	222 (69)	271 (83)	124 (67)	165 (84)
Median in months   (95% CI)	12.7 (10.5, 14.4)	9.8 (8.8, 10.8)	13.5 (11.1, 15.6)	9.4 (8.0, 10.7)
Hazard ratio Based on the stratified Cox proportional hazard model (95% CI)	0.71 (0.59, 0.84)		0.62 (0.49, 0.78)
p-Value Based on a stratified log-rank test; p-Value for CPS ≥1 not included (not pre-specified subgroup)			<0.0001
PFS
Number of events (%)	252 (79)	291 (89)	140 (75)	174 (88)
Median in months   (95% CI)	6.3 (6.2, 7.1)	5.7 (4.6, 6.0)	7.5 (6.2, 8.2)	5.5 (4.3, 6.0)
Hazard ratio (95% CI)	0.62 (0.52, 0.73)		0.51 (0.41, 0.65)
p-Value			<0.0001
Objective Response Rate
ORR, % Confirmed complete response or partial response   (95% CI)	45 (40, 51)	29 (24, 34)	51 (44, 59)	27 (21, 34)
Number (%) of complete responses	19 (6)	9 (2.8)	11 (6)	5 (2.5)
Number (%) of partial responses	126 (39)	85 (26)	84 (45)	48 (24)
Duration of Response
Median in months   (range)	8.6 (1.2+, 31.0+)	5.8 (1.5+, 25.0+)	10.4 (1.9+, 28.9+)	5.6 (1.5+, 25.0+)

Figure 22: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590 (CPS ≥1)

Figure 22 (Keytruda Qlex 23)

Figure 23: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590 (CPS ≥10)

Figure 23 (Keytruda Qlex 24)

In 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 Cancer for Tumors Expressing PD-L1 (CPS≥ 10)

KEYNOTE-181

The efficacy of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression. Patients randomized to intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab (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 intravenous pembrolizumab 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 intravenous pembrolizumab as compared with chemotherapy. Table 79 and Figure 24 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS ≥10.

Table 79: Efficacy Results in Patients with Recurrent or Metastatic ESCC (CPS ≥10) in KEYNOTE-181

Endpoint	Intravenous Pembrolizumab 200 mg every 3 weeks n=85	Chemotherapy   n=82
OS
Number (%) of patients with event	68 (80%)	72 (88%)
Median in months (95% CI)	10.3 (7.0, 13.5)	6.7 (4.8, 8.6)
Hazard ratio Based 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 event	76 (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 responses	4 (5)	1 (1)
Number (%) of partial responses	15 (18)	5 (6)
Median duration of response in months (range)	9.3 (2.1+, 18.8+)	7.7 (4.3, 16.8+)

Figure 24: Kaplan-Meier Curve for Overall Survival in KEYNOTE-181 (ESCC CPS ≥10)

Figure 24 (Keytruda Qlex 25)

KEYNOTE-180

The efficacy of intravenous pembrolizumab 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 Reactions

• Inform 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 QLEX. 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 other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)].

    Hypersensitivity and Administration-Related Reactions

    • Advise patients to contact their healthcare provider immediately for signs or symptoms of hypersensitivity and administration-related systemic reactions [see Warnings and Precautions (5.2)].

    Complications of Allogeneic HSCT

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

    Embryo-Fetal Toxicity

    • Advise 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 QLEX and for 4 months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].

    Lactation

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

    Laboratory Tests

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

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