KEYTRUDA (pembrolizumab) injection, powder, lyophilized, for solution
Merck Sharp & Dohme LLC

Merck Sharp & Dohme LLC
KEYTRUDA
pembrolizumab
pembrolizumab
pembrolizumab
HISTIDINE
SUCROSE
POLYSORBATE 80
SODIUM HYDROXIDE
HYDROCHLORIC ACID
KEYTRUDA
pembrolizumab
pembrolizumab
pembrolizumab
HISTIDINE
SUCROSE
POLYSORBATE 80
WATER
Indications and Usage (1) 06/2024
Dosage and Administration (2) 06/2024
Warnings and Precautions (5) 03/2024

1 INDICATIONS AND USAGE

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated:

Melanoma

  • for the treatment of patients with unresectable or metastatic melanoma. (1.1)
  • for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. (1.1)

Non-Small Cell Lung Cancer (NSCLC)

  • in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. (1.2)
  • in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC. (1.2)
  • as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, 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. (1.2, 2.1)
  • as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. (1.2, 2.1)
  • for the treatment of 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. (1.2)
  • as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. (1.2)

Head and Neck Squamous Cell Cancer (HNSCC)

  • in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. (1.3)
  • as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. (1.3, 2.1)
  • as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. (1.3)

Classical Hodgkin Lymphoma (cHL)

  • for the treatment of adult patients with relapsed or refractory cHL. (1.4)
  • for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. (1.4)

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

  • for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy. (1.5)
  • Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Cancer

  • in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. (1.6)
  • as a single agent for the treatment of 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. (1.6)
  • as a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. (1.6)

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

  • for the treatment of adult and pediatric patients 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. (1.7, 2.1)

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC)

  • for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. (1.8, 2.1)

Gastric Cancer

  • in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, 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.1 (1.9)
  • in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. (1.9)

Esophageal Cancer

  • for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
    • in combination with platinum- and fluoropyrimidine-based chemotherapy, 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. (1.10, 2.1)

Cervical Cancer

  • in combination with chemoradiotherapy, for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. (1.11)
  • in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. (1.11, 2.1)
  • as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. (1.11, 2.1)

Hepatocellular Carcinoma (HCC)

  • for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. (1.12)

Biliary Tract Cancer (BTC)

  • in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer. (1.13)

Merkel Cell Carcinoma (MCC)

  • for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. (1.14)

Renal Cell Carcinoma (RCC)

  • in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. (1.15)
  • in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. (1.15)
  • for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (1.15)

Endometrial Carcinoma

  • in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. (1.16)
  • in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.16, 2.1)
  • as a single agent, 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. (1.16, 2.1)

Tumor Mutational Burden-High (TMB-H) Cancer

  • for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.1 (1.17, 2.1)
  • Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma (cSCC)

  • for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. (1.18)

Triple-Negative Breast Cancer (TNBC)

  • for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (1.19)
  • in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA approved test. (1.19, 2.1)

Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks

  • for use at an additional recommended dosage of 400 mg every 6 weeks for Classical Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma in adults.2 (1.20, 2.2)

1 This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

2 This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.1 Melanoma

KEYTRUDA® is indicated for the treatment of patients with unresectable or metastatic melanoma.

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

1.2 Non-Small Cell Lung Cancer

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

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

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations, and is:

  • Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
  • metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA is indicated for the treatment of 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, 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.

1.3 Head and Neck Squamous Cell Cancer

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

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test [see Dosage and Administration (2.1)].

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

1.4 Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

1.5 Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

1.6 Urothelial Cancer

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

KEYTRUDA, as a single agent, is indicated for the treatment of 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, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

1.7 Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, 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)].

1.8 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

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

1.9 Gastric Cancer

KEYTRUDA, 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)].

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.9)]. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, 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.

1.10 Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

  • in combination with platinum- and fluoropyrimidine-based chemotherapy, 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)].

1.11 Cervical Cancer

KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer.

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

1.12 Hepatocellular Carcinoma

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

1.13 Biliary Tract Cancer

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

1.14 Merkel Cell Carcinoma

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

1.15 Renal Cell Carcinoma

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

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

KEYTRUDA is indicated for the adjuvant treatment of 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)].

1.16 Endometrial Carcinoma

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

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, 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, 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)].

1.17 Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test [see Dosage and Administration (2.1)], that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.17)]. 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 in pediatric patients with TMB-H central nervous system cancers have not been established.

1.18 Cutaneous Squamous Cell Carcinoma

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

1.19 Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of 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, in combination with chemotherapy, is indicated for the treatment of 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)].

1.20 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks

KEYTRUDA is indicated for use at an additional recommended dosage of 400 mg every 6 weeks for classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma in adults [see Indications and Usage (1.4, 1.5), Dosage and Administration (2.2)]. This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety [see Clinical Pharmacology (12.2), Clinical Studies (14.20)]. Continued approval for this dosage may be contingent upon verification and description of clinical benefit in the confirmatory trials.

2 DOSAGE AND ADMINISTRATION

  • Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2)
  • NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2)
  • Urothelial Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2)
  • MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • HCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • BTC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2)
  • RCC: 200 mg every 3 weeks or 400 mg every 6 weeks as a single agent in the adjuvant setting, or in the advanced setting with either:
    • axitinib 5 mg orally twice daily or
    • lenvatinib 20 mg orally once daily. (2.2)
  • Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks
    • in combination with carboplatin and paclitaxel regardless of MMR or MSI status, or
    • in combination with lenvatinib 20 mg orally once daily for pMMR or not MSI-H tumors, or
    • as a single agent for MSI-H or dMMR tumors. (2.2)
  • TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2)
  • cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2)
  • Administer KEYTRUDA as an intravenous infusion over 30 minutes after dilution. (2.4)
  • See Full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions. (2.3, 2.4)

2.1 Patient Selection

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 as a single agent based on the presence of positive PD-L1 expression in:

For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.7, 14.8)].

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

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 in combination with chemotherapy and trastuzumab, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma [see Clinical Studies (14.9)].

For use of KEYTRUDA 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 in combination with lenvatinib based on MSI or MMR status in tumor specimens [see Clinical Studies (14.16)].

For use of KEYTRUDA 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)].

Additional Patient Selection Information

  • An FDA-approved test for the detection of not MSI-H is currently unavailable for the selection of patients with not MSI-H endometrial carcinoma for treatment with KEYTRUDA in combination with lenvatinib [see Clinical Studies (14.16)].

2.2 Recommended Dosage

Table 1: Recommended Dosage
Indication Recommended Dosage of
KEYTRUDA
Duration/Timing of Treatment
  Monotherapy
  Adult patients with unresectable or
  metastatic melanoma
200 mg every 3 weeks30-minute intravenous infusion
or
400 mg every 6 weeks
  Until disease progression or
  unacceptable toxicity
  Adjuvant treatment of adult patients
  with melanoma, NSCLC, or RCC
200 mg every 3 weeks

or
400 mg every 6 weeks
  Until disease recurrence, unacceptable
  toxicity, or up to 12 months
  Adult patients with NSCLC, HNSCC,
  cHL, PMBCL, locally advanced or
  metastatic Urothelial Carcinoma, MSI-H
  or dMMR Cancer, MSI-H or dMMR
  CRC, MSI-H or dMMR Endometrial
  Carcinoma, Esophageal Cancer,
  Cervical Cancer, HCC, MCC, TMB-H
  Cancer, or cSCC
200 mg every 3 weeks

or
400 mg every 6 weeks
  Until disease progression, unacceptable
  toxicity, or up to 24 months
  Adult patients with high-risk BCG-
  unresponsive NMIBC
200 mg every 3 weeks

or
400 mg every 6 weeks
  Until persistent or recurrent high-risk
  NMIBC, disease progression,
  unacceptable toxicity, or up to
  24 months
  Pediatric patients with cHL, PMBCL,
  MSI-H or dMMR Cancer, MCC, or TMB-
  H Cancer
2 mg/kg every 3 weeks (up to a
maximum of 200 mg)
  Until disease progression, unacceptable
  toxicity, or up to 24 months
  Pediatric patients (12 years and older)
  for adjuvant treatment of melanoma
2 mg/kg every 3 weeks (up to a
maximum of 200 mg)
  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 for recommended dosing information, as appropriate.
  Adult patients with resectable NSCLC 200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA 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 as a single agent after
  surgery for 39 weeks or until disease
  recurrence or unacceptable toxicity
  Adult patients with NSCLC, HNSCC,
  HER2-negative Gastric Cancer,
  Esophageal Cancer, or BTC
200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA 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
200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA 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
200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA prior to
trastuzumab and chemotherapy
when given on the same day.
  Until disease progression, unacceptable
  toxicity, or up to 24 months
  Adult patients with Cervical Cancer 200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA 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, up to
  24 months
  Adult patients with RCC 200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA in
combination with axitinib 5 mg
orally twice dailyWhen axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer.
or
Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily.
  Until disease progression, unacceptable
  toxicity, or for KEYTRUDA, up to
  24 months
  Adult patients with Endometrial
  Carcinoma
200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA prior to
carboplatin and paclitaxel when
given on the same day.
or
Administer KEYTRUDA in
combination with lenvatinib
20 mg orally once daily.
  Until disease progression, unacceptable
  toxicity, or for KEYTRUDA, up to
  24 months
  Adult patients with high-risk early-stage
  TNBC
200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA prior to chemotherapy when given on the same day.
  Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent for up to 27 weeks (9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks) or until disease recurrence or unacceptable toxicityPatients who experience disease progression or unacceptable toxicity related to KEYTRUDA with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA.
  Adult patients with locally recurrent
  unresectable or metastatic TNBC
200 mg every 3 weeks

or
400 mg every 6 weeks

Administer KEYTRUDA prior to
chemotherapy when given on
the same day.
  Until disease progression, unacceptable
  toxicity, or up to 24 months

2.3 Dose Modifications

No dose reduction for KEYTRUDA is recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA for Life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for KEYTRUDA for adverse reactions that require management different from these general guidelines are summarized in Table 2.

Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction SeverityBased on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Pneumonitis Grade 2 WithholdResume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
Grade 3 or 4 Permanently discontinue
Colitis Grade 2 or 3 Withhold
Grade 4 Permanently discontinue


Hepatitis with no tumor involvement
of the liver
AST or ALT increases to more than 3
and up to 8 times ULN
or
Total bilirubin increases to more than
1.5 and up to 3 times ULN
Withhold
For liver enzyme elevations in
patients treated with combination
therapy with axitinib, see Table 3.
AST or ALT increases to more than
8 times ULN
or
Total bilirubin increases to more than
3 times ULN
Permanently discontinue
Hepatitis with tumor involvement of
the liverIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on recommendations for hepatitis with no liver involvement.
Baseline AST or ALT is more than 1
and up to 3 times ULN and increases to
more than 5 and up to 10 times ULN
or
Baseline AST or ALT is more than 3
and up to 5 times ULN and increases to
more than 8 and up to 10 times ULN
Withhold
ALT or AST increases to more than
10 times ULN
or
Total bilirubin increases to more than
3 times ULN
Permanently discontinue
Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently
discontinue depending on severity
Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold
Grade 4 increased blood creatinine Permanently discontinue
Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold
Confirmed SJS, TEN, or DRESS Permanently discontinue
Myocarditis Grade 2, 3, or 4 Permanently discontinue
Neurological Toxicities Grade 2 Withhold
Grade 3 or 4 Permanently discontinue
Hematologic toxicity in patients with
cHL or PMBCL
Grade 4 Withhold until resolution to Grades 0 or 1
Other Adverse Reactions
Infusion-related reactions
[see Warnings and Precautions (5.2)]
Grade 1 or 2 Interrupt or slow the rate of infusion
Grade 3 or 4 Permanently discontinue

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

Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA in Combination with Axitinib
Treatment Adverse Reaction Severity Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
KEYTRUDA in
combination with
axitinib
Liver enzyme elevationsConsider corticosteroid therapy ALT or AST increases to at least 3 times but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both KEYTRUDA
and axitinib until resolution to
Grades 0 or 1Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information.
ALT or AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN
or ALT or AST ≥10 times ULN
Permanently discontinue both
KEYTRUDA and axitinib

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

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

2.4 Preparation and Administration

Preparation for Intravenous Infusion

  • Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.
  • Dilute KEYTRUDA injection (solution) prior to intravenous administration.
  • Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.
  • Discard any unused portion left in the vial.

Storage of Diluted Solution

The product does not contain a preservative.

Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:

  • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake.

Discard after 6 hours at room temperature or after 96 hours under refrigeration.

Do not freeze.

Administration

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

3 DOSAGE FORMS AND STRENGTHS

  • Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial
  • Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial (3)

4 CONTRAINDICATIONS

None.

None. (4)

5 WARNINGS AND PRECAUTIONS

  • Immune-Mediated Adverse Reactions (5.1)
    • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection.
    • Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
    • Withhold or permanently discontinue based on severity and type of reaction.
  • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue KEYTRUDA based on the severity of reaction. (5.2)
  • Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3)
  • Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.4)
  • Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective method of contraception. (5.5, 8.1, 8.3)

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA 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 depending on severity [see Dosage and Administration (2.3)]. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) of patients and withholding of KEYTRUDA in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients.

In clinical studies enrolling 389 adult patients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31 (8%) patients, including Grades 3-4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received KEYTRUDA 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 KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) of patients and withholding of KEYTRUDA in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) of patients and withholding of KEYTRUDA in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.3)].

With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both KEYTRUDA and axitinib. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)].

Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)].

Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)].

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

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

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

Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement.

The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA 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 depending on severity [see Dosage and Administration (2.3)].

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

Immune-Mediated Nephritis with Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) of patients and withholding of KEYTRUDA in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)].

Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of KEYTRUDA in 0.1% (2) of patients and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, 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, 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

5.2 Infusion-Related Reactions

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

5.3 Complications of Allogeneic HSCT

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.

5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone

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

5.5 Embryo-Fetal Toxicity

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

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling.

Most common adverse reactions (reported in ≥20% of patients) were:

  • KEYTRUDA as a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. (6.1)
  • KEYTRUDA in combination with chemotherapy or chemoradiotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. (6.1)
  • KEYTRUDA in combination with chemotherapy and bevacizumab: peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite. (6.1)
  • KEYTRUDA in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. (6.1)
  • KEYTRUDA in combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury. (6.1)
  • KEYTRUDA in combination with enfortumab vedotin: rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC, a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

Melanoma

Ipilimumab-Naive Melanoma

The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year.

The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 4 and 5 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.

Table 4: SelectedAdverse reactions occurring at same or higher incidence than in the ipilimumab arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006
  Adverse Reaction KEYTRUDA
10 mg/kg every 2 or 3 weeks
Ipilimumab
n=555 n=256
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
  Fatigue 28 0.9 28 3.1
Skin and Subcutaneous Tissue
  RashIncludes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. 24 0.2 23 1.2
  VitiligoIncludes skin hypopigmentation 13 0 2 0
Musculoskeletal and Connective Tissue
  Arthralgia 18 0.4 10 1.2
  Back pain 12 0.9 7 0.8
Respiratory, Thoracic and Mediastinal
  Cough 17 0 7 0.4
  Dyspnea 11 0.9 7 0.8
Metabolism and Nutrition
  Decreased appetite 16 0.5 14 0.8
Nervous System
  Headache 14 0.2 14 0.8

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

Table 5: SelectedLaboratory abnormalities occurring at same or higher incidence than in ipilimumab arm Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205. KEYTRUDA
10 mg/kg every 2 or 3 weeks
Ipilimumab
All GradesGraded per NCI CTCAE v4.0
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
Chemistry
  Hyperglycemia 45 4.2 45 3.8
  Hypertriglyceridemia 43 2.6 31 1.1
  Hyponatremia 28 4.6 26 7
  Increased AST 27 2.6 25 2.5
  Hypercholesterolemia 20 1.2 13 0
Hematology
  Anemia 35 3.8 33 4.0
  Lymphopenia 33 7 25 6

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4).

Ipilimumab-Refractory Melanoma

The safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ≥6 months and 4% were exposed for ≥12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ≥6 months and 6% of patients were exposed to KEYTRUDA for ≥12 months.

The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis.

In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.

Table 6: SelectedAdverse reactions occurring at same or higher incidence than in chemotherapy arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-002
  Adverse Reaction KEYTRUDA
2 mg/kg or 10 mg/kg every 3 weeks
ChemotherapyChemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin
n=357 n=171
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Skin and Subcutaneous Tissue
  Pruritus 28 0 8 0
  RashIncludes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic 24 0.6 8 0
Gastrointestinal
  Constipation 22 0.3 20 2.3
  Diarrhea 20 0.8 20 2.3
  Abdominal pain 13 1.7 8 1.2
Respiratory, Thoracic and Mediastinal
  Cough 18 0 16 0
General
  Pyrexia 14 0.3 9 0.6
  Asthenia 10 2.0 9 1.8
Musculoskeletal and Connective Tissue
  Arthralgia 14 0.6 10 1.2

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

Table 7: SelectedLaboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA n=247 and chemotherapy n=116; decreased bicarbonate: KEYTRUDA n=263 and chemotherapy n=123. KEYTRUDA
2 mg/kg or 10 mg/kg every 3 weeks
Chemotherapy
All GradesGraded per NCI CTCAE v4.0
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
Chemistry
  Hyperglycemia 49 6 44 6
  Hypoalbuminemia 37 1.9 33 0.6
  Hyponatremia 37 7 24 3.8
  Hypertriglyceridemia 33 0 32 0.9
  Increased alkaline phosphatase 26 3.1 18 1.9
  Increased AST 24 2.2 16 0.6
  Decreased bicarbonate 22 0.4 13 0
  Hypocalcemia 21 0.3 18 1.9
  Increased ALT 21 1.8 16 0.6

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

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma

Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA 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 KEYTRUDA as a single agent.

Adjuvant Treatment of Stage III Resected Melanoma

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer.

The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes).

Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054.

Table 8: SelectedAdverse reactions occurring at same or higher incidence than in placebo arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-054
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
n=509
Placebo

n=502
All GradesGraded per NCI CTCAE v4.03
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Gastrointestinal
  Diarrhea 28 1.2 26 1.2
  Nausea 17 0.2 15 0
Skin and Subcutaneous Tissue
  Pruritus 19 0 12 0
  Rash 13 0.2 9 0
Musculoskeletal and Connective Tissue
  Arthralgia 16 1.2 14 0
Endocrine
  Hypothyroidism 15 0 2.8 0
  Hyperthyroidism 10 0.2 1.2 0
Respiratory, Thoracic and Mediastinal
  Cough 14 0 11 0
General
  Asthenia 11 0.2 8 0
  Influenza like illness 11 0 8 0
Investigations
  Weight loss 11 0 8 0
Table 9: SelectedLaboratory abnormalities occurring at same or higher incidence than placebo. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 503 to 507 patients) and placebo (range: 492 to 498 patients). KEYTRUDA
200 mg every 3 weeks
Placebo
All GradesGraded per NCI CTCAE v4.03
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
Chemistry
  Increased ALT 27 2.4 16 0.2
  Increased AST 24 1.8 15 0.4
Hematology
  Lymphopenia 24 1 16 1.2

NSCLC

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

The safety of KEYTRUDA in combination with pemetrexed and investigator's choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Seventy-two percent of patients received carboplatin.

The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-189.

Table 10: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy
n=405
Placebo

Pemetrexed
Platinum Chemotherapy
n=202
All GradesGraded per NCI CTCAE v4.03
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Gastrointestinal
  Nausea 56 3.5 52 3.5
  Constipation 35 1.0 32 0.5
  Diarrhea 31 5 21 3.0
  Vomiting 24 3.7 23 3.0
General
  FatigueIncludes asthenia and fatigue 56 12 58 6
  Pyrexia 20 0.2 15 0
Metabolism and Nutrition
  Decreased appetite 28 1.5 30 0.5
Skin and Subcutaneous Tissue
  RashIncludes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 25 2.0 17 2.5
Respiratory, Thoracic and Mediastinal
  Cough 21 0 28 0
  Dyspnea 21 3.7 26 5
Table 11: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). KEYTRUDA
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy
Placebo

Pemetrexed
Platinum Chemotherapy
All GradesGraded per NCI CTCAE v4.03
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
Hematology
  Anemia 85 17 81 18
  Lymphopenia 64 22 64 25
  Neutropenia 48 20 41 19
  Thrombocytopenia 30 12 29 8
Chemistry
  Hyperglycemia 63 9 60 7
  Increased ALT 47 3.8 42 2.6
  Increased AST 47 2.8 40 1.0
  Hypoalbuminemia 39 2.8 39 1.1
  Increased creatinine 37 4.2 25 1.0
  Hyponatremia 32 7 23 6
  Hypophosphatemia 30 10 28 14
  Increased alkaline phosphatase 26 1.8 29 2.1
  Hypocalcemia 24 2.8 17 0.5
  Hyperkalemia 24 2.8 19 3.1
  Hypokalemia 21 5 20 5

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

The safety of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin.

The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases.

KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).

The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

Previously Untreated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator's choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months.

The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (Stage IV), 13% had Stage III disease (2% Stage IIIA and 11% Stage IIIB), and 5% had treated brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%).

Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042.

Table 12: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
n=636
Chemotherapy

n=615
All GradesGraded per NCI CTCAE v4.03
(%)
Grades 3-5
(%)
All Grades
(%)
Grades 3-5
(%)
General
  FatigueIncludes fatigue and asthenia 25 3.1 33 3.9
  Pyrexia 10 0.3 8 0
Metabolism and Nutrition
  Decreased appetite 17 1.7 21 1.5
Respiratory, Thoracic and Mediastinal
  Dyspnea 17 2.0 11 0.8
  Cough 16 0.2 11 0.3
Skin and Subcutaneous Tissue
  RashIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 15 1.3 8 0.2
Gastrointestinal
  Constipation 12 0 21 0.2
  Diarrhea 12 0.8 12 0.5
  Nausea 12 0.5 32 1.1
Endocrine
  Hypothyroidism 12 0.2 1.5 0
Infections
  Pneumonia 12 7 9 6
Investigations
  Weight loss 10 0.9 7 0.2
Table 13: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173. KEYTRUDA
200 mg every 3 weeks
Chemotherapy
All GradesGraded per NCI CTCAE v4.03
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
Chemistry
  Hyperglycemia 52 4.7 51 5
  Increased ALT 33 4.8 34 2.9
  Hypoalbuminemia 33 2.2 29 1.0
  Increased AST 31 3.6 32 1.7
  Hyponatremia 31 9 32 8
  Increased alkaline phosphatase 29 2.3 29 0.3
  Hypocalcemia 25 2.5 19 0.7
  Hyperkalemia 23 3.0 20 2.2
  Increased prothrombin INR 21 2.0 15 2.9
Hematology
  Anemia 43 4.4 79 19
  Lymphopenia 30 7 41 13

Previously Treated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months.

The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease.

In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010.

Table 14: SelectedAdverse reactions occurring at same or higher incidence than in docetaxel arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-010
  Adverse Reaction KEYTRUDA
2 or 10 mg/kg every 3 weeks
n=682
Docetaxel
75 mg/m2 every 3 weeks
n=309
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
All Grades

(%)
Grades 3-4
(%)
Metabolism and Nutrition
  Decreased appetite 25 1.5 23 2.6
Respiratory, Thoracic and Mediastinal
  Dyspnea 23 3.7 20 2.6
  Cough 19 0.6 14 0
Gastrointestinal
  Nausea 20 1.3 18 0.6
  Constipation 15 0.6 12 0.6
  Vomiting 13 0.9 10 0.6
Skin and Subcutaneous Tissue
  RashIncludes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic 17 0.4 8 0
  Pruritus 11 0 3 0.3
Musculoskeletal and Connective Tissue
  Arthralgia 11 1.0 9 0.3
  Back pain 11 1.5 8 0.3

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

Table 15: SelectedLaboratory abnormalities occurring at same or higher incidence than in docetaxel arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients). KEYTRUDA
2 or 10 mg/kg every 3 weeks
Docetaxel
75 mg/m2 every 3 weeks
All GradesGraded per NCI CTCAE v4.0
%
Grades 3-4
%
All Grades

%
Grades 3-4
%
Chemistry
  Hyponatremia 32 8 27 2.9
  Increased alkaline phosphatase 28 3.0 16 0.7
  Increased AST 26 1.6 12 0.7
  Increased ALT 22 2.7 9 0.4

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4).

Neoadjuvant and Adjuvant Treatment of Resectable NSCLC

The safety of KEYTRUDA in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA 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 (14.2)]. 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 KEYTRUDA 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 KEYTRUDA 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 KEYTRUDA in combination with chemotherapy.

Neoadjuvant Phase of KEYNOTE-671

A total of 396 patients received at least 1 dose of KEYTRUDA 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 KEYTRUDA 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 KEYTRUDA 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 KEYTRUDA-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 KEYTRUDA arm was interstitial lung disease (1%).

Of the 325 KEYTRUDA-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 KEYTRUDA-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 KEYTRUDA arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment.

Of the patients who received single agent KEYTRUDA 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 KEYTRUDA due to an adverse reaction occurred in 12% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%).

Adjuvant Treatment of Resected NSCLC

The safety of KEYTRUDA 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 (14.2)]. A total of 1161 patients received KEYTRUDA 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 KEYTRUDA was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months.

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

HNSCC

First-line treatment of metastatic or unresectable, recurrent HNSCC

The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.3)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab.

The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for ≥12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin.

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

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

Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048.

Table 16: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-048
  KEYTRUDA
200 mg every 3 weeks
KEYTRUDA
200 mg every 3 weeks
Platinum
FU
Cetuximab
Platinum
FU
Adverse Reaction n=300 n=276 n=287
  All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
All Grades

(%)
Grades 3-4
(%)
All Grades

(%)
Grades 3-4
(%)
General
  FatigueIncludes fatigue, asthenia 33 4 49 11 48 8
  Pyrexia 13 0.7 16 0.7 12 0
  Mucosal inflammation 4.3 1.3 31 10 28 5
Gastrointestinal
  Constipation 20 0.3 37 0 33 1.4
  Nausea 17 0 51 6 51 6
  DiarrheaIncludes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis 16 0.7 29 3.3 35 3.1
  Vomiting 11 0.3 32 3.6 28 2.8
  Dysphagia 8 2.3 12 2.9 10 2.1
  Stomatitis 3 0 26 8 28 3.5
Skin
  RashIncludes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis 20 2.3 17 0.7 70 8
  Pruritus 11 0 8 0 10 0.3
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough 18 0.3 22 0 15 0
  DyspneaIncludes dyspnea, exertional dyspnea 14 2.0 10 1.8 8 1.0
Endocrine
  Hypothyroidism 18 0 15 0 6 0
Metabolism and Nutrition
  Decreased appetite 15 1.0 29 4.7 30 3.5
  Weight loss 15 2 16 2.9 21 1.4
Infections
  PneumoniaIncludes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal 12 7 19 11 13 6
Nervous System
  Headache 12 0.3 11 0.7 8 0.3
  Dizziness 5 0.3 10 0.4 13 0.3
  Peripheral sensory neuropathyIncludes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia 1 0 14 1.1 7 1
Musculoskeletal
  MyalgiaIncludes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia 12 1.0 13 0.4 11 0.3
  Neck pain 6 0.7 10 1.1 7 0.7
Psychiatric
  Insomnia 7 0.7 10 0 8 0
Table 17: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-048
  KEYTRUDA
200 mg every 3 weeks
KEYTRUDA
200 mg every 3 weeks
Platinum
FU
Cetuximab
Platinum
FU
Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/chemotherapy (range: 235 to 266 patients), KEYTRUDA (range: 241 to 288 patients), cetuximab/chemotherapy (range: 249 to 282 patients). All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
All Grades

(%)
Grades 3-4
(%)
All Grades

(%)
Grades 3-4
(%)
Hematology
  Lymphopenia 54 25 69 35 74 45
  Anemia 52 7 89 28 78 19
  Thrombocytopenia 12 3.8 73 18 76 18
  Neutropenia 7 1.4 67 35 71 42
Chemistry
  Hyperglycemia 47 3.8 55 6 66 4.7
  Hyponatremia 46 17 56 20 59 20
  Hypoalbuminemia 44 3.2 47 4.0 49 1.1
  Increased AST 28 3.1 24 2.0 37 3.6
  Increased ALT 25 2.1 22 1.6 38 1.8
  Increased alkaline phosphatase 25 2.1 27 1.2 33 1.1
  Hypercalcemia 22 4.6 16 4.3 13 2.6
  Hypocalcemia 22 1.1 32 4 58 7
  Hyperkalemia 21 2.8 27 4.3 29 4.3
  Hypophosphatemia 20 5 35 12 48 19
  Hypokalemia 19 5 34 12 47 15
  Increased creatinine 18 1.1 36 2.3 27 2.2
  Hypomagnesemia 16 0.4 42 1.7 76 6

Previously treated recurrent or metastatic HNSCC

Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.3)], the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012.

The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.

KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.1)].

Relapsed or Refractory cHL

KEYNOTE-204

The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.4)]. Adults with relapsed or refractory cHL received KEYTRUDA 200 mg intravenously every 3 weeks (n=148) or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC ≥1000/µL, platelet count ≥75,000/µL, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment.

Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia.

Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy.

Table 18 summarizes adverse reactions in KEYNOTE-204.

Table 18: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-204
      Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=148
Brentuximab Vedotin
1.8 mg/kg every 3 weeks
N=152
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3- 4
(%)
All Grades

(%)
Grades 3- 4Adverse reactions in BV arm were Grade 3 only.
(%)
Infections
  Upper respiratory tract infectionIncludes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection 41 1.4 24 0
  Urinary tract infection 11 0 3 0.7
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity 32 0 29 1.3
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 22 2.7 17 1.3
  Nausea 14 0 24 0.7
  Vomiting 14 1.4 20 0
  Abdominal painIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper 11 0.7 13 1.3
General
  Pyrexia 20 0.7 13 0.7
  FatigueIncludes fatigue, asthenia 20 0 22 0.7
Skin and Subcutaneous Tissue
  RashIncludes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular‚ rash maculo-papular, rash papular, rash pruritic, toxic skin eruption 20 0 19 0.7
  Pruritus 18 0 12 0
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough 20 0.7 14 0.7
  PneumonitisIncludes pneumonitis, interstitial lung disease 11 5 3 1.3
  DyspneaIncludes dyspnea, dyspnea exertional, wheezing 11 0.7 7 0.7
Endocrine
  Hypothyroidism 19 0 3 0
Nervous System
  Peripheral neuropathyIncludes dysesthesia, hypoesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy 11 0.7 43 7
  HeadacheIncludes headache, migraine, tension headache 11 0 11 0

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare.

Table 19 summarizes laboratory abnormalities in KEYNOTE-204.

Table 19: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204
  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 143 to 148 patients) and BV (range: 146 to 152 patients); hypomagnesemia: KEYTRUDA n=53 and BV n=50. KEYTRUDA
200 mg every 3 weeks
Brentuximab Vedotin
1.8 mg/kg every 3 weeks
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
All Grades

(%)
Grades 3-4
(%)
Chemistry
  Hyperglycemia 46 4.1 36 2.0
  Increased AST 39 5 41 3.9
  Increased ALT 34 6 45 5
  Hypophosphatemia 31 5 18 2.7
  Increased creatinine 28 3.4 14 2.6
  Hypomagnesemia 25 0 12 0
  Hyponatremia 24 4.1 20 3.3
  Hypocalcemia 22 2.0 16 0
  Increased alkaline phosphatase 21 2.1 22 2.6
  Hyperbilirubinemia 16 2.0 9 1.3
  Hypoalbuminemia 16 0.7 19 0.7
  Hyperkalemia 15 1.4 8 0
Hematology
  Lymphopenia 35 9 32 13
  Thrombocytopenia 34 10 26 5
  Neutropenia 28 8 43 17
  Anemia 24 5 33 8

KEYNOTE-087

Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.4)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.

Table 20: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-087
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=210
All GradesGraded per NCI CTCAE v4.0
(%)
Grade 3
(%)
General
  FatigueIncludes fatigue, asthenia 26 1.0
  Pyrexia 24 1.0
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough 24 0.5
  DyspneaIncludes dyspnea, dyspnea exertional, wheezing 11 1.0
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 21 1.0
  Arthralgia 10 0.5
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 20 1.4
  Vomiting 15 0
  Nausea 13 0
Skin and Subcutaneous Tissue
  Rash Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrheic dermatitis, dermatitis psoriasiform 20 0.5
  Pruritus 11 0
Endocrine
  Hypothyroidism 14 0.5
Infections
  Upper respiratory tract infection 13 0
Nervous System
  Headache 11 0.5
  Peripheral neuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 10 0

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).

Table 21: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL who Received KEYTRUDA in KEYNOTE-087
  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 208 to 209 patients) KEYTRUDA
200 mg every 3 weeks
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
Chemistry
  HypertransaminasemiaIncludes elevation of AST or ALT 34 2
  Increased alkaline phosphatase 17 0
  Increased creatinine 15 0.5
Hematology
  Anemia 30 6
  Thrombocytopenia 27 4
  Neutropenia 24 7

Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).

PMBCL

Among the 53 patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions that occurred in >2% of patients included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170.

Table 22: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=53
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain 30 0
Infections
  Upper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection 28 0
General
  Pyrexia 28 0
  FatigueIncludes fatigue, asthenia 23 2
Respiratory, Thoracic and Mediastinal
  CoughIncludes allergic cough, cough, productive cough 26 2
  Dyspnea 21 11
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis 13 2
  Abdominal pain Includes abdominal pain, abdominal pain upper 13 0
  Nausea 11 0
Cardiac
  Arrhythmia Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia 11 4
Nervous System
  Headache 11 0

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).

Table 23: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170
  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 44 to 48 patients) KEYTRUDA
200 mg every 3 weeks
All GradesGraded per NCI CTCAE v4.0
(%)
Grades 3-4
(%)
Hematology
  Anemia 47 0
  Leukopenia 35 9
  Lymphopenia 32 18
  Neutropenia 30 11
Chemistry
  Hyperglycemia 38 4
  Hypophosphatemia 29 10
  HypertransaminasemiaIncludes elevation of AST or ALT 27 4
  Hypoglycemia 19 0
  Increased alkaline phosphatase 17 0
  Increased creatinine 17 0
  Hypocalcemia 15 4
  Hypokalemia 15 4

Urothelial Cancer

Patients with urothelial cancer in combination with enfortumab vedotin

The safety of KEYTRUDA 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 KEYTRUDA 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 KEYTRUDA and enfortumab vedotin, the median duration of exposure to KEYTRUDA was 8.5 months (range: 9 days to 28.5 months).

Fatal adverse reactions occurred in 3.9% of patients treated with KEYTRUDA 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 KEYTRUDA in combination with enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA 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 KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%).

Dose interruptions of KEYTRUDA occurred in 61% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA 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 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-A39.

Table 24: Adverse Reactions ≥20% (All Grades) in Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-A39
Adverse Reaction KEYTRUDA in combination with
Enfortumab Vedotin
n=440
Chemotherapy

n=433
All GradesGraded per NCI CTCAE v4.03
%
Grades 3-4
%
All Grades

%
Grades 3-4
%
Skin and subcutaneous tissue disorders
  RashIncludes multiple terms 68 15 15 0
  Pruritus 41 1.1 7 0
  Alopecia 35 0.5 8 0.2
General disorders and administration site conditions
  Fatigue
51 6 57 7
Nervous system disorders
  Peripheral neuropathy
67 8 14 0
  Dysgeusia 21 0 9 0
Metabolism and nutrition disorders
  Decreased appetite 33 1.8 26 1.8
Gastrointestinal disorders
  Diarrhea 38 4.5 16 1.4
  Nausea 26 1.6 41 2.8
  Constipation 26 0 34 0.7
Investigations
  Weight loss 33 3.6 9 0.2
Eye disorders
  Dry eye
24 0 2.1 0
Infections and infestations
  Urinary tract infection 21 5 19 8

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%).

Table 25: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-A39
Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 407 to 439 patients) KEYTRUDA
200 mg every 3 weeks and
Enfortumab Vedotin
Chemotherapy
All GradesGraded per NCI CTCAE v4.03
%
Grades 3-4
%
All Grades

%
Grades 3-4
%
Chemistry
  Increased aspartate aminotransferase 75 4.6 39 3.3
  Increased creatinine 71 3.2 68 2.6
  Hyperglycemia 66 14 54 4.7
  Increased alanine aminotransferase 59 5 49 3.3
  Hyponatremia 46 13 47 13
  Hypophosphatemia 44 9 36 9
  Hypoalbuminemia 39 1.8 35 0.5
  Hypokalemia 26 5 16 3.1
  Hyperkalemia 24 1.4 36 4.0
  Hypercalcemia 21 1.2 14 0.2
Hematology
  Lymphopenia 58 15 59 17
  Anemia 53 7 89 33
  Neutropenia 30 9 80 50

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

The safety of KEYTRUDA 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 receive