Keytruda (pembrolizumab) - 19 indications

Scroll down for information on each indication:

• unresectable or metastatic melanoma; approved September 2014
• non-small cell lung cancer; approved October 2015
• head and neck squamous cell cancer; approved August 2016
• classical Hodgkin Lymphoma; approved March 2017
• urothelial carcinoma (bladder cancer) including Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC); Approved May 2017
• previously treated microsatellite instability-high or mismatch repair deficient solid tumors and colorectal cancer; approved May 2017
• gastric or gastroesophageal junction adenocarcinoma regardless of histology or PD-L1 expression; approved September 2017
• recurrent or metastatic cervical cancer; approved June 2018
• primary mediastinal B-cell lymphoma; approved June 2018
• hepatocellular carcinoma; approved November 2018
• Merkel cell carcinoma; approved December 2018
• advanced renal cell carcinoma; approved April 2019
• recurrent esophageal cancer with PD-L1 expressing tumors; approved July 2019
• unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer; approved June 2020
• recurrent, metastatic or locally advanced cutaneous squamous cell carcinoma that is not curable by surgery or radiation; approved June of 2020
• unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors; approved June of 2020
• PD-L1 expressing triple negative breast cancer; approved November of 2020
• MSI-H or dMMR unresectable or metastatic advanced endometrial carcinoma; approved March of 2022
• locally advanced unresectable or metastatic biliary tract cancer; approved October of 2023

General Information

Keytruda (pembrolizumab) is a programmed death receptor-1 (PD-1)-blocking antibody.

Keytruda is specifically indicated for the following conditions:

Melanoma

• for the treatment of patients with unresectable or metastatic melanoma
• for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection
• for the adjuvant treatment of patients <12 years of age with stage IIB or IIC melanoma following complete resection.
• as adjuvant treatment for stage III melanoma following complete resection in pediatric patients (12 years and older)

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
• in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC
• 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: 1) stage III where patients are not candidates for surgical resection or definitive chemoradiation, or 2) metastatic
• 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
• as a single agent, for adjuvant treatment following surgical resection and platinum-based chemotherapy for adult patients with stage IB, II, or IIIA NSCLC
• for the treatment of patients with resectable (tumors ≥4 centimeters [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.

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
• 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
• as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy

Classical Hodgkin Lymphoma (cHL)

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

Urothelial Carcinoma

• for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status
• for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum containing chemotherapy
• 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

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) 1) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or 2) colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

Gastric Cancer

• in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma
• as a single agent for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy
• in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma

Cervical Cancer

• for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
• 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.
•  in combination with chemoradiotherapy (CRT) for the treatment of patients with FIGO (International Federation of Gynecology and Obstetrics) 2014 Stage III-IVA cervical cancer. 

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

Hepatocellular Carcinoma (HCC)

• for the treatment of patients with HCC who have been previously treated with sorafenib

Merkel Cell Carcinoma (MCC)

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

Renal Cell Carcinoma (RCC)

• in combination with axitinib, for the first-line treatment of patients with advanced RCC
• 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

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: 1) in combination with platinum- and fluoropyrimidine-based chemotherapy, or 2) 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

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

• for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer

Cutaneous Squamous Cell Carcinoma (cSCC)

• for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation; subsequently expanded to include locally advanced cSCC that is not curable by surgery or radiation

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

Triple-Negative Breast Cancer (TNBC)

• in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA approved test

Endometrial Cancer

• patients with advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair deficient (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
• 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.

Billiary Tract Cancer

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

Keytruda is supplied as an injection for intravenous administration. Scroll down to see the recommended dosing/administration for each condition.

Mechanism of Action

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

Side Effects

Adverse effects associated with the use of Keytruda as a single agent may include, but are not limited to, the following:

• fatigue
• musculoskeletal pain
• decreased appetite
• pruritus
• diarrhea
• nausea
• rash
• pyrexia
• cough
• dyspnea
• constipation
• pain
• abdominal pain

Adverse effects associated with the use of Keytruda in combination with chemotherapy may include, but are not limited to, the following: 

• fatigue/asthenia
• nausea
• constipation
• diarrhea
• decreased appetite
• rash
• vomiting
• cough
• dyspnea
• pyrexia
• alopecia
• peripheral neuropathy
• mucosal inflammation
• stomatitis
• headache
• weight loss

Adverse effects associated with the use of Keytruda in combination with axitinib may include, but are not limited to, the following: 

• diarrhea
• fatigue/asthenia
• hypertension
• hepatotoxicity
• hypothyroidism
• decreased appetite
• palmar-plantar erythrodysesthesia
• nausea
• stomatitis/mucosal inflammation
• dysphonia
• rash
• cough
• constipation

Indication 1 - unresectable or metastatic melanoma

approved September 2014

Dosing/Administration

• Adult patients with unresectable or metastatic melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression or unacceptable toxicity.
• Adjuvant treatment of adult patients with melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease recurrence, unacceptable toxicity, or up to 12 months.

Clinical Trial Results

The efficacy was Keytruda was evaluated in an open label, randomized, comparative dose trial in subjects with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab.  The subjects were randomized to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of Keytruda every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Assessment of tumor status was performed every 12 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review and duration of response. The ORR was 24% (95% confidence interval: 15, 34) in the 2 mg/kg arm, consisting of 1 complete response and 20 partial responses. Among the 21 subjects with an objective response, 3 (14%) had progression of disease 2.8, 2.9, and 8.2 months after initial response. The remaining 18 subjects (86%) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 subjects with ongoing responses of 6 months or longer. One additional subject developed two new asymptomatic lesions at the first tumor assessment concurrent with a 75% decrease in overall tumor burden; Keytruda was continued and this reduction in tumor burden was durable for 5+ months. There were objective responses in subjects with and without BRAF V600 mutation-positive melanoma. Similar ORR results were observed in the 10 mg/kg arm. 

Indication 2 - non-small cell lung cancer

approved October 2015

Dosing/Administration

• Monotherapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Combination therapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion. Administer Keytruda prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The FDA approval of Keytruda for the first-line treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations was based on the Phase 3 KEYNOTE-042 trial. The randomized, multi-center, open-label, active-controlled trial in patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors expressed PD-L1 (TPS ≥1%) and who had not received prior systemic treatment for metastatic NSCLC. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within two years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within 26 weeks prior to initiation of study treatment were ineligible. The study enrolled 1,274 patients who were randomized (1:1) to receive Keytruda 200 mg intravenously every three weeks (n=637) or investigator’s choice of either of the following chemotherapy regimens (n=637):

• Pemetrexed 500 mg/m2 every three weeks and carboplatin AUC 5 to 6 mg/mL/min every three weeks on Day 1 for a maximum of six cycles followed by optional pemetrexed 500 mg/m2 every three weeks for patients with nonsquamous histologies; or
• Paclitaxel 200 mg/m2 every three weeks and carboplatin AUC 5 to 6 mg/mL/min every three weeks on Day 1 for a maximum of six cycles followed by optional pemetrexed 500 mg/m2 every three weeks for patients with nonsquamous histologies

Treatment with Keytruda continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. In the trial, Keytruda monotherapy demonstrated a statistically significant improvement in OS compared with chemotherapy alone in patients whose tumors expressed PD-L1 with a TPS ≥50%, with a TPS ≥20%, and then in the entire study population (TPS ≥1%).

Indication 3 - head and neck squamous cell cancer

approved August 2016

Dosing/Administration

• Monotherapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Combination therapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion. Administer Keytruda prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The FDA approval of Keytruda for head and neck cancer was based on a multicenter, nonrandomized, open-label, multicohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients received KEYTRUDA 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST 1.1, as assessed by blinded independent central review, and duration of response. The ORR was 16% with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median duration of response had not been reached (range 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and duration of response were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.

Indication 4 - classical Hodgkin Lymphoma

approved March 2017

Dosing/Administration

• Adults: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Pediatrics: 2 mg/kg every 3 weeks (up to a maximum of 200 mg) as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The efficacy of Keytruda was investigated in KEYNOTE-087, a multicenter, non-randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, CRR, and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Data demonstrated an overall response rate of 69 percent after receiving 200 mg every three weeks, with a complete remission rate of 22 percent and a partial remission rate 47 percent.

Indication 5 - urothelial carcinoma (bladder cancer) including Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC)

Approved May 2017

Dosing/Administration

• locally advanced or metastatic urothelial carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion 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 as a 30-minute intravenous infusion until persistent or recurrent high-risk NMIBC, disease progression, unacceptable toxicity, or up to 24 months

Clinical Trial Results

Locally advanced or metastatic urothelial carcinoma

The FDA approval was based on results from the KEYNOTE-052 Phase 2 trial and the KEYNOTE-045 Phase 3 trial. 

KEYNOTE-052 included 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for Platinol-containing chemotherapy. All participants received Keytruda once every three weeks for up to 24 weeks, unless they presented signs of treatment-related toxicity. The treatment had an objective response rate (ORR) of 29%, including 7% complete responses and 22% partial responses. The duration of response ranged from 1.4 to 17.8 months. At the time of the analysis, less than half of patients who responded had seen their disease progress again, hence the median duration of response was unattainable.

KEYNOTE-045 was a multicenter, placebo-controlled study in 542 patients with locally advanced or metastatic urothelial carcinoma, whose disease progressed on or after platinum-based chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy. Patients were randomized to receive either Keytruda every three weeks or investigator’s choice chemotherapy. Chemotherapy regimens included Taxol (paclitaxel), Taxotere (docetaxel), or vinflunine. Overall, Keytruda treatment demonstrated a superior overall survival (OS) compared to the other treatment regimens, with a 27% reduction in the risk of death. Keytruda treatment resulted in a median OS of 10.3 months, compared to 7.4 months in the chemotherapy arm. No statistically significant difference in progression-free survival (PFS) was observed between groups, with those receiving Keytruda having a median PFS of 2.1 months, compared to 3.3 months in the chemotherapy arm. Keytruda was also seen to improve objective response rate compared to chemotherapy regimens. The ORR was 21% in the Keytruda-treated group vs. 11% in the chemotherapy group.

High-risk BCG unresponsive NMIBC

The FDA approval of Keytruda for adult patients with high-risk BCG unresponsive NMIBC was based on data from KEYNOTE-057, a multicenter, open-label, single-arm trial in 96 patients with BCG-unresponsive, high-risk, NMIBC with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. In this study, BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression.

Patients received Keytruda 200 mg every three weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response.

The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Keytruda demonstrated a complete response rate of 41%. Among the 39 patients who achieved a complete response, the median duration of response was 16.2 months, and 46% had a response of 12 months or longer.

Indication 6 - previously treated microsatellite instability-high or mismatch repair deficient solid tumors and colorectal cancer

approved May 2017

Dosing/Administration

• Adults: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Pediatrics: 2 mg/kg every 3 weeks (up to a maximum of 200 mg) as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The FDA approval of Keytruda for adult and pediatric patients who have unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer following progression on a fluoropyrimidine, oxaliplatin and irinotecan was based on data from 149 patients with MSI-H or dMMR cancers enrolled across five single-arm clinical trials. Ninety patients had colorectal cancer (CRC) and the remaining 59 patients had one of 14 other tumor types. The objective response rate (ORR) with Keytruda was 39.6 percent, including 11 (7.4 percent) complete responses (CRs) and 48 (32.2 percent) partial responses (PRs). The ORR was 36 percent in patients with CRC and 46 percent in patients with other tumor types. The median duration of response was not yet reached (range, 1.6+ months to 22.7+ months). Among patients who responded to Keytruda, 78 percent had responses that lasted for at least six months.

Indication 7 - gastric or gastroesophageal junction adenocarcinoma regardless of histology or PD-L1 expression

approved September 2017

Dosing/Administration

• Monotherapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Combination therapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion. Administer Keytruda prior to trastuzumab and chemotherapy when given on the same day

Clinical Trial Results

Recurrent Gastric or GEJ Cancer: 

The FDA approval of Keytruda was based on KEYNOTE-059, a multicenter, non-randomized, open-label multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by blinded independent central review, and duration of response. Among the 259 patients, 55% (n = 143) had tumors that expressed PD-L1. For the 143 patients, the ORR was 13.3%; 1.4% had a complete response and 11.9% had a partial response. Among the 19 responding patients, the duration of response ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and 5 patients (26%) having responses of 12 months or longer.

Gastric or GEJ Cancer Regardless of histology or PD-L1 expression: 

FDA approval was based on the Phase 3 multicenter, randomized, placebo-controlled KEYNOTE-590 trial. The trial enrolled 749 patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. Patients were randomized (1:1) to receive either Keytruda (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with cisplatin (80 mg/m2 on Day 1 every three weeks for up to six cycles) plus FU (800 mg/m2 per day on Days 1 to 5 every three weeks, or per local standard for FU administration, for up to 24 months); all study medications were administered via intravenous infusion. The trial demonstrated significant improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for Keytruda plus fluorouracil (FU) and cisplatin versus FU and cisplatin alone, regardless of histology or PD-L1 expression status. For OS and PFS, Keytruda plus FU and cisplatin reduced the risk of death by 27% and reduced the risk of disease progression or death by 35% versus FU and cisplatin alone. The ORR, an additional efficacy outcome measure, was 45% for patients who received Keytruda plus FU and cisplatin and 29% for those who received FU and cisplatin alone. 

Indication 8 - recurrent or metastatic cervical cancer

approved June 2018

Dosing/Administration

200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months

Clinical Trial Results

The efficacy of Keytruda was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158, a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by blinded independent central review, and duration of response. Among the 98 patients, approval was based on 77 (79%) patients who had tumors that expressed PD-L1 with a CPS ≥1 and who had received at least one line of chemotherapy for metastatic disease. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit. With a median follow-up time of 11.7 months, the ORR in 77 patients was 14.3%, including 2.6% complete responses and 11.7% partial responses. The estimated median response duration based on 11 patients with a response by independent review was not reached; 91% had a response duration of greater than or equal to 6 months. No responses were observed in patients whose tumors did not have PD-L1 expression (CPS ˂1).

Indication 9 - primary mediastinal B-cell lymphoma

approved June 2018

Dosing/Administration

• Adults: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Pediatrics: 2 mg/kg every 3 weeks (up to a maximum of 200 mg) as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The approval of Keytruda for PMBCL was based on data from the KEYNOTE-170 study, a multicenter, open-label, single-arm trial that included 53 patients with relapsed or refractory PMBCL. Patients were treated with Keytruda 200mg IV every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress; efficacy was based on overall response rate (ORR) and duration of response. Results showed that for the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range: 2.1 to 8.5 months); median follow-up time was 9.7 months. The ORR was 45% (11% complete response, 34% partial response) while median duration of response was not reached (range: 1.1+ months to 19.2+ months).

Indication 10 - hepatocellular carcinoma

approved November 2018

Dosing/Administration

200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months

Clinical Trial Results

The FDA approval of Keytruda for patients with hepatocellular carcinoma who have been previously treated with sorafenib was based on KEYNOTE 224, a single-arm, multicenter trial enrolling 104 patients with hepatocellular carcinoma. Patients were required to have disease progression on or after sorafenib or were intolerant to sorafenib, have measurable disease, and Child-Pugh Class A liver impairment. Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity, investigator-assessed confirmed disease progression (based on repeat scan at least 4 weeks from the initial scan showing progression), or completion of 24 months of Keytruda. The major efficacy outcome measure was confirmed overall response rate, as assessed by independent central review (ICR) according to RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The confirmed ICR-assessed overall response rate was 17%, with one complete response and 17 partial responses. Response durations ranged from 3.1 to 16.7 months; 89% of responders had response durations of 6 months or longer and 56% had response durations of 12 months or longer.

Indication 11 - Merkel cell carcinoma

approved December 2018

Dosing/Administration

• Adults: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Pediatrics: 2 mg/kg every 3 weeks (up to a maximum of 200 mg) as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The efficacy of Keytruda was investigated in KEYNOTE-017, a multicenter, nonrandomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients received Keytruda 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and duration of response as assessed by BICR per RECIST v1.1. The overall tumor response rate was 56%. The median duration was response was not reached. Twenty seven patients (96%) had a duration ≥6 months, while 15 patients (54%) had a duration ≥12 months.

Indication 12 - advanced renal cell carcinoma

approved April 2019

Dosing/Administration

• 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion. 
• Administer Keytruda in combination with axitinib 5 mg orally twice daily until disease progression, unacceptable toxicity, or for Keytruda, up to 24 months.

Clinical Trial Results

The FDA approval of Keytruda for RCC was based on the pivotal Phase 3 KEYNOTE-426 trial. The randomized, multi-center, open-label trial was conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”). Patients with active autoimmune disease requiring systemic immunosuppression within the last two years were ineligible. The patients were randomized (1:1) to one of the following treatment arms:

• Keytruda 200 mg intravenously every three weeks up to 24 months in combination with axitinib 5 mg orally, twice daily (n=432).
• Sunitinib 50 mg orally, once daily for four weeks and then off treatment for two weeks (n=429).

Treatment with the Keytruda-axitinib combination continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease or unacceptable toxicity. The main efficacy outcome measures were OS and PFS as assessed by BICR according to modified RECIST v1.1. Additional efficacy outcome measures included ORR, as assessed by BICR. For the main efficacy outcome measures of OS and PFS, the Keytruda-axitinib combination reduced the risk of death by 47% compared to sunitinib; for PFS, the Keytruda-axitinib combination showed a reduction in the risk of progression of disease or death of 31% compared to sunitinib. The ORR, an additional efficacy outcome measure, was 59% for patients who received the Keytruda-axitinib combination and 36% for those who received sunitinib.

The FDA approval of Keytruda 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 was based on data from the pivotal Phase 3 KEYNOTE-564 trial. The trial enrolled 994 patients. Keytruda demonstrated a statistically significant improvement in disease-free survival (DFS), reducing the risk of disease recurrence or death by 32% compared to placebo. 

Indication 13 - recurrent esophageal cancer with PD-L1 expressing tumors

approved July 2019

Dosing/Administration

• Monotherapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Combination therapy: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion. Administer Keytruda prior to prior to chemotherapy when given on the same day until disease progression, unacceptable toxicity, or up to 24 months

Clinical Trial Results

The FDA approval of Keytruda for esophageal cancer was based on the KEYNOTE-181 and KEYNOTE-180 clinical trials.  

KEYNOTE-181 was a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer whose tumors express PD-L1 and who progressed on or after one prior line of systemic treatment for advanced disease. Patients were randomized (1:1) to receive either Keytruda 200 mg every three weeks or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every four-week cycle, docetaxel 75 mg/m2 every three weeks, or irinotecan 180 mg/m2 every two weeks. Treatment with Keytruda or chemotherapy continued until unacceptable toxicity or disease progression. The trial met its primary endpoint of significantly improving overall survival (OS), with a 31% decrease in the risk of death compared to a chemotherapy regimen of paclitaxel, docetaxel or irinotecan.

 KEYNOTE-180 was a multicenter, non-randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least two prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR). The ORR in the 35 patients with ESCC expressing PD-L1 (CPS ≥10) was 20%. Among the seven responding patients, the DoR ranged from 4.2 to 25.1+ months, with five patients (71%) having responses of six months or longer and three patients (57%) having responses of 12 months or longer.

Indication 14 - unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer

approved June 2020

Dosing/Administration

200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The FDA approval of Keytruda as monotherapy for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer was based on data from KEYNOTE-177, a multi-center, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR colorectal cancer. Patients were randomized 1:1 to receive Keytruda 200 mg intravenously every three weeks or investigator’s choice of mFOLFOX6 or FOLFIRI given intravenously every two weeks. In this study, Keytruda monotherapy significantly reduced the risk of disease progression or death by 40% and showed a median PFS of 16.5 months compared with 8.2 months for patients treated with chemotherapy.

Indication 15 - recurrent, metastatic or locally advanced cutaneous squamous cell carcinoma that is not curable by surgery or radiation

approved June of 2020; July of 2021

Dosing/Administration

200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The FDA approval of Keytruda for recurrent or metastatic cutaneous squamous cell carcinoma was based on KEYNOTE-629, a multi-center, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR).  Patients received Keytruda 200 mg intravenously every three weeks until documented disease progression, unacceptable toxicity or a maximum of 24 months. Keytruda demonstrated an ORR of 34%, with a complete response rate of 4% and a partial response rate of 31%. Among the 36 responding patients, 69% had ongoing responses of six months or longer. After a median follow-up time of 9.5 months, the median DOR had not been reached (range, 2.7 to 13.1+ months). The label expansion for locally advanced disease was based on data from the second interim analysis of the Phase 2 KEYNOTE-629 trial, in which KEYTRUDA demonstrated an objective response rate (ORR) of 50% (n=54), including a complete response rate of 17% and a partial response rate of 33% in the cohort of patients with locally advanced disease. Among the 27 responding patients, 81% had a duration of response (DOR) of six months or longer, and 37% had a DOR of 12 months or longer.

Indication 16 - unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors

approved June of 2020

Dosing/Administration

• Adults: 200 mg every 3 weeks or 400 mg every 6 weeks as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.
• Pediatrics: 2 mg/kg every 3 weeks (up to a maximum of 200 mg) as a 30-minute intravenous infusion until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The FDA approval was based on data from a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158, a multicenter, non-randomized, open-label trial evaluating Keytruda (200 mg every three weeks). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. Tumor response was assessed every nine weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) in the patients who received at least one dose of Keytruda as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

In KEYNOTE-158, 1,050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥10 mut/Mb.

In the 102 patients whose tumors were TMB-H, Keytruda demonstrated an ORR of 29%, with a complete response rate of 4% and a partial response rate of 25%. After a median follow-up time of 11.1 months, the median DOR had not been reached. Among the 30 responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer.

In a pre-specified analysis of patients with TMB ≥13 mut/Mb (n=70), Keytruda demonstrated an ORR of 37%, with a complete response rate of 3% and a partial response rate of 34%. After a median follow-up time of 11.1 months, the median DOR had not been reached. Among the 26 responding patients, 58% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. In an exploratory analysis in 32 patients whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13%, including two complete responses and two partial responses.

Indication 17 - PD-L1 expressing triple negative breast cancer

approved November of 2020

Dosing/Administration

200 mg every 3 weeks or 400 mg every 6 weeks as a 30 minute intravenous infusion. Administer Keytruda prior to chemotherapy when given on the same day until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trial Results

The FDA approval was based on data from KEYNOTE-355, a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients were randomized (2:1) to receive either Keytruda (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with the following chemotherapy; all medications were administered via intravenous infusion:

• Pac (90 mg/m2 on Days 1, 8 and 15 every 28 days); or
• Nab-paclitaxel (100 mg/m2 on Days 1, 8 and 15 every 28 days); or
• Gem/carbo (1,000 mg/m2 and AUC 2 mg/mL/min, respectively, on Days 1 and 8 every 21 days).

Randomization was stratified by chemotherapy treatment (pac or nab-paclitaxel vs. gem and carbo), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx kit and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no). Assessment of tumor status was performed at Weeks 8, 16 and 24, then every nine weeks for the first year and every 12 weeks thereafter. The main efficacy outcome measure was PFS. 

In KEYNOTE-355, efficacy results were in patients who were PD‑L1 positive with a CPS ≥10 (n=323) and randomized to receive Keytruda in combination with pac, nab-paclitaxel or gem/carbo compared with the same chemotherapy regimens alone. Keytruda in combination with pac, nab-paclitaxel or gem/carbo (n=220) reduced the risk of disease progression or death by 35%, with a median PFS of 9.7 months versus 5.6 months with the same chemotherapy regimens alone (n=103). For PFS, 62% (n=136) of patients experienced an event with Keytruda in combination with pac, nab-paclitaxel or gem/carbo versus 77% (n=79) with the same chemotherapy regimens alone. For patients who received Keytruda in combination with pac, nab-paclitaxel or gem/carbo, the ORR was 53%, with a complete response rate of 17% and a partial response rate of 36%. For patients treated with the same chemotherapy regimens alone, the ORR was 40%, with a complete response rate of 13% and a partial response rate of 27%. Median DOR was 19.3 months with Keytruda in combination with pac, nab-paclitaxel or gem/carbo versus 7.3 months with the same chemotherapy regimens alone.

Indication 18 - MSI-H or dMMR unresectable or metastatic advanced endometrial carcinoma

approved March of 2022; expanded June of 2024

Dosing/Administration

200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months

Clinical Trial Results

The FDA approval was based on new data from Cohorts D and K of the KEYNOTE-158 trial. The multicenter, non-randomized, open-label, multi-cohort trial enrolled 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in Cohorts D and K who received at least one dose of Keytruda. Patients received Keytruda 200 mg intravenously every three weeks until unacceptable toxicity or documented disease progression. Patients treated with Keytruda without disease progression could be treated for up to 24 months.

The objective response rate (ORR) was 46% for patients who received Keytruda, including a complete response rate of 12% and a partial response rate of 33%, at a median follow-up time of 16.0 months. Of the responding patients (n=41), 68% had responses lasting 12 months or longer, and 44% had responses lasting 24 months or longer. Median duration of response (DOR) was not reached (range, 2.9 to 55.7+ months).

The FDA approval of Keytruda 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 was based on data from the Phase 3 KEYNOTE-868 trial, in which Keytruda plus carboplatin and paclitaxel followed by Keytruda alone reduced the risk of disease progression or death by 40% in patients whose cancer was mismatch repair proficient (pMMR) and by 70% in patients whose cancer was mismatch repair deficient (dMMR), compared to placebo with carboplatin and paclitaxel followed by placebo alone.

Indication 19- locally advanced unresectable or metastatic biliary tract cancer

Dosing/Administration

200 mg every 3 weeks or 400 mg every 6 weeks

Clinical Trial Results

FDA approval was based on results from the Phase 3 KEYNOTE-966 trial, in which Keytruda plus chemotherapy demonstrated a statistically significant improvement in the study’s primary endpoint of overall survival (OS), reducing the risk of death by 17% compared to chemotherapy alone at the trial’s pre-specified final analysis for OS. Median OS was 12.7 months for Keytruda plus chemotherapy versus 10.9 months for chemotherapy alone.