FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for First-Line Treatment of Patients With Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer

KEYTRUDA Is the First Single-Agent, Anti-PD-1 Therapy Approved for the First-Line Treatment of These Patients

Approval Received Less Than One Month Following Submission of sBLA Application Based on Results of KEYNOTE-177

KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, 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. The approval is based on results from the Phase 3 KEYNOTE-177 trial, in which KEYTRUDA significantly reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.45-0.80; p=0.0004]) compared with chemotherapy, the current standard of care. In the study, treatment with KEYTRUDA also more than doubled median progression-free survival (PFS) compared with chemotherapy (16.5 months [95% CI, 5.4-32.4] versus 8.2 months [95% CI, 6.1-10.2]).

Today’s approval has the potential to change the treatment paradigm for the first-line treatment of patients with MSI-H colorectal cancer, based on the important findings from KEYNOTE-177 that showed KEYTRUDA monotherapy demonstrated superior progression-free survival compared to standard of care chemotherapy,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Our commitment to pursuing biomarker research continues to help us bring new treatments to patients, particularly for those who have few available options.”

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

This approval was granted less than one month following the submission of a new supplemental Biologics License Application (sBLA), which was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program. This review also was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. For this application, a modified Project Orbis was undertaken, and the FDA is collaborating with the Australian Therapeutic Goods Administration, Health Canada and Swissmedic on their ongoing review of the application.

Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options,” said Luis A. Diaz, M.D., head of the division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center. “In patients who were treated with KEYTRUDA and responded (n=67) in the KEYNOTE-177 trial, 43% of patients experienced a duration of response lasting two years or longer. This approval helps address the unmet need to provide a new monotherapy treatment option for patients.”

Data Supporting the Approval

The approval was based on data from KEYNOTE-177 (NCT02563002), 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. Microsatellite instability (MSI) or mismatch repair (MMR) tumor status was determined locally using polymerase chain reaction or immunohistochemistry, respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients were randomized 1:1 to receive KEYTRUDA 200 mg intravenously every three weeks or investigator’s choice of the following chemotherapy regimens given intravenously every two weeks:

  • mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) or mFOLFOX6 in combination with either bevacizumab or cetuximab: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and fluorouracil 400 mg/m2 bolus on Day 1, then fluorouracil 2,400 mg/m2 over 46-48 hours; plus bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
  • FOLFIRI (irinotecan, leucovorin, and fluorouracil) or FOLFIRI in combination with either bevacizumab or cetuximab: irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and fluorouracil 400 mg/m2 bolus on Day 1, then fluorouracil 2,400 mg/m2 over 46-48 hours; plus bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.

Treatment with KEYTRUDA or chemotherapy continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every nine weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, and overall survival (OS). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR).

Patients were enrolled and randomized to KEYTRUDA (n=153) or chemotherapy (n=154). The baseline characteristics of these 307 patients were: median age of 63 years (range, 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, and 48% had an ECOG PS of 1; and 27% received prior adjuvant or neoadjuvant chemotherapy. Among the 154 patients randomized to receive chemotherapy, 143 received chemotherapy per the protocol. Of these 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI. The median follow-up time was 27.6 months (range, 0.2 to 48.3 months).

In this study, KEYTRUDA monotherapy significantly reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.45-0.80; p=0.0004]) and showed a median PFS of 16.5 months (95% CI, 5.4-32.4) compared with 8.2 months (95% CI, 6.1-10.2) for patients treated with chemotherapy. For PFS, in the KEYTRUDA arm, there were 82 patients (54%) with an event versus 113 patients (73%) in the chemotherapy arm. At the time of the PFS analysis, the OS data were not mature (66% of the required number of events for the OS final analysis). For patients treated with KEYTRUDA, the ORR was 44% (95% CI, 35.8-52.0), with a complete response rate of 11% and a partial response rate of 33%, and for patients treated with chemotherapy, the ORR was 33% (95% CI, 25.8-41.1), with a complete response rate of 4% and a partial response rate of 29%. Median DOR was not reached (range, 2.3+ to 41.4+) with KEYTRUDA versus 10.6 months (range, 2.8 to 37.5+) with chemotherapy. Based on 67 patients with a response in the KEYTRUDA arm and 51 patients with a response in the chemotherapy arm, 75% in the KEYTRUDA arm had a duration of response greater than or equal to 12 months versus 37% in the chemotherapy arm, and 43% in the KEYTRUDA arm had a duration of response greater than or equal to 24 months versus 18% in the chemotherapy arm.

Among the 153 patients with MSI-H or dMMR colorectal cancer treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range, 1 day to 30.6 months). Adverse reactions occurring in patients with MSI-H or dMMR colorectal cancer were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer treated with KEYTRUDA as a single agent.

About KEYTRUDA® (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA® (pembrolizumab) Indications

Melanoma

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

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

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, 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, 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.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. 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 confirmatory trials.

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.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. 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.

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. 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 confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) 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. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

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

Microsatellite Instability-High (MSI-H) Cancer

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

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

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. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Colorectal Cancer

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

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. 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.

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Tumor Mutational Burden-High (TMB-H)

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, 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination 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. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. 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.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.

Contacts

Media Contacts:

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(267) 305-3558

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Investor Contacts:

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(908) 740-1037

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(908) 740-6132

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