KENILWORTH, N.J. - Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced that the European Commission has approved KEYTRUDA, Merck's anti-PD-1 therapy, as monotherapy for the treatment of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors in adults with: unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy; advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation; unresectable or metastatic gastric, small intestine or biliary cancer, who have disease progression on or following at least one prior therapy. This is the second approval for KEYTRUDA in Europe based on the MSI-H/dMMR biomarker. KEYTRUDA is also approved for the first-line treatment of metastatic MSI-H or dMMR colorectal cancer in adults.

'Our company has a strong track record of applying precision medicine, through biomarkers like MSI-H and dMMR, to help identify patients most likely to respond to KEYTRUDA based on the genetic makeup of their individual cancer,' said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. 'For patients with MSI-H/dMMR colorectal cancer, KEYTRUDA monotherapy was approved in Europe as a first-line option in January 2021. Building on that approval, we are pleased that KEYTRUDA is now approved for the treatment of additional MSI-H/dMMR tumors, in certain second- or later-line patients with colorectal, endometrial, gastric, small intestine or biliary cancer.'

'In the two studies supporting this approval, KEYTRUDA monotherapy showed strong objective response rates and durability of response in patients with five different types of MSI-H/dMMR cancers,' said Dr. Aurelien Marabelle, Immuno-Oncologist at Gustave Roussy Cancer Center and Professor of Clinical Immunology at the University of Paris Saclay. 'The EU approval of KEYTRUDA is an important milestone for patients living with these MSI-H/dMMR cancers who have had few treatment options and face worse outcomes when diagnosed at an advanced stage.'

This approval allows marketing of KEYTRUDA monotherapy in all 27 European Union (EU) member states plus Iceland, Lichtenstein, Norway and Northern Ireland.

Data Supporting the European Approval

The approval was based on data from KEYNOTE-164 (NCT02460198) and KEYNOTE-158 (NCT02628067), multicenter, non-randomized, open-label Phase 2 trials evaluating KEYTRUDA in patients with advanced MSI-H or dMMR solid tumors. The KEYNOTE-164 trial enrolled 124 patients with unresectable or metastatic MSI-H or dMMR colorectal cancer that progressed following prior fluoropyrimidine-based therapy in combination with irinotecan and/or oxaliplatin. The KEYNOTE-158 trial enrolled 355 patients with unresectable or metastatic MSI-H or dMMR solid tumors, including endometrial, gastric, small intestine or biliary cancer. Microsatellite instability or MMR tumor status was determined by prospectively using polymerase chain reaction or immunohistochemistry, respectively. Patients received KEYTRUDA 200 mg administered intravenously every three weeks until unacceptable toxicity or disease progression. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Patients without disease progression were treated for up to 24 months (up to 35 cycles). The primary efficacy outcome measure for the trials was objective response rate (ORR) as assessed by blinded independent central review using RECIST v1.1. The secondary efficacy outcome measures for the trials included duration of response (DOR), progression-free survival and overall survival.

Efficacy results from the KEYNOTE-164 and KEYNOTE-158 trials are summarized below. For patients with:

Colorectal cancer (n=124), the ORR was 34% (95% CI, 25.6-42.9), including a complete response (CR) rate of 10% and a partial response (PR) rate of 24%, at a median follow-up time of 37.3 months (range, 0.1 to 65.2). Median DOR was not reached (range, 4.4 to 58.5+ months), and of responding patients, 92% had responses lasting at least three years.

Endometrial cancer (n=83), the ORR was 51% (95% CI, 39.4-61.8), including a CR rate of 16% and a PR rate of 35%, at a median follow-up time of 21.9 months (range, 1.5 to 64.0). Median DOR was not reached (range, 2.9 to 60.4+ months), and of responding patients, 85% had responses lasting at least one year, and 60% had responses lasting at least three years.

Gastric cancer (n=51), the ORR was 37% (95% CI, 24.1-51.9), including a CR rate of 14% and a PR rate of 24%, at a median follow-up time of 13.9 months (range, 1.1 to 66.9). Median DOR was not reached (range, 6.2 to 63.0+ months), and of responding patients, 90% had responses lasting at least one year, and 81% had responses lasting at least three years.

Small intestine cancer (n=27), the ORR was 56% (95% CI, 35.3-74.5), including a CR rate of 15% and a PR rate of 41%, at a median follow-up time of 29.1 months (range, 4.2 to 67.7). Median DOR was not reached (range, 3.7+ to 57.3+ months), and of responding patients, 93% had responses lasting at least one year, and 73% had responses lasting at least three years.

Biliary cancer (n=22), the ORR was 41% (95% CI, 20.7-63.6), including a CR rate of 14% and a PR rate of 27%, at a median follow-up time of 19.4 months (range, 1.1 to 60.8). Median DOR was 30.6 months (range, 6.2 to 46.0+), and of responding patients, 89% had responses lasting at least one year, and 42% had responses lasting at least three years.

The safety of KEYTRUDA as monotherapy has been evaluated in 7,148 patients with advanced melanoma, resected stage III melanoma (adjuvant therapy), non-small cell lung cancer, classical Hodgkin lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, colorectal cancer, endometrial, gastric, small intestine, biliary, pancreatic cancer or adjuvant therapy of renal cell carcinoma across four doses (2 mg/kg bodyweight [bw] every three weeks, 200 mg every three weeks or 10 mg/kg bw every two or three weeks) in clinical studies. In this patient population, the most frequent adverse reactions with KEYTRUDA were fatigue (31%), diarrhea (22%) and nausea (21%). The majority of adverse reactions reported for KEYTRUDA monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions. The incidences of immune-related adverse reactions were 36.1% for all Grades and 8.9% for Grades 3-5 for KEYTRUDA monotherapy in the adjuvant setting (n=1,480) and 24.2% for all Grades and 6.4% for Grades 3-5 for KEYTRUDA monotherapy in the metastatic setting (n=5,375). No new immune-related adverse reactions were identified in the adjuvant setting.

About Microsatellite Instability-High (MSI-H) and Deficient Mismatch Repair (dMMR)

Microsatellite instability (MSI) and deficient mismatch repair (dMMR) are biomarkers that have been identified in many different types of cancer and that can be hereditary or random. MSI is a change that occurs in the DNA of certain cells, such as cancer cells, in which the number of repeated DNA bases in a microsatellite (which is a short, repeated sequence of DNA) is different from what it was when the microsatellite was inherited. dMMR describes cells that have mutations in certain genes involved in correcting mistakes made when DNA is copied into a cell when dividing. High levels of MSI (MSI-H) and dMMR can occur when a cell is unable to repair mistakes during that division process.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (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 1,700 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.

Merck's Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world - and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

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