FDA Converts to Full Approval Indication for KEYTRUDA® (pembrolizumab) for Certain Adult and Pediatric Patients With Advanced Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Solid Tumors
KEYTRUDA is approved for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options
RAHWAY, NJ, USA I March 29, 2023 I Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has granted full approval to KEYTRUDA, Merck’s anti-PD-1 therapy, 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. The conversion from an accelerated to a full (regular) approval is based on results from the Phase 2 KEYNOTE-158, KEYNOTE-164 and KEYNOTE-051 trials and includes data in 504 adult and pediatric patients across more than 30 types of cancer. This marks the first full approval for an immunotherapy based on a predictive biomarker, regardless of solid tumor type.
“This approval reinforces the important role of KEYTRUDA in certain patients with MSI-Hor dMMR solid tumors facing a variety of cancers,” said Dr. Luis A. Diaz, Jr., head of the Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center. “These data also further underscore the need for biomarker testing to identify patients who may be eligible for this therapy.”
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 during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune- mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently 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.
"Today’s approval builds on the 2017 accelerated approval of KEYTRUDA as the first immunotherapy with a tumor agnostic indication and supports the role of KEYTRUDA as an effective immunotherapy option based on a pan-tumor predictive biomarker," said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. “This milestone reflects Merck’s longstanding commitment to biomarker research and personalizing treatment strategies for patients.”
Data supporting the approval
The full approval was based on data from three multicenter, non-randomized, open-label multi-cohort trials. KEYNOTE-164 (NCT02460198) enrolled 124 patients with advanced MSI-H/dMMR colorectal cancer that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan with or without anti-VEGF/EGFRmAb-based therapy. KEYNOTE-158 (NCT02628067) enrolled 373 patients with advanced MSI-H/dMMR non-colorectal cancers who had disease progression following prior therapy. Patients were either prospectively enrolled with MSI-H/dMMR tumors (Cohort K) or retrospectively identified in one of 10 solid tumor cohorts (Cohorts A-J). KEYNOTE-051 (NCT02332668) enrolled seven pediatric patients with MSI-H/dMMR cancers. All trials excluded patients with autoimmune disease or a medical condition that required immunosuppression. Regardless of histology, MSI or MMR tumor status was determined using polymerase chain reaction (local or central) or immunohistochemistry (local or central), respectively.
Adult patients received KEYTRUDA 200 mg administered intravenously every three weeks (pediatric patients received 2 mg/kg every three weeks) until unacceptable toxicity, disease progression or a maximum of 24 months. In KEYNOTE‑164 and KEYNOTE‑158, assessment of tumor status was performed every nine weeks through the first year, then every 12 weeks thereafter. In KEYNOTE‑051, assessment of tumor status was performed every eight weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ in KEYNOTE-158) and as assessed by the investigator according to RECIST v1.1 in KEYNOTE-051.
In a pooled analysis of the three trials, KEYTRUDA demonstrated an ORR of 33.3% (95% CI, 29.2-37.6), including a complete response rate of 10.3% and partial response rate of 23.0% at a median follow-up time of 20.1 months (range, 0.1 to 71.4 months). Of the responding patients (n=168), 77% had responses lasting 12 months or longer, and 39% had responses lasting 36 months or longer. Median DOR was 63.2 months (range, 1.9+ to 63.9+ months).
In KEYNOTE-158 and KEYNOTE-164, the median duration of exposure to KEYTRUDA was 6.2 months (range, 1 day to 53.5 months). In KEYNOTE-051, the median duration of exposure was 2.1 months (range: 1 day to 25 months).
About Microsatellite Instability-High (MSI-H) and Deficient Mismatch Repair (dMMR)
Microsatellite instability (MSI) and 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. MSI-H and dMMR can occur when a cell is unable to repair mistakes during that division process.
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 1,600 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.
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.
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:
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.
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.
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 HNSCC with disease progression on or after platinum-containing chemotherapy.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
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.
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.
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.
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.
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.
KEYTRUDA, as a single agent, is indicated for the treatment of 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.
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] 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.
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.
At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting https://www.merckaccessprogram-keytruda.com/.
Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The KEY+YOU Patient Support Program provides a range of resources and support. For further information and to sign up, eligible patients may call 85-KEYTRUDA (855- 398-7832) or visit www.keytruda.com.
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.
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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