On February 20, 2024 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported the U.S. Food and Drug Administration (FDA) has accepted for priority review a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with standard of care chemotherapy (carboplatin and paclitaxel), followed by KEYTRUDA as a single agent for the treatment of patients with primary advanced or recurrent endometrial carcinoma (Press release, Merck & Co, FEB 20, 2024, View Source [SID1234640285]). The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 21, 2024.
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The sBLA is based on data from the Phase 3 NRG-GY018 trial. Results from the study, presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer and simultaneously published in the New England Journal of Medicine, showed KEYTRUDA plus chemotherapy reduced the risk of disease progression or death by 46% (HR=0.54 [95% CI, 0.41-0.71]; p<0.00001) in patients whose cancer was mismatch repair proficient (pMMR) and by 70% (HR=0.30 [95% CI, 0.19-0.48]; p<0.00001) in patients whose cancer was mismatch repair deficient (dMMR), compared to chemotherapy alone.
"Endometrial cancer is the most common type of gynecological cancer, and frontline treatment options are limited for patients with advanced stage or recurrent disease," said Dr. Ramez Eskander, principal investigator and gynecologic oncologist, University of California San Diego, Moores Cancer Center. "The use of KEYTRUDA in this setting has the potential to address a significant unmet need for these patients."
"If approved, KEYTRUDA would be the first immunotherapy indicated for the frontline treatment of advanced endometrial cancer regardless of mismatch repair status," said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. "We are committed to working closely with the FDA to bring KEYTRUDA to these patients who are in need of additional treatment options, and we thank our collaborators for their partnership on this study."
This trial was sponsored by the U.S. National Cancer Institute (NCI), part of the National Institutes of Health. NRG Oncology designed and led the trial with funding from the NCI and participation from all the National Clinical Trials Network (NCTN) Groups. Merck provided funding and support through a Cooperative Research and Development Agreement (CRADA) between Merck and NCI.
This review is also being 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. Health authorities in Israel, Canada, Australia, Singapore and Brazil will review this application as part of Project Orbis.
In the U.S., KEYTRUDA has two approved indications in endometrial cancer. One indication, based on KEYNOTE-775/Study 309, is in combination with LENVIMA (lenvatinib), in collaboration with Eisai, for the treatment of patients with advanced endometrial carcinoma that is pMMR, as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. The second indication, based on KEYNOTE-158, is as a single agent, 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.
Merck has a comprehensive clinical development program in breast and gynecologic (ovarian, cervical, and endometrial) cancers, comprised of more than 20 Merck-sponsored Phase 3 studies evaluating KEYTRUDA as monotherapy and in combination with other medicines. In endometrial cancer, Merck is evaluating KEYTRUDA in the first-line setting for advanced or recurrent disease that is dMMR (KEYNOTE-C93/ENGOT-en15/GOG-3064) and in the adjuvant setting (KEYNOTE-B21/ENGOT-en11/GOG-3053).
About NRG-GY018
NRG-GY018, also known as Merck’s KEYNOTE-868, is a randomized, blinded, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03914612) evaluating KEYTRUDA in combination with standard of care chemotherapy (carboplatin and paclitaxel) versus placebo plus standard of care chemotherapy for the treatment of measurable stage III, IVA, IVB or recurrent endometrial cancer in pMMR and dMMR cohorts. The primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, objective response rate, duration of response and safety. The trial enrolled 816 patients who were randomized to receive:
KEYTRUDA plus chemotherapy (carboplatin and paclitaxel) every three weeks for approximately six cycles followed by KEYTRUDA as a single agent every six weeks for up to 14 cycles, or
Placebo plus chemotherapy (carboplatin and paclitaxel) every three weeks for approximately six cycles.
Enrolled patients were required to have MMR IHC testing prior to randomization; 591 patients were determined to have pMMR tumors, and 225 were determined to have dMMR tumors.
About endometrial carcinoma
Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. In the U.S., it is estimated there will be approximately 67,880 new cases of uterine body cancer and approximately 13,250 deaths from the disease in 2024. Globally, endometrial cancer is the sixth most common cancer in women and 15th most common cancer overall.