FDA Approves KEYTRUDA Combo for Advanced/Recurrent Endometrial Carcinoma

Merck & Co. has announced that the U.S. Food and Drug Administration (FDA) has approved its anti-PD-1 therapy, KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA alone, for treating adult patients with primary advanced or recurrent endometrial carcinoma. This approval marks the third indication for KEYTRUDA in endometrial carcinoma and its 40th overall indication in the U.S.

The approval is based on the results from the Phase 3 NRG-GY018 trial, also referred to as KEYNOTE-868. The trial demonstrated that the combination of KEYTRUDA with carboplatin and paclitaxel, followed by KEYTRUDA alone, significantly reduced the risk of disease progression or death by 40% in patients with proficient mismatch repair (pMMR) and by 70% in those with deficient mismatch repair (dMMR), compared to a placebo with chemotherapy.

Dr. Ramez N. Eskander, the principal investigator, emphasized that this is the first Phase 3 trial to independently evaluate patients with pMMR and dMMR tumors. He noted the significant and clinically meaningful progression-free survival benefit of adding pembrolizumab to chemotherapy for these patients.

Patients in the pMMR group treated with the KEYTRUDA combination had a median progression-free survival (PFS) of 11.1 months compared to 8.5 months for those receiving placebo. In the dMMR group, median PFS was not reached in the KEYTRUDA group but was 6.5 months in the placebo group. The trial included 810 patients with advanced or recurrent endometrial carcinoma, with 27% in the dMMR cohort and 73% in the pMMR cohort.

The trial design involved randomization of patients to receive either KEYTRUDA with carboplatin and paclitaxel or a placebo with the same chemotherapy regimen. Treatments continued until disease progression, unacceptable toxicity, or up to 20 cycles. The major outcome measure was PFS, with overall survival (OS) as an additional measure. At the time of PFS analysis, OS data were not yet mature.

Safety data indicated that serious adverse reactions occurred in 35% of patients receiving the KEYTRUDA combination, compared to 19% in the placebo group. Fatal adverse reactions were observed in 1.6% of patients on the KEYTRUDA regimen. Immune-mediated adverse reactions, which can be severe or fatal, were noted and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and dermatologic reactions. Early identification and management of these reactions are crucial for the safe use of KEYTRUDA.

KEYTRUDA also has two additional approved indications in the U.S. for endometrial carcinoma. One, based on the KEYNOTE-775/Study 309, is in combination with LENVIMA for patients with advanced endometrial carcinoma that is pMMR or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. The second, based on KEYNOTE-158, is as a single agent for patients with advanced endometrial carcinoma that is MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

This latest approval was reviewed under the FDA's Project Orbis initiative, which allows for concurrent review of oncology drugs with international partners. The application is still under review by health authorities in several countries including Israel, Canada, Australia, Singapore, Brazil, and the United Kingdom.

This development is significant as endometrial cancer is the most common gynecologic cancer in the U.S., with deaths from the disease expected to surpass those from ovarian cancer by 2024, highlighting the need for more treatment options. The approval of KEYTRUDA provides a new treatment avenue for patients with primary advanced or recurrent endometrial carcinoma, regardless of mismatch repair status.