Merck's Keytruda Approved for 40th Indication: First-Line Treatment for Endometrial Cancer

On June 17, 2024, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) in combination with chemotherapy drugs carboplatin and paclitaxel, followed by pembrolizumab monotherapy, for adult patients with primary advanced or recurrent endometrial carcinoma.

According to Merck, Keytruda is currently the first and only anti-PD-1 therapy approved by the FDA for use in combination with chemotherapy for adult patients with primary advanced or recurrent endometrial carcinoma, regardless of mismatch repair (MMR) status. Mismatch repair is a DNA repair mechanism that corrects errors in DNA molecules containing mismatched bases, and it is one of the commons clinical biomarkers used in endometrial carcinoma.

Keytruda, developed by Merck, is a PD-1 inhibitor that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. This action releases the inhibition mediated by the PD-1 pathway on the immune response, thereby activating T lymphocytes that can affect both tumor and healthy cells. This enhances the body's immune system's ability to recognize and destroy cancer cells. According to Merck's 2023 financial reports, Keytruda achieved sales of $25 billion in 2023, making it the highest-selling drug worldwide.

Endometrial cancer is one of the few malignancies with increasing incidence and mortality rates. Data suggest that by 2040, it will become the third most prevalent cancer and the fourth leading cause of cancer death among women. The standard first-line chemotherapy for endometrial cancer is a paclitaxel plus carboplatin. The efficacy of immune checkpoint inhibitors (such as Keytruda monotherapy and dostarlimab-gxly) as second-line and later treatments has been established for patients with microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) endometrial cancer. Keytruda's patent is set to expire in 2028. Merck has been exploring the potential of combining Keytruda with other therapies and expanding its oncology portfolio. Previously, Keytruda had already received two FDA approvals for indications in endometrial cancer.

This latest approval marks the third indication for Keytruda in endometrial cancer. Since it's initial FDA approval for the treatment of advanced melanoma in 2014, Keytruda had received FDA approvals for at least 16 types of cancer.

According to the FDA, this approval is primarily based on results from a Phase III clinical trial (KEYNOTE-868/NRG-GY018). This multicenter, randomized, double-blind, placebo-controlled trial enrolled 810 patients with advanced or recurrent endometrial cancer. The trial included two independent cohorts based on MMR status: 222 patients with deficient mismatch repair (dMMR) and 588 patients with proficient mismatch repair (pMMR). Patients were randomized (1:1) to receive Keytruda combined with chemotherapy (carboplatin and paclitaxel) followed by Keytruda monotherapy, or placebo combined with chemotherapy followed by placebo monotherapy.

The primary efficacy endpoint of the trial was progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression or death. In the dMMR cohort, the median PFS was not reached in the Keytruda combination therapy group, while the placebo group had a median PFS of 6.5 months, showing a significant statistical difference. In the pMMR cohort, the median PFS was 11.1 months in the Keytruda combination therapy group compared to 8.5 months in the placebo group, also showing a statistical difference. In the trial, treatment-related adverse events in the Keytruda combination therapy group were generally consistent with previously reported studies, although there was a higher incidence of rash among patients.