Keytruda falls short in newly diagnosed endometrial cancer patients

Merck & Co. has encountered a hurdle in its quest to further expand the use of Keytruda (pembrolizumab) in the treatment of endometrial cancer. The company's Phase III KEYNOTE-B21 study revealed that the PD-1 inhibitor did not significantly improve disease-free survival (DFS) in certain newly diagnosed patients with endometrial cancer. This outcome hampers Merck's ongoing competition with GSK's Jemperli (dostarlimab) in this therapeutic area.

The KEYNOTE-B21 clinical trial investigated the efficacy of Keytruda combined with chemotherapy, with or without radiotherapy, as an adjuvant treatment in newly diagnosed, high-risk endometrial cancer patients who had undergone surgery with curative intent. The randomized trial included 1095 participants. However, a pre-specified interim analysis showed that the combination of Keytruda and chemotherapy did not achieve the primary endpoint of significantly extending DFS compared to the placebo plus chemotherapy group. As the DFS target was not met, the study did not proceed to formally evaluate overall survival, which was another primary objective. Merck is currently reviewing the complete data set and plans to disseminate the findings within the scientific community.

Keytruda has two existing FDA approvals for endometrial cancer. One approval is for its combination with Eisai's Lenvima (lenvatinib) in the treatment of advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) in patients with previous disease progression. The other approval is for Keytruda as a standalone treatment for advanced endometrial carcinoma with MSI-H or mismatch repair deficient (dMMR) following prior systemic therapy.

In comparison, GSK's Jemperli has been making strides in the endometrial cancer market. Jemperli, combined with chemotherapy, secured FDA approval in July for newly diagnosed advanced or recurrent endometrial cancer patients with dMMR or MSI-H tumors, thereby surpassing Merck in obtaining a first-line treatment approval. GSK is also aiming to further expand Jemperli's indications. Recently, the FDA accepted GSK's application to extend Jemperli's use to all newly diagnosed advanced endometrial cancer patients, including those with pMMR/microsatellite stable (MSS) tumors, based on survival data from the Phase III RUBY trial. A decision from the FDA is expected by August 23.

Meanwhile, Merck has ongoing pivotal trials such as NRG-GY018/KEYNOTE-868, which evaluates Keytruda in combination with chemotherapy, followed by Keytruda alone in patients with primary advanced or recurrent endometrial carcinoma. Previous data from these studies suggest that both Jemperli and Keytruda are competitive in terms of progression-free survival (PFS) in the dMMR patient population, although Keytruda showed a PFS benefit of 46% among pMMR patients. The FDA recently granted a priority review to Merck's application based on the NRG-GY018/KEYNOTE-868 trial, with a decision due by June 21.

Merck's development pipeline for Keytruda also includes the Phase III KEYNOTE-C93 study, which is comparing the drug to chemotherapy in patients with dMMR advanced or recurrent endometrial carcinoma. Additionally, the company is conducting the Phase III MK-2870-005 trial, which compares the Trop2-directed antibody-drug conjugate sacituzumab tirumotecan with the physician's choice of treatment in endometrial carcinoma patients previously treated with platinum-based chemotherapy and immunotherapy.

In summary, while Merck's efforts with Keytruda in endometrial cancer have faced challenges, the company continues to pursue multiple clinical trials to broaden its therapeutic utility and compete within this market.