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Keytruda Combination Falls Short of Disease-Free Survival Primary Endpoint in Phase III Trial for High-Risk Endometrial Cancer

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Keytruda (pembrolizumab; Merck) plus chemotherapy as adjuvant therapy, with or without radiotherapy, in the treatment of patients with newly diagnosed high-risk endometrial cancer following surgery with curative intent did not achieve the primary endpoint of disease-free survival (DFS) in the Phase III KEYNOTE-B21 (NCT04634877) trial. Keytruda, an anti-PD-1 therapy, bolsters the ability of the immune system to detect and eliminate tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands—PD-L1 and PD-L2—which activates T lymphocytes that could impact the tumor and healthy cells.

“While these results were not what we had hoped, we are focused on continuing to build on the established role of Keytruda in advanced endometrial carcinoma through our approved indications, while rapidly progressing clinical research evaluating Keytruda-based combinations and other investigational candidates, including antibody-drug conjugates, in endometrial and other types of gynecologic malignancies,” said Gursel Aktan, MD, PhD, vice president, global clinical development, Merck Research Laboratories, said in a press release. “We would like to thank all the patients, the investigators and our study collaborators for their participation in this trial.”1

Endometrial cancer develops when malignant cells form in the tissues of the endometrium. Risk factors for the disease include obesity, metabolic syndrome, use of tamoxifen for breast cancer, and taking estrogen alone without progesterone.2 According to the American Cancer Society, approximately 67,880 new cases of uterine cancers will be diagnosed in 2024, with approximately 13,250 deaths resulting from the disease.3

The randomized, double-blind KEYNOTE-B21 trial compared adjuvant Keytruda combined with chemotherapy, with or without radiotherapy, vs. adjuvant placebo with chemotherapy, with or without radiotherapy, in the treatment of patients with newly diagnosed, high-risk endometrial cancer following surgery with curative intent. The trial’s primary endpoints are DFS and overall survival (OS), with secondary endpoints that include safety.

Investigators randomly assigned approximately 1,095 patients to receive either Keytruda at a dose of 200 mg every three weeks for six cycles with concurrent standard of care chemotherapy for four or six cycles, followed by Keytruda at a dose of 400 mg every six weeks for an additional six cycles, with or without radiotherapy; or placebo administered every three weeks for six cycles plus concurrent standard of care chemotherapy for four or six cycles, followed by placebo every six weeks for an additional six cycles, with or without radiotherapy.

A pre-specified interim analysis by an independent Data Monitoring Committee found that adjuvant treatment with the Keytruda combination did not meet the trial’s pre-specified statistical criteria for DFS compared with the placebo adjuvant chemotherapy combination, with or without radiotherapy. The other primary endpoint of OS was not formally evaluated because the DFS findings did not achieve superiority. In terms of safety, findings for Keytruda were consistent with has previously been reported in clinical trials, with no new safety signals identified.

To date, more than 1600 trials are evaluating Keytruda across a range of cancer types and treatment settings. Keytruda also has approved indications in melanoma; non-small cell lung cancer; head and neck squamous cell cancer; classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma; urothelial carcinoma; gastric cancer; microsatellite instability-high or mismatch repair deficient cancer; microsatellite instability-high or mismatch repair deficient colorectal cancer; esophageal cancer; cervical cancer; hepatocellular carcinoma; Merkel cell carcinoma; renal cell carcinoma; endometrial carcinoma; tumor mutational burden-high cancer; cutaneous squamous cell carcinoma; and triple-negative breast cancer.

In endometrial cancer, Keytruda has two FDA-approved indications: combined with Lenvima (lenvatinib) in the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient or not microsatellite instability-high (MSI-H), and as a monotherapy for patients with advanced endometrial carcinoma that is MSI-H or mismatch repair deficient.

Merck stated that a full evaluation of data from the KEYNOTE-B21 trial is ongoing, and the company will meet with investigators to share these findings with the scientific community.

References

1. Merck Provides Update on Phase 3 KEYNOTE-B21 Trial Evaluating KEYTRUDA® (pembrolizumab) Plus Chemotherapy, With or Without Radiotherapy, for Patients With Newly Diagnosed, High-Risk Endometrial Cancer After Surgery With Curative Intent. News release. Merck. May 9, 2024. Accessed May 9, 2024. https://www.merck.com/news/merck-provides-update-on-phase-3-keynote-b21-trial-evaluating-keytruda-pembrolizumab-plus-chemotherapy-with-or-without-radiotherapy-for-patients-with-newly-diagnosed-high-risk-endometrial-c/

2. National Cancer Institute. Endometrial Cancer Treatment (PDQ®)–Patient Version. Webpage. Updated November 13, 2020. Accessed May 9, 2024. https://www.cancer.gov/types/uterine/patient/endometrial-treatment-pdq#:~:text=Endometrial%20cancer%20is%20a%20disease,the%20risk%20of%20endometrial%20cancer.

3. American Cancer Society. Key Statistics for Endometrial Cancer. Webpage. Updated January 17, 2024. Accessed May 9, 2024. https://www.cancer.org/cancer/types/endometrial-cancer/about/key-statistics.html