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RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the Phase 3 KEYNOTE-B21 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy as adjuvant treatment, with or without radiotherapy, did not meet its primary endpoint of disease-free survival (DFS) for the treatment of patients with newly diagnosed, high-risk endometrial cancer after surgery with curative intent.
At a pre-specified interim analysis conducted by an independent Data Monitoring Committee, adjuvant treatment with KEYTRUDA plus chemotherapy, with or without radiotherapy, did not meet the study’s pre-specified statistical criteria for DFS compared to placebo plus adjuvant chemotherapy, with or without radiotherapy. The study’s other primary endpoint of overall survival (OS) was not formally tested since superiority was not reached for DFS. The safety profile of KEYTRUDA was consistent with that observed in previously reported studies; no new safety signals were identified. A full evaluation of the data from this study is ongoing. Merck will work with investigators to share the results with the scientific community.
“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 Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “We would like to thank all the patients, the investigators and our study collaborators for their participation in this trial.”
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 mismatch repair proficient (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 mismatch repair deficient (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 endometrial carcinoma, including the NRG-GY018/KEYNOTE-868 trial evaluating KEYTRUDA 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. As previously announced, the U.S. Food and Drug Administration (FDA) has granted priority review for Merck’s supplemental Biologics License Application (sBLA) based on this study and has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 21, 2024.
The program also includes the KEYNOTE-C93 study evaluating KEYTRUDA versus chemotherapy in dMMR advanced or recurrent endometrial carcinoma, as well as the MK-2870-005 study evaluating sacituzumab tirumotecan (sac-TMT), an investigational trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) being developed in collaboration with Kelun-Biotech, compared to a treatment of physicians’ choice in patients with endometrial carcinoma who have received prior platinum-based chemotherapy and immunotherapy.
About KEYNOTE-B21/ENGOT-en11/GOG-3053 KEYNOTE-B21, also known as ENGOT-en11/GOG-3053, is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT04634877) sponsored by Merck and conducted in collaboration with the European Network for Gynecologic Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) investigating adjuvant treatment with KEYTRUDA plus chemotherapy, with or without radiotherapy, compared to adjuvant placebo plus chemotherapy, with or without radiotherapy, for the treatment of newly diagnosed, high-risk endometrial cancer after surgery with curative intent. The primary endpoints are DFS and OS, and secondary endpoints include safety. The trial enrolled an estimated 1,095 patients who were randomized to receive:
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 patients diagnosed with uterine body cancer and approximately 13,250 patient deaths from the disease in 2024. Globally, endometrial cancer is the sixth most common cancer in women and the 15th most common cancer overall. Following primary treatment, patients face a risk of their cancer returning, often as distant metastasis, which is associated with poorer outcomes.
About Merck’s research in breast and gynecologic cancers Merck is advancing research aimed at improving outcomes for patients affected by breast and gynecologic (ovarian, cervical and endometrial) cancers. Merck has a comprehensive clinical development program across these cancers comprised of more than 20 Merck-sponsored Phase 3 studies evaluating KEYTRUDA as monotherapy and in combination with other medicines. In the U.S., KEYTRUDA currently has two approved indications for triple-negative breast cancer, including one for high-risk early-stage disease, and five approved indications across certain types of cervical and endometrial cancers (see indications below). Among Merck’s research efforts are trials focused on evaluating KEYTRUDA in earlier stages of these cancers, as well as identifying new combinations and coformulations with KEYTRUDA.
About Merck’s early-stage cancer clinical program Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with more than 25 ongoing registrational studies across multiple types of cancer.
About KEYTRUDA® (pembrolizumab) injection, 100 mg KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.Endometrial Carcinoma KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
KEYTRUDA, as a single agent, is indicated 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.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
Selected Important Safety Information for KEYTRUDA Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (
