Merck & Co., Inc. announced the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck?s anti-PD-1 therapy, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. This approval marks the third endometrial carcinoma indication and the 40th indication overall for KEYTRUDA in the U.S. The approval is based on data from the Phase 3 NRG-GY018 trial, also known as KEYNOTE-868, in which KEYTRUDA plus carboplatin and paclitaxel followed by KEYTRUDA alone reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.46-0.78]; p<0.0001) in patients whose cancer was mismatch repair proficient (pMMR) and by 70% (HR=0.30 [95% CI, 0.19-0.48]; p<0.0001) in patients whose cancer was mismatch repair deficient (dMMR), compared to placebo with carboplatin and paclitaxel followed by placebo alone. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously.

Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA.

Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman.

For more information, see ?Selected Important Safety Information? below. For patients whose cancer was pMMR, median progression-free survival (PFS) in the KEYTRUDA plus carboplatin and paclitaxel arm was 11.1 months (95% CI, 8.7-13.5) versus 8.5 months (95% CI, 7.2-8.8) for the placebo plus carboplatin and paclitaxel arm; for patients whose cancer was dMMR, median PFS was not reached (95% CI, 30.7-NR) in the KEYTRUDA plus carboplatin and paclitaxel arm versus 6.5 months (95% CI, 6.4-8.7) for the placebo plus carboplatin and paclitaxel arm.

This trial was sponsored by the U.S. National Cancer Institute (NCI), part of the National Institutes of Health. NRG Oncology designed and led the trial with funding from the NCI and participation from all the National Clinical Trials Network (NCTN) groups. Merck provided funding and support through a Cooperative Research and Development Agreement (CRADA) between Merck and NCI.

In the U.S., KEYTRUDA has two additional approved indications in endometrial carcinoma. One indication, based on KEYNOTE-775/Study 309, is in combination with LENVIMA® (lenvatinib), in collaboration with Eisai, for the treatment of adult patients with advanced endometrial carcinoma that is 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 adult 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.

This approval was reviewed under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent review of oncology drugs among its international partners. Under this project, the NRG-GY018/KEYNOTE-868 application is still under review by health authorities in Israel, Canada, Australia, Singapore, Brazil and the United Kingdom. NRG-GY018, also known as Merck?s KEYNOTE-868, is a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03914612) evaluating KEYTRUDA in combination with carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel.

The trial enrolled 810 patients with advanced or recurrent endometrial carcinoma. The study design included two separate cohorts based on MMR status; 222 patients (27%) were in the dMMR cohort and 588 patients (73%) were in the pMMR cohort. The trial enrolled measurable Stage III, measurable Stage IVA, Stage IVB or recurrent endometrial cancer (with or without measurable disease).

Patients who had not received prior systemic therapy or had received prior chemotherapy in the adjuvant setting were eligible. Patients who had received prior adjuvant chemotherapy were only eligible if their chemotherapy-free interval was at least 12 months. Patients with endometrial sarcoma, including carcinosarcoma, or patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Randomization was stratified according to MMR status, Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2), and prior adjuvant chemotherapy. Patients were randomized (1:1) to one of the following treatment arms: KEYTRUDA (200 mg) every three weeks (Q3W) plus paclitaxel (175 mg/m2) and carboplatin (Area Under Curve [AUC] 5 mg/mL/min) for six cycles, followed by KEYTRUDA (400 mg) every six weeks (Q6W) for up to 14 cycles, or Placebo Q3W plus paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) for six cycles, followed by placebo Q6W for up to 14 cycles.

All study medications were administered as intravenous infusion on Day 1 of each treatment cycle. Treatment continued until disease progression, unacceptable toxicity or a maximum of 20 cycles (up to approximately 24 months). Patients with measurable disease who had RECIST-defined stable disease or partial response at the completion of cycle six were permitted to continue receiving paclitaxel and carboplatin with KEYTRUDA or placebo for up to 10 cycles as determined by the investigator.

Assessment of tumor status was performed every nine weeks for the first nine months and then every 12 weeks thereafter. The major efficacy outcome measure was PFS as assessed by the investigator according to RECIST 1.1. An additional efficacy outcome measure was overall survival (OS).