Merck announced that 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 40 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 per cent (HR=0.60 [95 per cent CI, 0.46-0.78]; p<0.0001) in patients whose cancer was mismatch repair proficient (pMMR) and by 70 per cent (HR=0.30 [95 per cent 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.
“This is the first Phase 3 trial to statistically evaluate an anti-PD-1 immunotherapy plus chemotherapy combination in patients with pMMR and dMMR tumours as two independent cohorts,” said Dr Ramez N. Eskander, principal investigator, associate professor in the Department of Obstetrics, Gynecology, and Reproductive Services at University of California San Diego School of Medicine and gynecologic oncologist at Moores Cancer Center at University of California San Diego Health.
“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,” informed the statement.
“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,” it further added.
For patients whose cancer was pMMR, median progression-free survival (PFS) in the KEYTRUDA plus carboplatin and paclitaxel arm was 11.1 months (95 per cent CI, 8.7-13.5) versus 8.5 months (95 per cent 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 per cent CI, 30.7-NR) in the KEYTRUDA plus carboplatin and paclitaxel arm versus 6.5 months (95 per cent 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.
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.
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 per cent) were in the dMMR cohort and 588 patients (73 per cent) 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).
The trial demonstrated statistically significant improvements in PFS for patients randomised to KEYTRUDA in combination with paclitaxel and carboplatin compared to placebo in combination with paclitaxel and carboplatin in both the dMMR and pMMR populations. At the time of the PFS analysis, OS data were not mature with 12 per cent deaths in the dMMR population and 17 per cent deaths in the pMMR population.
A total of 759 patients received KEYTRUDA (200 mg) every three weeks and chemotherapy for six cycles followed by KEYTRUDA (400 mg) every six weeks for up to 14 cycles (n=382) or placebo and chemotherapy for six cycles followed by placebo for up to 14 cycles (n=377).
The median duration of exposure to KEYTRUDA was 5.6 months (range, 1 day to 24.0 months). Serious adverse reactions occurred in 35 per cent of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19 per cent of patients receiving placebo in combination with chemotherapy. Fatal adverse reactions occurred in 1.6 per cent of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5 per cent), and cardiac arrest (0.3 per cent).
KEYTRUDA was discontinued for an adverse reaction in 14 per cent of patients. Chemotherapy dose reduction was required in 29 per cent of patients receiving KEYTRUDA in combination with chemotherapy, compared to 23 per cent of patients receiving placebo in combination with chemotherapy. There were no clinically meaningful differences in chemotherapy discontinuations or interruptions between arms. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone with the exception of rash (33 per cent all Grades; 2.9 per cent Grades 3-4).