April 12 2023
Written by NRG-GY018 Principal Investigator, Ramez Eskander, MD
Unlike other solid malignancies, there has been limited improvement in survival for women with metastatic or recurrent endometrial cancer (EC) over the last 4 decades. NRG-GY018 was designed to determine if the addition of the immune checkpoint inhibitor, pembrolizumab, to carboplatin and paclitaxel followed by pembrolizumab maintenance would result in improved survival. Based on prior trials in alternate solid tumors, most notably colorectal cancer, it was anticipated that a more robust improvement would be identified in the mismatch repair deficient (dMMR) EC population. As such, the trial was designed to enroll 2 separate and independent patient populations, mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) EC. Furthermore, preclinical, and clinical data suggested that the addition of immunotherapy to chemotherapy, may help induce immunogenic cell death, priming an immune response in tumors that are historically not responsive to single agent immune checkpoint inhibition.
This randomized, phase 3, blinded and placebo-controlled trial activated to accrual in July 2019 and completed accrual in both patient populations in December 2022. Of note, due to the COVID-19 pandemic and public health crises, trial accrual was paused from April 2020 until October 2020 in an effort to develop appropriate mitigation strategies given the placebo-controlled trial design. A total of 1064 patients were enrolled on trial across 395 sites in 4 countries. Two hundred and forty-eight patients were ineligible, leaving 225 dMMR EC and 591 pMMR EC patients.
The statistical plan for the trial defined a prespecified interim efficacy analysis at the time in which accrual was completed in both the pMMR and dMMR EC cohorts, with at least half the information fraction. This analysis was triggered on December 6th 2022 for the pMMR EC cohort and on December 16th 2022 in the dMMR EC cohort. Following review of the data by the DSMC, and based on the magnitude of benefit observed in both patient populations, the decision was made to issue Dear Doctor and Dear Patient letters, outlining a statistically significant and clinically meaningful benefit with addition of pembrolizumab in both the dMMR and pMMR cohorts. Key findings included a 70% reduction in the risk of disease progression or death in the pembrolizumab arm of the dMMR EC population (HR 0.30; 95% CI 0.19-0.48; P<0.00001), and a 46% reduction in the risk of disease progression or death in the pembrolizumab arm of the pMMR EC population (HR 0.54; 95% CI 0.41-0.71; P<0.0001).No new safety signals were noted in either arm of the trial, and the combination did not appear to increase the frequency or severity of chemotherapy or immunotherapy related adverse events.
This important, and potentially practice changing data was subsequently shared as a late breaking abstract at the 2023 Society of Gynecologic Oncology Annual Meeting (Tampa, Fl), and simultaneously published in the New England Journal of Medicine. We are hopeful that the results will help inform a new standard of care treatment option for women suffering from advanced stage or recurrent endometrial cancer.