In a phase III, NRG-GY018 study conducted among the patients with advanced or recurrent endometrial cancer, adding pembrolizumab to standard chemotherapy and followed by pembrolizumab maintenance, resulted in a 70% lower risk of disease progression or death in the cohort of patients with mismatch repair–deficient (dMMR) tumours and a 46% lower risk in the cohort with mismatch repair–proficient (pMMR) tumours than in the placebo group along with combination chemotherapy with paclitaxel plus carboplatin.
The study findings suggest that the incorporation of immune checkpoint inhibitor (ICI) into the first-line treatment of patients with advanced or recurrent endometrial cancer translates into improved outcomes, regardless of MMR status or histology. The findings are reporterd by Dr. Ramez N. Eskander of the University of California, San Diego, Rebecca and John Moores Comprehensive Cancer Center in La Jolla, CA, US and colleagues on 27 March 2023 in The New England Journal of Medicine, simultaneously with a late breaking abstract presentation at the Society of Gynecologic Oncology 2023 Annual Meeting (25-28 March, Tampa, FL, US).
The authors wrote in the background that the GOG0209 investigators established the non-inferiority of paclitaxel plus carboplatin as compared with paclitaxel plus doxorubicin plus cisplatin as standard first-line chemotherapy for patients with advanced or recurrent endometrial cancer. Researchers in the Cancer Genome Atlas Network found that 28% of endometrial cancers had high microsatellite instability (H-MSI). Monotherapy with an ICI, e.g., pembrolizumab or dostarlimab-gxly, has established efficacy as the second-line treatment and beyond in patients with dMMR endometrial cancer with H-MSI. Pembrolizumab in combination with lenvatinib has shown efficacy in pMMR, microsatellite-stable endometrial cancer.
A phase III, international, double-blind, randomised, placebo-controlled NRG-GY018 study was performed to evaluate standard chemotherapy with paclitaxel plus carboplatin plus either pembrolizumab or placebo in patients with advanced or recurrent endometrial cancer. The two treatment strategies were analyzed in two independent cohorts, patients with dMMR and those with pMMR tumours, as determined by central immunohistochemical analysis.
The NRG-GY018 investigators assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination chemotherapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had dMMR or pMMR tumours. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival (PFS) in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort.
In the 12-month analysis, Kaplan–Meier estimates of PFS in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio [HR] for progression or death 0.30; 95% confidence interval [CI] 0.19 to 0.48; p < 0.001), a 70% difference in relative risk. In the pMMR cohort, median PFS was 13.1 months with pembrolizumab and 8.7 months with placebo (HR 0.54; 95% CI 0.41 to 0.71; p < 0.001).
Adverse events were as expected for pembrolizumab and combination chemotherapy. The incidence of immune-mediated adverse events was not greater than that observed in previous studies of pembrolizumab monotherapy in patients with endometrial cancer.
The authors commented that the efficacy curves in the two MMR cohorts separated early in the course of treatment, with a preserved separation throughout the evaluation period. This benefit was observed in most subgroups, including patients who had received previous adjuvant chemotherapy or radiotherapy and among those with less common histologic subtypes. The question of whether pembrolizumab plus chemotherapy has greater efficacy than pembrolizumab monotherapy in patients with newly diagnosed, advanced or recurrent dMMR endometrial cancer warrants additional study.
The study was supported by grants from the US National Cancer Institute (NCI). Funding was provided by Merck through a cooperative research and developmental agreement with the NCI. Merck also provided supplemental funding to NRG Oncology for this study.
Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. NEJM; Published online 27 March 2023. DOI: 10.1056/NEJMoa2302312