NRG-GY018 trial

Prof Ramez Eskander, a gynaecological oncologist at the University of California, San Diego, provided a comprehensive overview of the NRG-GY018 trial, a phase 3 randomised placebo-controlled international study to assess the potential advantages of including pembrolizumab in the treatment regimen of carboplatin and paclitaxel, followed by pembrolizumab maintenance. This study focused on patients with advanced-stage, recurrent, or metastatic endometrial cancer. The primary outcome of this clinical trial was presented and simultaneously published in the New England Journal of Medicine (N Engl J Med 2023;388:2159-70).

At the ESMO conference, an update on some of the study’s findings was shared, based on a median follow-up of around 17 months in both the mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) endometrial cancer populations. Each participant in the study underwent central mismatch repair IHC testing, and the results from both local and central reviews exhibited a strong correlation.

The objective response rate strongly supported the primary PFS benefit observed. In the dMMR group, adding pembrolizumab to chemotherapy and maintaining it led to an increase in the objective response rate from 71% to 82%. In the pMMR group, there was an even more significant improvement, with the objective response rate rising from 58% to 71%. Notably, there was a doubling in the number of complete responses. This improvement was also reflected in the analysis of the duration of response, with substantial and statistically significant enhancements in the median duration of response observed for both dMMR and pMMR patients with the addition of pembrolizumab to chemotherapy. Animated waterfall plots effectively demonstrated that these responses were distributed fairly evenly among all responsive patients.

Furthermore, the study examined the impact of the mechanism of mismatch repair loss. Conflicting clinical and preclinical data had suggested that patients with mismatch repair loss due to promoter hypermethylation might not respond as well as those with a mismatch repair gene mutation. The mismatch repair IHC data of all mismatch repair deficient patients in the study were analysed. In the dMMR group, 72% of patients had MLH1 promoter hypermethylation, 13% had a mismatch repair gene mutation, and 15% were non-evaluable. Importantly, the presence or absence of promoter hypermethylation did not prove to be prognostic or predictive of response to chemotherapy in the standard-of-care arm, which is a significant finding. Even more crucially, in dMMR patients who received pembrolizumab, there was no substantial difference in PFS, regardless of whether they had a mutation in the mismatch repair gene or methylation of the MLH1 promoter. It’s worth noting that the majority of dMMR patients treated with pembrolizumab exhibited promoter methylation, while only a small number had a mismatch repair gene mutation. The substantial benefit observed in the dMMR population primarily resulted from the promoter hypermethylation population, which is known to be more prevalent. However, based on this data, there didn’t appear to be a substantial difference in response to pembrolizumab in the dMMR population, whether they had a mutation or methylation and were treated with pembrolizumab.

Finally, a hypothesis-generating forest plot was created to examine the response to pembrolizumab in the pMMR population based on histology. While histology isn’t an exact match for molecular characterisation, it did show a consistent benefit when pembrolizumab was added to chemotherapy and continued as maintenance therapy.