ENGOT-en11/GOG-3053/KEYNOTE-B21

In this video, Prof Dr Toon Van Gorp discusses the data of the ENGOT-EN11/GOG-3053/KEYNOTE B-21 that he presented at ESMO 2024 and puts them in the broader perspective of the adjuvant treatment of high-risk endometrial cancer. 

The ENGOT-EN11/GOG-3053/KEYNOTE-B21 study explored the use of pembrolizumab in combination with chemotherapy in the adjuvant setting for high-risk endometrial cancer patients who had undergone complete surgery. The study was driven by the rising incidence and prevalence of endometrial cancer and the promising results seen with pembrolizumab in metastatic or recurrent settings, where it has demonstrated significant improvements in both PFS and overall survival OS. Specifically, the NRG-GY018 study showed pembrolizumab providing a hazard ratio of 0.54 in mismatch repair-proficient (MMRp) and 0.30 in mismatch repair-deficient (MMRd) populations.

This study focused on high-risk patients post-surgery, where PFS typically ranges between 58% and 65%. The goal was to evaluate whether adding pembrolizumab to standard adjuvant chemotherapy would benefit these patients.A total of 1,095 patients were randomised into the trial. All were high-risk endometrial cancer patients with no residual disease post-surgery. The eligibility criteria included those with FIGO stage I–II non-endometrioid tumours with myometrial invasion, FIGO stage I–II endometrioid tumours with p53 abnormalities or TP53 mutations, or FIGO stage III–IVa of any histology. All patients received standard adjuvant chemotherapy, with or without radiotherapy, and were further randomised into two arms: one receiving pembrolizumab and the other a placebo. The primary endpoints were DFS and OS, with MMR status being a key stratification factor.

The two groups were well-balanced in terms of baseline characteristics, and the study population was as expected, with 25% of patients being MMRd and two-thirds receiving radiotherapy. Most patients had either endometrioid or non-endometrioid histology, aligning with the study’s design.

Unfortunately, the trial’s interim analysis showed that the primary endpoint of disease-free survival was not met, with a hazard ratio of 1.02, indicating no benefit from pembrolizumab in the overall population. A closer look at subgroup analyses revealed no significant differences between the arms, except in the MMRd group, where pembrolizumab demonstrated a substantial benefit. In this subgroup, the hazard ratio was 0.31, significantly reducing events (8 in the pembrolizumab arm versus 25 in the placebo arm). However, this analysis was not powered to demonstrate statistical significance, though the clinical implications are compelling.

Regarding safety, adverse events were similar between both arms, largely driven by chemotherapy rather than pembrolizumab. Immune-mediated adverse events, such as thyroid dysfunction and skin reactions, were more frequent in the pembrolizumab arm, as expected with PD-1 inhibitors. Importantly, pembrolizumab did not interfere with patients completing chemotherapy or radiotherapy, although there was a slightly higher rate of pembrolizumab discontinuation.

In conclusion, while the trial was technically negative, it provided significant insight into the potential benefit of pembrolizumab for MMRd endometrial cancer patients. Despite the lack of statistical significance, the clinical relevance of a hazard ratio of 0.31 in this subgroup suggests pembrolizumab could play an important role in the adjuvant setting for these patients in the future.