Endometrial cancer is the most common gynecologic malignancy in developed countries, and outcomes remain poor for patients with advanced-stage or recurrent disease. The introduction of immune checkpoint inhibitors has transformed treatment strategies, particularly in mismatch repair-deficient (dMMR) tumors, which are highly responsive to immunotherapy.

The Phase III NRG-GY018 trial previously demonstrated significant progression-free survival improvements with pembrolizumab combined with carboplatin and paclitaxel in both dMMR and pMMR endometrial cancer populations. Importantly, NRG-GY018 remains the only Phase III study designed to independently evaluate these molecularly distinct patient groups. The updated analysis presented at ASCO 2026 focused on overall survival outcomes and the impact of subsequent immune checkpoint inhibitor therapy following study treatment.

Efficacy Outcomes:

dMMR Endometrial Cancer

Pembrolizumab plus chemotherapy continued to demonstrate a substantial survival advantage in patients with mismatch repair-deficient disease.

• 48-month overall survival (OS) rate: 80% with pembrolizumab + carboplatin/paclitaxel versus 60% with placebo + carboplatin/paclitaxel.

• 47% reduction in the risk of death (HR: 0.53; 95% CI: 0.32–0.89).

• This survival advantage was maintained despite at least 55% of dMMR EC patients in the placebo arm.

pMMR Endometrial Cancer

• Median OS: 46.9 months with pembrolizumab + carboplatin/paclitaxel

• Median OS: 35.1 months with placebo + carboplatin/paclitaxel

• Absolute survival improvement: 11.8 months 

• HR: 0.84 (95% CI: 0.66–1.06)

KOL Insights-

“Importantly, the overall survival benefit was maintained despite substantial use of subsequent immune checkpoint inhibitors in the placebo arms, representing the highest rate of post-study ICI treatment among contemporary Phase III trials in this setting. These findings further strengthen confidence in the established US and global approvals of this regimen.”– Expert Opinion

“Patients who had received pembrolizumab upfront most of whom later received lenvatinib plus pembrolizumab and those initially treated with placebo derived comparable benefit from subsequent immunotherapy, providing additional insight into treatment sequencing in this setting.”– Expert Opinion

Conclusion-

Advanced or recurrent endometrial cancer is the most common gynecologic malignancy in developed countries, with incidence continuing to rise globally. In the United States, approximately 15–20% of patients present with advanced-stage disease or eventually develop recurrent disease, where prognosis remains poor and treatment options are limited.

The updated Phase III NRG-GY018 trial reinforces the long-term clinical value of incorporating pembrolizumab into first-line carboplatin and paclitaxel treatment for advanced or recurrent endometrial cancer. The sustained survival benefit observed across both dMMR and pMMR populations, despite substantial use of subsequent immune checkpoint inhibitors in the control arm, underscores the importance of early immunotherapy intervention. The data reinforce the existing US FDA approved use of the pembrolizumab regimen in the first-line treatment of advanced or recurrent endometrial cancer, irrespective of MMR status.