Assessment of pembrolizumab in advanced endometrial carcinoma: a letter to the editor

To the Editor, The Food and Drug Administration recently approved pembrolizumab in combination with chemotherapy for advanced or recurrent endometrial carcinoma, particularly in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors. This decision has generated considerable interest, and examining the supporting evidence is important for clinical practice. The KEYNOTE-158 study reported a 37.7% response rate and a median progression-free survival (PFS) of 25.7 months in MSI-H/dMMR patients1. As a single-arm study, it focused on pretreated patients, limiting direct comparisons with standard therapy. In addition, single-arm studies may introduce some degree of patient selection bias, as trial participants often represent carefully selected populations with good performance status. The ENGOT-en11/GOG-3053/KEYNOTE-B21 trial evaluated pembrolizumab in the adjuvant setting for newly diagnosed high-risk patients2. While the overall disease-free survival (DFS) benefit was not significant, a dMMR subgroup showed encouraging results, although the small sample (n = 150) limited statistical power. Another point to consider is that outcomes from adjuvant trials cannot be directly compared with those from metastatic settings, since disease stage, prior treatment exposure, and treatment goals differ. Traditional chemotherapy remains an important reference point. Thigpen et al reported a median PFS of 7.2 months with doxorubicin–cisplatin in advanced endometrial carcinoma, compared to 5.7 months with doxorubicin alone3. These findings indicate that standard regimens continue to provide meaningful outcomes and form a reliable treatment backbone. Within current treatment strategies for advanced endometrial carcinoma, systemic chemotherapy has historically been the standard first-line approach, while immunotherapy is increasingly being explored for biomarker-defined subgroups such as MSI-H or dMMR tumors4. Across these studies, pembrolizumab shows promise, particularly for the dMMR subgroup, but current evidence is limited by small sample sizes, single-arm designs, and variation in trial settings. Direct comparisons between adjuvant and metastatic contexts are challenging, emphasizing the need for context-specific research. Integration of pembrolizumab with chemotherapy requires careful consideration to balance efficacy and potential toxicity while ensuring patient safety. Immune-related adverse events reported with pembrolizumab include conditions such as hypothyroidism, pneumonitis, hepatitis, and immune-mediated colitis, which may require careful monitoring and timely management in clinical practice5. Future research should focus on large, well-designed phase III trials with at least 500 dMMR patients. These studies should evaluate efficacy, safety, and long-term outcomes to clarify which patients benefit most. Comparing outcomes from immunotherapy trials with historical chemotherapy results may also help clarify the clinical value of checkpoint inhibition in this disease setting. By combining immunotherapy with established chemotherapy regimens, clinicians can optimize treatment strategies while avoiding unnecessary risks. In conclusion, pembrolizumab offers a promising addition to therapy for advanced endometrial carcinoma, particularly in MSI-H/dMMR patients. Current evidence supports cautious optimism, but larger trials are essential to confirm effectiveness and guide integration into clinical practice. Overall, the available evidence suggests encouraging activity in biomarker-selected populations, although larger randomized trials will be important to confirm these findings. A balanced approach, leveraging established therapies alongside targeted immunotherapy, will help maximize patient benefit while advancing the field. Ethical approval Not applicable. Consent Not applicable.