Checkpoint inhibitor rechallenge in advanced endometrial cancer: revisiting the immune landscape beyond first-line therapy.

The integration of immune checkpoint inhibitors into frontline therapy for advanced or recurrent endometrial cancer has transformed treatment paradigms, particularly for patients with mismatch repair-deficient (dMMR) tumors. However, this advancement has introduced a pressing clinical challenge: how to manage patients who experience disease progression following exposure to a prior immune checkpoint inhibitor. Despite the absence of prospective guidance, immune checkpoint inhibitor rechallenge is already occurring in clinical practice. Notably, 35% of patients in the dostarlimab arm of the RUBY trial received subsequent immunotherapy off-protocol, highlighting the gap between evolving clinical behavior and available evidence. Emerging retrospective data suggest that retreatment with immune checkpoint inhibitors may be clinically and biologically plausible, particularly in biomarker-enriched populations. In a study, 54.5% of patients with dMMR endometrial cancer responded to second-line immune checkpoint inhibitor rechallenge, including complete responses. Additional reports indicate that combining immune checkpoint inhibitors with anti-vascular endothelial growth factors or multi-kinase inhibitors, such as lenvatinib or cabozantinib, may enhance immune reactivation even in microsatellite-stable or carcinosarcoma histologies. Nonetheless, toxicity remains a concern, with grade 3 to 4 immune-related adverse events and high rates of dose modification reported. Mechanistic insights point to immune escape pathways, including vascular endothelial growth factor-driven immunosuppression, MLH1 methylation, and high subclonal neoantigen burden, as contributors to immune checkpoint inhibitor resistance. These findings support the use of rational combinations and novel targets. Prospective trials such as NRG-GY025 are now evaluating dual checkpoint blockade in immune checkpoint inhibitor-pretreated dMMR endometrial cancer. In contrast, synthetic lethality strategies, such as the Werner helicase inhibitor HRO761 in high microsatellite instability tumors, represent promising non-immune-based rechallenge approaches. As immune checkpoint inhibitor exposure becomes commonplace in earlier treatment settings, there is an urgent need for biologically informed, individualized strategies to guide post-immune checkpoint inhibitor management. Future progress will depend on refining rechallenge criteria, optimizing combination regimens, and developing predictive biomarkers to identify patients most likely to benefit from retreatment.