This NCI-led clinical trials planning report outlines the rapidly evolving, molecularly driven treatment landscape in endometrial cancer. The now-standard four molecular subtypes (POLEm, dMMR/MSI-H, NSMP, p53abn) carry distinct therapeutic implications: dMMR tumors are immunotherapy-sensitive, while p53abn cancers lean chemo/RT-sensitive. While immunotherapy-monotherapy is standard for dMMR tumors, recent FDA approvals have pushed immunotherapy with or without chemo/anti-angiogenics into the frontline for metastatic/recurrent disease across subtypes with clear survival benefit in pMMR populations when pembro is paired with lenvatinib. But success breeds questions. Optimal sequencing, duration, and retreatment strategies remain undefined—especially as many patients now progress after immunotherapy. Meanwhile, combining radiation with immunotherapy introduces another layer of complexity: preclinical and early clinical data suggest that where and when we radiate (tumor-only versus nodal, concurrent versus sequential delivery, etc) may dictate immune activation versus suppression. Novel trial designs with molecularly stratified approaches are underway to sort signal from noise. | Corr, JNCI 2026
