Following the Keynote B21 trial, clinicians have become more selective with adjuvant immunotherapy in endometrial cancer. The study showed minimal benefit for pMMR patients and less impressive gains overall in its lower-risk population compared to advanced disease trials. This has led to a practice of reserving adjuvant chemo-IO primarily for stage 3 dMMR patients.

Clinicians should consider re-biopsying tumors at recurrence, not upfront. Endometrial cancer can evolve, and a metastatic site may develop new targetable markers, like HER2, that were not present in the primary tumor, opening up new treatment avenues.

The KEYNOTE-B21 adjuvant trial revealed a crucial paradox: adding pembrolizumab may worsen outcomes for mismatch repair proficient (pMMR) patients (HR 1.2), while being highly beneficial for dMMR patients. This highlights that metastatic and adjuvant settings are not equivalent.

Clinicians anecdotally report that immunotherapy is changing the pattern of recurrence in endometrial cancer. Instead of widespread disease, patients often develop isolated recurrences in a single location. This shift allows for the use of local therapies, like radiation, to treat the single spot while continuing the effective systemic immunotherapy.

While immunotherapy is transformational for DMMR endometrial cancer, its benefit is much smaller for the PMMR majority (two-thirds of patients). This reality requires more nuanced patient counseling and selective use in this population.

The future of GYN oncology immunotherapy is diverging. For responsive cancers like endometrial, the focus is on refining biomarkers and overcoming resistance. For historically resistant cancers like ovarian, the strategy shifts to using combinatorial approaches (e.g., CAR-NKs, vaccines) to fundamentally alter the tumor microenvironment itself, making it more receptive to an immune response.

Clinicians increasingly re-biopsy recurrent or metastatic endometrial tumors, rather than relying on the primary tumor's profile. This is because biomarkers like HER2 can change or emerge as the disease progresses, opening up new targeted therapy options that were not previously available.

For endometrial or cervical cancer patients who progress after receiving a checkpoint inhibitor, re-challenging with a single-agent immunotherapy is a less desirable approach. Emerging data suggests that a combination therapy—such as an ICI paired with a TKI like lenvatinib or a bispecific antibody—offers a more promising chance of response.

For dMMR endometrial cancer patients on combination therapy, clinicians are quicker to reduce or stop chemotherapy (like taxanes) when side effects arise. This practice reflects a growing confidence that immunotherapy is the primary driver of efficacy in this subgroup, allowing for a reduction in chemotherapy-related toxicity.