The GOG-B21 trial found that while adding pembrolizumab to chemotherapy benefits the dMMR subgroup, it paradoxically leads to worse outcomes in the pMMR subgroup. This highlights the critical need for molecular testing to avoid potential harm.

Based on translational data from the RUBY trial, experts are most cautious about recommending frontline checkpoint inhibitors for patients in the "No Specific Molecular Profile" (NSMP) subgroup of pMMR endometrial cancer, suggesting this group may not benefit.

Despite multiple clinical trials, adding checkpoint inhibitors to frontline therapy for ovarian cancer has not demonstrated a proven survival benefit. The role of immunotherapy in this setting remains confined to rare subsets like DMMR or TMB-high tumors, and it is not standard practice for the general population.

Following positive Phase III data for adjuvant atezolizumab plus chemotherapy in Stage III MSI-high colon cancer, clinicians are extrapolating this approach to high-risk Stage II patients. For some, they favor using immunotherapy alone, omitting chemotherapy due to its perceived limited additional benefit in the Stage II setting.

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.

With dostarlimab, pembrolizumab, and durvalumab showing similar efficacy in endometrial cancer, the final selection often depends on non-clinical factors like clinician familiarity, specific trial criteria, or insurance company mandates.

Disparate clinical trial results in endometrial cancer suggest a mechanistic difference between immunotherapy targets. PD-1 inhibitors (dostarlimab, pembrolizumab) have shown pronounced responses, whereas the PD-L1 inhibitor atezolizumab did not, indicating that targeting the PD-1 receptor may be a more robust strategy in GYN cancers.

Mirroring success in rectal cancer, a new trial is exploring neoadjuvant immunotherapy for localized, MSI-high endometrial cancer. This strategy could potentially allow patients to avoid surgery and radiation, which is a particularly compelling option for those who wish to preserve their fertility.