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.
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The NCI 9673 trial demonstrated that adding the CTLA-4 inhibitor ipilimumab to the PD-1 inhibitor nivolumab did not improve response rate, PFS, or overall survival in patients with previously treated anal cancer. This finding discourages this combination approach, avoiding unnecessary toxicity.
The treatment landscape for platinum-resistant ovarian cancer has rapidly evolved into a biomarker-driven paradigm. Clinicians must now test for and choose between therapies targeting distinct markers like folate receptor alpha (mirvetuximab), HER2 (T-DXd), and PD-L1 (pembrolizumab), requiring a sophisticated sequencing strategy.
Data from the Podium-303 trial's crossover arm suggests that waiting to use a PD-1 inhibitor after progression on chemotherapy is less effective than using it concurrently from the start. This supports the synergistic effect of chemo-immunotherapy and favors the concurrent approach as the standard of care.
Despite significant interest, circulating tumor DNA (ctDNA) is not yet an actionable tool for guiding the duration of maintenance immunotherapy in endometrial cancer. While studies like DuoE show ctDNA levels correlate with outcomes, there is no evidence to support using its clearance to decide when to stop treatment. It remains a prognostic, not a predictive, biomarker for this purpose.
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.
Despite the KEYNOTE-B96 trial showing a statistically significant survival benefit, the expert's enthusiasm for adding pembrolizumab in platinum-resistant ovarian cancer is only "neutral." This hesitation stems from challenges in sequencing it with other effective therapies and uncertainty about which patient subgroups truly benefit.
Successful immunotherapies like anti-PD-1 work by shifting the battlefield's arithmetic. They enhance the efficiency of each T-cell, allowing one cell to destroy five or ten cancer cells instead of three. This turns the fight into a 'numbers game' that the immune system can finally win.
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.
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.
While checkpoint inhibitors are standard for dMMR endometrial cancer, a clear clinical boundary is emerging for the pMMR subgroup. Based on trial data showing no benefit for fully resected disease (e.g., B21 trial), oncologists are not offering immunotherapy to pMMR patients without measurable disease, avoiding significant toxicity without proven efficacy.