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.

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.

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.

While chemo plus immunotherapy showed a benefit in MS-stable patients, it's not curative. The expert predicts clinicians may shift away from using it universally upfront, potentially favoring other agents first for this non-curative but beneficial therapy.

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.

While PARP inhibitors plus immunotherapy (e.g., in the RUBY-2 trial) improved progression-free survival (PFS) in pMMR endometrial cancer, the overall survival (OS) curves crossed, showing no OS benefit. This cautionary signal suggests the combination may not be advantageous long-term and requires further investigation.

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.

Even in elderly or frail patients with MSI-high endometrial cancer, the rapid and effective tumor response from combination chemotherapy and immunotherapy often improves quality of life so significantly that it's the preferred approach over single-agent IO.

Unlike other cancers, re-treating with immunotherapy after recurrence is considered a viable strategy for dMMR endometrial cancer. Experts theorize that these tumors are constantly evolving and may benefit from a "re-education" of the immune system, challenging the conventional wisdom that progression on a drug class means permanent resistance.