Role of Combination I/O in Advanced Endometrial Cancer (EC)

Shannon N. Westin, MD, MPH, FACOG: There are several reasons why we’re exploring combination therapy for patients with advanced and recurrent endometrial cancer. Specifically, we’re really trying to augment the activity of immunotherapy. The most important reason is that we need to do better. Our outcomes for patients with advanced and recurrent endometrial cancer are just not good enough. We can get patients to no evidence of disease or partial response with chemotherapy alone, but it is not durable. Conversely, we’ve seen great outcomes for patients who are treated with immunotherapy. But it’s very patient specific, or really tumor specific, where we see our best outcomes for immunotherapy for those patients that have microsatellite instability in their tumor. But that’s only 20% to 30% of patients, so there’s a huge unmet need, and a large number of patients that need better outcomes.

That’s why we’ve been exploring combination strategies. We’ve seen a number of combinations—we’ve seen combinations of chemotherapy with immunotherapy and we’ve seen combinations of antiangiogenics with immunotherapy. The rationale behind this is to help reduce the chance of relapse, reduce the chance of recurrence, improve our overall outcomes, and extend that efficacy to more patients. When we’re looking at combining something such as chemotherapy with immunotherapy, the hope is that we’re creating more damage that allows the immune system to identify the tumor and the cancer, and clear it more easily. We also are hoping that the antigen-presenting cells will be able to present the tumor easier to different immune cells, like NK [natural killer] cells and dendritic cells. All those things are supposed to work together to allow this to work better.

So far, it’s unclear in other cancer types, and it’s to be determined in endometrial cancer, where there are a number of studies that are ongoing. But we’ve had a lot of enthusiasm around the combination of immunotherapy with antiangiogenic agents. Specifically, that’s because there are a number of things that VEGF, which is 1 of the ligands of angiogenesis, does to help build those bad blood vessels that support the tumor. VEGF does a lot of stuff in relationship to the immune system as well, including directly inhibiting T-cell function, reducing T-cell trafficking into tumors, reducing lymphocyte adhesion into vessel walls, and generally inhibiting our immune cell function. If you can block VEGF through a number of strategies, then you can potentially accentuate the activity of those immuno-oncology agents.

Transcript Edited for Clarity