EP621 - Characterizing Immunotherapy Non-Responders in dMMR/MSI-H Rectal Cancer: An Institutional Experience

Purpose/Background: The treatment of rectal cancer has rapidly evolved to include immunotherapy as the preferred neoadjuvant, and potentially definitive, treatment for microsatellite instability-high (MSI-H) or Mismatch Repair deficient (dMMR) rectal cancer. Driven by numerous clinical trials, The National Comprehensive Cancer Network (NCCN) now recommends neoadjuvant immunotherapy with a PD-1 inhibitor as the preferred approach for stage II–III dMMR/MSI-H rectal cancer, with surveillance if a complete clinical response is achieved. Chemoradiation or surgery is reserved for non-responders or those with persistent disease. However, little is known about why certain dMMR/MSI-H rectal cancer patients do not respond to immunotherapy. Recent literature by Cercek et al. has highlighted that PD-1 blockade for dMMR rectal cancer can achieve a reported 100% initial complete clinical response (CCR) sustained CCR in 75% (37/49) of patients at one year. While this is a remarkable finding, it suggests that nearly all MSI-H rectal cancer patients will have an initial complete response, and furthermore fails to address the underlying reason as to why certain patients, 25% in this study, end up recurring. This study aims to describe our institution’s ongoing work to identify and provide full genetic sequencing for dMMR/MSI-H rectal cancer patients who do not respond to immunotherapy.

Methods/Interventions: Our institution became NAPRC accredited in October of 2022. As part of our accreditation, a prospective database was created and used to document treatment for all rectal cancer patients treated at our institution. This database was then reviewed for individual patients who participated in watch and wait therapy for rectal cancer and received neoadjuvant immunotherapy.

Results/Outcomes: In total, 6 patients were identified. Of these patients, 2 individuals were found to be non-responders and underwent traditional chemotherapy, radiation, or surgery. Both of these patients were found to be MLH1 and PMS2 deficient. One of these patients ended up undergoing surgery with disease noted on final path while the other is still undergoing chemoXRT. There other 4 patients had a CCR and are in our standard surveillance pathway. All 6 patients were offered genomic sequencing to identify additional genetic findings that could contribute to the difference in response to immunotherapy.

Conclusion/Discussion: In an era of incredible advances in immunotherapy for rectal cancer care, understanding the various elements that can lead patients to not respond to therapy is of great importance. Among these elements are potential unreported genetic variations that have yet to be identified. This report describes our ongoing work to identify genetic drivers of incomplete response to
neoadjuvant immunotherapy. Future works will focus on the reporting of complete sequencing of non-responders form our institution.