Analysis of age, tumor-sidedness, and mismatch repair (MMR) genes with response to immune checkpoint inhibitors (ICIs) in MMR-deficient (dMMR) colorectal cancer (CRC) patients (pts): A multi-institutional study.

Abstract

e15029 Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age < 50 and 50-65 years old had better ORRs compared to pts with age >65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts > 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]