Differential responses to immune checkpoint inhibitors are governed by diverse mismatch repair gene alterations

Abstract Purpose: The response to immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR) colorectal cancer (CRC) and endometrial cancer (EC) is variable. Here, we explored the differential response to ICIs according to different MMR alterations. Experimental Design: CRC (N=13701) and EC (N=3315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan-Meier. The prediction of high, intermediate and low affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2) Results: Compared to mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all CRC (54.6m vs. 36m; p=0.0.025) and EC (81.5m vs. 48.2m; p<0.001) patients. In ICIs-treated patients, the mOS was longer in mutS co-loss in CRC (not reached (NR) vs. 36m; p=0.011). In EC, the mOS was NR vs. 42.2m; p=0.711). The neoantigen load (NAL) in mutS co-loss compared to mutL co-loss was higher in CRC (high-affinity epitopes: 25.5 vs 19; q=0.017, intermediate: 39 vs. 32; q=0.004, low: 87.5 vs. 73; q<0.001) and EC (high-affinity epitopes: 15 vs. 11; q=0.002, intermediate: 27.5 vs. 19; q<0.001, low: 59 vs. 41; q<0.001) respectively. R2 ranged from 0.25 in mutS co-loss CRC to 0.95 in mutL co-loss EC. Conclusions: Patients with mutS co-loss experienced longer mOS in CRC and EC and better response to ICIs in CRC. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL