BRAF^V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors

Background: We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAF^V600E mutations and Lynch syndrome (LS). Patients and Methods: Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAF^V600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P <. 2) if limited number of events. Results: Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAF^V600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAF^V600E-mutated (PFS HR= 1.20, P =. 372; OS HR = 1.06, P =. 811) and RAS-mutated patients (PFS HR = 0.93, P =. 712, OS HR = 0.75, P =. 202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P =. 036). The adjusted HR for OS was 0.56 with no significance (P =. 143). No adjustment on BRAF^V600E mutation was done due to collinearity. Conclusion: In this cohort, RAS/BRAF^V600E mutations were not associated with survival while LS conferred an improved PFS.