Impact of Lynch Syndrome, BRAFV600E, and RAS Mutations on Outcomes in MSI/dMMR Metastatic Colorectal Cancer (mcrc) Treated with Immune Checkpoint Inhibitors (ICI): Analysis of Combined International Cohorts.

171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p < 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]