Gene-specific outcomes in patients with Lynch syndrome treated by immune checkpoint blockade for advanced cancer.

10504 Background: Lynch syndrome (LS), caused by germline pathogenic variants (gPVs) in DNA mismatch repair genes ( MLH1, MSH2, MSH6, PMS2 ), is characterized by microsatellite instability (MSI)/mismatch repair deficiency (MMRd) of associated tumors. The impact of the underlying gPV on the prognosis of LS patients with advanced cancer receiving ICB has not been elucidated. Methods: Consecutive cancer-affected LS pts consented to tumor-normal DNA sequencing via MSK-IMPACT (NCT01775072), from 01/2014-01/2024 with advanced solid tumors and receiving ≥1 ICB dose were identified. In cases of multiple cancers, only the first one was considered. MSI and MMRd was assessed via NGS-derived MSISensor score or IHC staining, respectively. Radiological response rates and survival were assessed. Results: Among 186 LS patients, 132 had an ICB treated advanced tumor with the following prevalence of gPV: MSH2 41% (N=54), MLH1 28% (N=37), PMS2 17% (N=23), and MSH6 14% (N=18). The most represented tumor types were colorectal (35%, N=46), urothelial (14%, N=18), pancreatic/biliary (13%, N=17), upper gastro-intestinal (11%, N=15), endometrial (11%, N=15). Objective response rate was 58%, including 35% with radiological complete response (CR) with higher CR rates in g MLH1 and g MSH2 patients (Table). Median follow-up was 53 months [range:0.3-116.3]. Median overall survival (mOS) / Progression free survival (mPFS) were significantly prolonged in non-gPMS2 patients vs. g PMS2 patients (Table). MMR IHC was available for 107 (80%) tumors identifying 88% (n=94) as MMRd and 12% (n=13) as MMRp tumors. 69% (9/13) of MMRp tumors were in PMS2 patients with 8 being both MMRp and MSS suggesting a sporadic origin rather than LS-related cancer. Stratifying by MMRd and MSI status, mOS was similar in patients with MMRd/MSI and MMRd/MSS tumors (109 months vs not reached (NR); HR=0.86; 95%CI [0.35-2.13]), but significantly diminished in in pts with MMRp as compared to MMRd tumors (20 vs 109 months, HR=0.27; 95%CI [0.77-0.96]). In g PMS2 patients with MMRd tumors, median OS was 27.7 months. Conclusions: ICB treatment results in high CR rates in LS patients. The shorter mOS amongst LS patients with gPMS2 compared to other LS genes is partially explained by the higher prevalence of sporadic MMRp tumors. Even in the context of an MMRd tumor, patients with g PMS2 have worse outcomes than LS patients with other gPVs. Treatment Total Complete Response% (n) Objective Response Rate% (n) Disease Control rate% (n) mPFS (months) mOS (months) MSH2 54 46% (25) 65% (35) 89% (48) 45 109 MLH1 37 41% (15) 65% (24) 81% (30) 50 NR PMS2 23 9% (2) 30% (7) 74% (17) 11 20 MSH6 18 22% (4) 61% (11) 78% (14) 109 NR MLH1/MSH2/MSH6 109 40% (44) 64% (70) 84% (92) 52 109 Non-PMS2 vs PMS2 - OR=7.195%CI [1.7-31.6]P=0.003 OR=4.195%CI [1.5-10.3]P=0.005 OR=1.995%CI [0.64-5.6]P=0.24 HR=0.21 95%CI [0.13-0.35].P<0.0001 HR=0.19 95%CI [0.10-0.35]P=0.0005