Mismatch-Repair Gene Shapes Immune Checkpoint Blocker Outcomes: MLH1/MSH2 Hit 40-46% CR, PMS2 Falls to 9% and 20-mo OS

In a retrospective MSK-IMPACT series (NCT01775072), 132 patients with Lynch syndrome and advanced solid tumors—including colorectal cancer (35%), genitourinary cancers (14%), and pancreatic or biliary cancers (13%)—received a PD-1/PD-L1 blockade. Germline variants were distributed as follows: MSH2 in 54 patients, MLH1 in 37, PMS2 in 23, and MSH6 in 18. Across all gene groups, the ORR was 58%, with a notable 35% complete response (CR) rate. However, the CR rate varied significantly by gene: 41% for MLH1, 46% for MSH2, 22% for MSH6, and only 9% for PMS2. The mPFS/OS were 52 months/not reached (NR) for MLH1, MSH2, and MSH6, versus 11 months (PFS) and 20 months (OS) for PMS2 (HR for OS 0.19, p=0.0005). MMR-proficient tumors—8 out of 13 were both MMRp and MSS—were more common among PMS2 carriers, partially explaining the lower response rates. Even among PMS2 carriers with MMR-deficient tumors, the mOS was only 27.7 months.