Programmed death-1 blockade in mismatch repair deficient cancer independent of tumor histology.

3003 Background: Mismatch repair deficiency (MRD) is feature of many cancers at a frequency of approximately 1 in 30 patients independent of tumor histology. Tumors with MRD are deficient in the repair of specific DNA replication errors and as a result accumulate hundreds to thousands of mutations per tumor genome. The high number of somatic mutations increase the chances for at least one of these mutations to result in a highly immunogenic neo-antigenic protein that can trigger a potent anti-tumor immune response in the presence of PD-1 blockade. Methods: To further test this hypothesis, we conducted a phase 2 study to evaluate the activity of pembrolizumab (pembro), a programmed death-1 (PD-1) antibody in MRD tumors independent of tumor histology using a basket design. Pembro was administered at 10 mg/kg every 14 days in patients with > 1 prior therapy. The co-primary endpoints were response and progression-free survival rate at 20 weeks. Secondary endpoints included disease control rate (DCR = CR+PR+SD), PFS, overall survival (OS) and safety. Results: A total of 29 patients were enrolled and treated on this study, including the following histologies: (endometrial: 9; pancreatic: 4; ampullary: 4; biliary: 3; small bowel: 3; gastric: 3; thyroid: 1; prostate: 1; sarcoma: 1). Median follow up time is 8.1 mos. Objective response and disease control rates were 48% (14/29, 95% confidence interval: 29-67%) and 72% (21/29), respectively. Twenty of 29 patients remain on treatment due to clinical benefit. Median overall Survival (OS) and progression-free survival (PFS) were 21 months and not reached (NR). The OS and PFS rates at 12 months were 79% and 54%, respectively, which support the durability of clinical benefit. Among the patients with an objective response, only 3 have developed secondary resistance to pembro with a median time to progression of 5 months. Conclusions: Independent of tumor histology, patients with advanced MRD cancers receive durable clinical benefit with Pembro. Clinical trial information: NCT01876511.