Clinical and molecular features of responders to PD-1 blockade for patients with microsatellite instability high or mismatch repair deficient advanced gastrointestinal tumors.

Abstract

e16550 Background: An anti-PD-1 inhibitor pembrolizumab showed a durable response for patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors. However, clinical and molecular features of responders to PD-1 blockade for MSI-H/dMMR advanced gastrointestinal (GI) tumors are not well understood. Methods: Patients with MSI-H/dMMR GI tumors who received anti‒PD-1 monotherapy were enrolled in this study. PD-L1 expression in tumor cells or immune cells as well as combined positive score (CPS) were assessed using the PDL1 IHC 22C3 pharmDx assay. Cancer genome alterations were evaluated by a next generation sequencing-based panel with Oncomine Comprehensive Assay for tumor tissue samples or Guardant360 ctDNA Assay for plasma samples. Results: A total of 43 patients with gastric cancer (n = 19), colorectal cancer (n = 16), cholangiocarcinoma (n = 4), small intestine cancer (n = 2) and pancreatic cancer (n = 2) were analyzed in this study. All patients had measurable lesions and objective response was observed in 20 patients (46%). Objective response rate (ORR) was significantly higher in patients with ECOG PS of 0 than in those with PS of 1 or 2 (64% vs. 22%, p = 0.01) and PD-L1+ in tumor cells than in those with PD-L1- in tumor cells (67% vs. 32%, p = 0.03). ORR was similar according to PD-L1 CPS; 45% in CPS < 1, 47% in CPS ≥1 and 56% in CPS ≥10, respectively. ORR was numerically lower in patients with PTEN mutation than in those with PTEN wild type (29% vs. 56%). Also, durable response rate (objective response lasting continuously ≥6 months) was significantly lower in patients with PTEN mutation than in those with PTEN wild type (0% vs. 52%, p = 0.03). In the overall population, median progression-free survival (PFS) was 10.0 months (95% CI, 4.0-not reached). In univariate analysis, PS (1 or 2 vs. 0) was the strongest clinical factor associated with PFS (3.9 months vs. not reached, HR 3.9; 95% CI 1.7-9.2, p = 0.002). After adjusted by PS, PTEN mutation was only molecular factor associated with shorter PFS (3.4 vs. 24.5 months, HR 3.0; 95% CI 1.1-8.4, p = 0.03). Conclusions: Some clinical and molecular factors were associated with response to PD-1 blockade for MSI-H/dMMR advanced GI tumors. Updated biomarker analysis with whole exome sequencing and multiplex IHC will be presented.