Comprehensive molecular characterization to predict immunotherapy response in advanced biliary tract cancer: a phase II trial of pembrolizumab

Background: Immune checkpoint inhibitors (ICIs) are effective in a subset of patients with metastatic solid tumors. However, the patients who would benefit most from ICIs in biliary tract cancer (BTC) are still controversial. Materials and methods: We molecularly characterized tissues and blood from 32 patients with metastatic BTC treated with the ICI pembrolizumab as second-line therapy. Results: All patients had microsatellite stable (MSS) type tumors. Three of the 32 patients achieved partial response (PR), with an objective response rate (ORR) of 9.4% (95% confidence interval [CI], 2.0–25.2) and nine showed stable disease (SD), exhibiting a disease control rate (DCR) of 37.5% (95% CI, 21.1–56.3). For the 31 patients who had access to PD-1 ligand 1 (PD-L1) combined positive score (CPS) testing (cut-off value ≥1%), the ORR was not different between those who had PD-L1-positive (PD-L1+; 1/11, 9.1%) and PDL1-(2/20, 10.0%) tumors (p = 1.000). The tumor mutational burden (TMB) of PD-L1+ BTC was comparable to that of PD-L1-BTC (p = 0.630). TMB and any exonic somatic mutations were also not predictive of pembrolizumab response. Molecular analysis of blood and tumor samples demonstrated a relatively high natural killer (NK) cell proportion in the peripheral blood before pembrolizumab treatment in patients who achieved tumor response. Moreover, the tumors of these patients presented high enrichment scores for NK cells, antitumor cytokines, and Th1 signatures, and a low enrichment score for cancer-associated fibroblasts. Conclusions: This study shows the molecular characteristics associated with the efficacy of pembrolizumab in BTC of the MSS type.