Efficacy and biomarker analysis of neoadjuvant carrizumab plus apatinib in patients with local advanced biliary tract cancers.

Abstract

e16126 Background: Camrelizumab (anti-PD-1 antibody) plus apatinib (VEGFR2 inhibitor) as combination therapy is highly effective in advanced osteosarcoma, hepatocellular carcinoma and extensive-stage SCLC. This study aimed to access the efficacy, safety and explore predictive biomarkers of neoadjuvant carrizumab plus apatinib in local advanced biliary tract cancers (BTCs) (ChiCTR2000034283). Methods: This single-arm, phase II trial enrolled patients with local advanced BTCs. Patients received camrelizumab 200 mg every 2 weeks plus apatinib 250 mg once per day for two cycles, clinical response was then evaluated. Gene expression profiling (GEP), using the 289-gene immune-related RNA panel sequencing, was performed on baseline tumor samples. Differential gene expression analysis was performed between responder (partial response and complete response) and non-responder (stable disease and progressive disease) using Wilcoxon rank-sum test. Results: Across these patients with local advanced BTCs, neoadjuvant camrelizumab plus apatinib demonstrated antitumor activity. Seventeen (n = 13 gallbladder carcinoma; n = 4 cholangiocarcinoma) response-evaluable patients received two cycles of combination therapy, of whom 12 (70.5%) patients achieved objective response, including 2 (11.7%) with complete response, and the DCR was 76.4%. To further assess the impact of the tumor microenvironment on the combination therapy response, we sequenced baseline tumor samples performed biomarker analyses using the 289-gene immune-related RNA panel. Of all enrolled patients with evaluable responses, 16 (94.1%) patients had available GEP data. Baseline tumor samples on differential genes revealed a significantly higher S100A8 (P = 0.004), IL1B (P = 0.002), KIR2DL3 (P = 0.007) expression in non-responders compared with responders. Extensive analyses on immune cell types were also performed. ECMES positive exhausted CD8 T cells (P = 0.009) and SIGLEC5 positive neutrophils (P = 0.0014) were significantly increased in baseline non-responders. In contrast, no significant differences of CD8 positive T cells, B-cells, cytotoxic cells, dendritic cells, macrophages cells or NK cells were found at baseline between groups. Meanwhile, signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures between responder and non-responder groups, and no noteworthy differences were found in TILs score, Cytolytic activity score, IFN-γ signature and Teff score. Conclusions: Neoadjuvant camrelizumab plus apatinib exhibited promising antitumor activity in patients with local advanced biliary tract cancers. Elevated S100A8, IL1B, KIR2DL3 expression levels may indicate resistance in clinical response. Increased ECMES positive exhausted CD8 T cells and SIGLEC5 positive neutrophils were predictive of response in non-responder tumors.