Biomarker exploration for SHR-1210 plus GEMOX as first-line treatment in advanced biliary tract cancer.

Abstract

536 Background: We conducted a trial to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as in untreated patients (pts) with biliary tract cancer (BTC) (NCT03486678). This study is to explore the predictive biomarkers for efficacy. Methods: Baseline lymphocyte count and lactate dehydrogenase (LDH) level were obtained from routine tests. Gene mutation and tumor mutation burden (TMB) from baseline tissue and blood samples were tested by the next generation sequencing (NGS) with a 425-gene panel. The expressions of PD-L1 and markers for lymphocyte, natural killer cells, and macrophages in baseline tumor tissue samples were analyzed by immunohistochemistry (IHC). Results: The median progression free survival (PFS) and overall survival (OS) in this trial was 6.2m and 12.1m, respectively. Firstly, pts with normal LDH level (≤271 U/L) had a tendency for longer PFS (6.2m vs 5.0m, p = 0.053) and significantly longer OS (p = 12.6m vs 6.8m, p < 0.001) than those with elevated LDH ( > 271 U/L). Low baseline lymphocyte count (≤ 1.1×109/L) was related to worse OS (12.6m vs 6.9m, p < 0.001) and PFS (6.2m vs 3.9m, p = 0.021). Secondly, baseline tissue and ctDNA gene mutations were detected in 33 and 30 pts, respectively. Tissue analysis showed that pts with STK11 (p = 0.0254), CTNNB1 (p < 0.001) and SMARCA4 (p = 0.0181) wild type showed significantly longer PFS than those with mutations. Pts with ARID1A gene wild type showed a tendency for longer PFS (p = 0.0634) and significantly longer OS (p = 0.0149). Gene mutations from baseline ctDNA revealed that pts with wild type SMARCA4, CTNNB1, STK11, and NF1 had longer PFS than those with mutations. Lastly, IHC meant that PD-L1 positivity may be related to longer PFS (TPS > 1%, p = 0.08; IPS > 1%, p = 0.05). Besides, pts with CD68+ HLA-DR+ macrophages > 0.01%, CD68+ HLA-DR- macrophages>2.5%, and CD56bright>1.7% and CD56dim > 0.05 also got PFS benefits (all p < 0.05). TMB (cutoff = 7 muts/mbp) was not associated with PFS. Conclusions: Despite limited sample size, biomarkers from routine blood test, gene mutation and immune microenvironment can be helpful to stratify pts who are sensitive to immunotherapy in advanced BTC. Clinical trial information: NCT03486678.