Tumor mutational burden identifies chemorefractory gastric cancer with overall survival advantage after receiving toripalimab, a PD-1 antibody.

Abstract

4021 Background: Tumor mutational burden (TMB) is correlated with enhanced objective response rate (ORR) and progression-free survival for certain cancers receiving immunotherapy. This study aimed to investigate the safety and activity of toripalimab, a humanized PD-1 antibody, in advanced gastric cancer (AGC), and the efficacy predictive value of biomarkers including TMB and PD-L1. Methods: This study was a part of phase Ib/II trial evaluating the safety and activity of toripalimab as a single agent therapy or in combination with chemotherapy in chemo-refractory or treatment-naïve AGC, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. This report focused on the chemo-refractory AGC cohort receiving toripalimab (3 mg/Kg d1, Q2W) as a single agent therapy. Primary endpoint was ORR. Biomarkers including tumor PD-L1 expression, TMB, microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection status were evaluated for their correlation with clinical efficacy as preplanned. Tumor PD-L1 expression was assessed with the SP142 immunohistochemistry assay, and the other biomarkers were assessed with whole exome sequencing based on tumor samples. Results: There were 58 subjects included in this cohort. The ORR was 12.1% and the disease control rate was 39.7%. Only 1 subject was MSI-H and achieved partial response. One out of 4 EBV positive subjects achieved partial response. Significant higher ORR was observed in subjects with positive PD-L1 expression (ORR 37.5%, 3/8) or TMB ≥12 Mutations/Mb (ORR 33.3%, 4/8) than those with negative PD-L1 expression (ORR 8.5%) or TMB < 12 Mutations/Mb (ORR 7.0%). The TMB-high subgroup showed significant superior OS than the TMB-low subgroup (HR = 0.48 [96% CI 0.24 to 0.96], p = 0.038), while PD-L1 expression status failed to differentiate OS. Conclusions: Toripalimab demonstrated promising anti-tumor activity in chemo-refractory AGC patients. TMB might serve as a better predictive marker for OS than PD-L1 expression for chemo-refractory AGC patients receiving PD-1 blockade immunotherapy. Clinical trial information: NCT02915432.