Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432

Abstract

Background: High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.

Patients and methods: We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1-d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.

Results: In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group [14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24-0.96), P = 0.038], while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.

Conclusions: Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.

Trial registration: ClinicalTrials.gov NCT02915432.

Keywords: gastric cancer; immunotherapy; programmed death ligand-1; tumor mutational burden.

Figure 1.

Tumor response in toripalimab monotherapy cohort assessed by investigator per RECIST v1.1. (A) Maximal change of tumor size from baseline in target lesion(s) (n = 41, patients with baseline and at least one post-treatment radiographic evaluation). ^#The response was unable to confirm and was classified as stable disease (SD). *The patient was characterized as progressive disease (PD) due to the development of new lesion(s) or progression of non-target lesion(s). (B) Change of individual tumor burden over time from baseline. (C) Clinical response in relation to tumor PD-L1 expression and tumor mutational burden (TMB).

Figure 2.

Kaplan–Meier plots of median (A) progression-free survival (PFS) and (B) overall survival (OS) of chemo-refractory patients treated with toripalimab monotherapy. Median (C) PFS and (D) OS of patients treated with toripalimab–XELOX combination therapy as first-line treatment. NR, not reached. Percentages of survival patients are shown at indicated time points.

Figure 3.

Kaplan–Meier plots of median (A) PFS and (B) OS of PD-L1+ versus PD-L1− patients. Median (C) PFS and (D) OS of TMB-H versus TMB-L patients. Median (E) PFS and (F) OS of PD-L1+ or TMB-H versus PD-L1- and TMB-L patients.

Figure 3.

Kaplan–Meier plots of median (A) PFS and (B) OS of PD-L1+ versus PD-L1− patients. Median (C) PFS and (D) OS of TMB-H versus TMB-L patients. Median (E) PFS and (F) OS of PD-L1+ or TMB-H versus PD-L1- and TMB-L patients.