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

BackgroundHigh 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 methodsWe 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.ResultsIn 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.ConclusionsToripalimab 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 registrationClinicalTrials.gov NCT02915432.

Prognostic impact of gene copy number instability and tumor mutation burden in patients with resectable gastric cancer

“…In accordance with these results, we found that a high CNI could be an independent marker for unfavorable prognosis in patients with resectable GC. TMB has been regarded as a biomarker for predicting the clinical response to immunotherapy and prognosis in various cancer types [12‐16]. In the present study, we identified TMB as a prognostic marker for GC patients who had undergone surgery plus adjuvant chemotherapy.…”

Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer

“…In a study on 126 patients with esophagogastric cancer using an upper 20 percentile cut-off for TMB (8.8 mt/mb) to distinguish TMBhigh and -low groups, TMB could predict clinical response to ICB (14). Recent clinical study in advanced gastric cancer patients investigating the safety and efficacy of toriparimab, a newly approved humanized PD-1 antibody, showed that high TMB (12 mt/mb, upper 20 percentile cut-off) was associated with improved patient responses and survival benefit after immunotherapy (18). In our study, a TMB cut-off of 14.31 mt/mb dichotomized patients into TMB-high and -low groups; eight patients were TMB-high and 55 were TMB-low.…”

“…However, its predictive effect in advanced gastric cancer had not yet been demonstrated (17). Recently, Wang et al (18) have identified TMB as a biomarker for survival benefit in chemo-refractory gastric cancer treated with toripalimab: High TMB group showed significant superior overall survival (OS) than the TMB-low group (14.6 vs. 4.0 months, HR = 0.48, P = 0.038). TMB has been traditionally determined by whole exome sequencing; however, high cost and lengthy turnaround time limit its widespread use in clinic (12,13,19,20).…”

“…However, most studies determining TMB by panel-based sequencing were performed in patients with non-small-cell lung cancer or melanoma (13,16,20). Although several studies evaluated TMB in gastric cancer, most studies proposed cut-off points for TMB and their relevance to survival (21)(22)(23), and only two studies included patients treated with ICB, in which TMB was measured by whole exome sequencing (18) and custom-designed large-sized panels (14). Moreover, despite efforts to standardize the TMB from multiple different genomic profiling panels (24), the cutoff value for TMB is not consistent and the associations with other biomarkers have not been fully defined in gastric cancer.…”

Safety and efficacy of toripalimab in advanced gastric cancer: A new clinical trial bringing hope for immunotherapy in gastric cancer

“…However, whether toripalimab is safe and effective in treating GC patients remains unknown. But now, based on a reported study entitled “Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemotherapy‐refractory gastric cancer treated with toripalimab, a PD‐1 antibody in phase Ib/II clinical trial NCT02915432,” published in Annals of Oncology [15], the safety and efficacy of this novel anti‐PD‐1 antibody has been evaluated in chemotherapy‐refractory advanced GC.…”