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.

A consensus treatment strategy for esophageal squamous cell carcinoma (ESCC) patients who recur after definitive radiochemotherapy/radiotherapy has not been established. This study compared the outcomes in ESCC patients who underwent salvage surgery, salvage chemoradiation (CRT) or best supportive care (BSC) for local recurrence. Ninety-five patients with clinical stage I to III ESCC who had completely responded to the initial definitive radiochemotherapy or radiotherapy alone and developed local recurrence were enrolled in this study. Fifty-one of them received salvage esophagectomy, and R0 resection was performed in 41 patients, 36 underwent salvage CRT, and the remaining eight patients received BSC only. The 5-year overall survival was 4.6% for the 87 patients receiving salvage surgery or CRT, while all patients in the BSC group died within 12.0 months, the difference was statistically significant (P = 0.018). The 1-, 3-, 5-year survival rates in the salvage surgery and salvage CRT groups were 45.1%, 20.0%, 6.9% and 51.7%, 12.2%, 3.1%, respectively, there was no difference of overall survival between the two groups (P = 0.697). Patients also presented with lymph node relapse had inferior survival compared to those with isolated local tumor recurrence after salvage therapy. In the salvage surgery group, infections occurred in eight patients, and three developed anastomotic leakage. In the salvage CRT group, grade 2-4 esophagitis and radiation pneumonitis was observed in 19 and 3 patients, respectively. Seven patients (19.4%) developed esophagotracheal fistula or esophageal perforation. This study of salvage CRT versus salvage surgery for recurrent ESCC after definitive radiochemotherapy or radiotherapy alone did not demonstrate a statistically significant survival difference, but the frequency of complications including esophagotracheal fistula and esophageal perforation following salvage CRT was high.

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