Camrelizumab plus CAPOX with camrelizumab based maintenance versus CAPOX alone as initial treatment for gastric or gastro-oesophageal junction adenocarcinoma: randomised phase 3 trial

Abstract Objective To compare camrelizumab plus capecitabine and oxaliplatin followed by camrelizumab plus apatinib (camre+CAPOX followed by camre+apa), CAPOX alone, and camrelizumab plus CAPOX followed by camrelizumab (camre+CAPOX followed by camre) as initial treatment for gastric or gastro-oesophageal junction adenocarcinoma. Design Randomised, open label, phase 3 study. Setting 75 hospitals in China, 13 March 2019 to 16 August 2021. Participants 885 adults (≥18 years) with previously untreated, human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Interventions Patients were randomised (2:2:1) to receive camre+CAPOX followed by camre+apa, CAPOX only, or camre+CAPOX followed by camre, stratified by Eastern Cooperative Oncology Group performance status, peritoneal metastasis, and programmed death ligand 1 (PD-L1) combined positive score. Assignment to camre+CAPOX followed by camre was introduced midway through enrolment. Main outcome measures The primary endpoint was overall survival for camre+CAPOX followed by camre+apa versus CAPOX alone in the PD-L1 positive population (combined positive score >1) and the overall population who received at least one dose of study drug. Comparisons of camre+CAPOX followed by camre versus CAPOX alone and of camre+CAPOX followed by camre+apa versus camre+CAPOX–camre were descriptive. Safety was assessed in all patients who received at least one dose of study drug. Results 352 patients received camre+CAPOX followed by camre+apa, 349 received CAPOX alone, and 177 received camre+CAPOX followed by camre. At the time of data cut off, 454 of 592 (76.7%) deaths had occurred in the PD-L1 positive population and 709 of 878 (80.8%) in the overall population. Overall survival was longer with camre+CAPOX followed by camre+apa than with CAPOX alone in the PD-L1 positive population (median 15.0 v 12.5 months; hazard ratio 0.80 (95% CI 0.65 to 0.98); one sided P=0.02) and in the overall population (median 13.5 v 12.1 months; hazard ratio 0.80 (0.68 to 0.94); one sided P=0.004). Use of camre+CAPOX followed by camre also showed longer overall survival versus CAPOX in the PD-L1 positive population (median 15.3 v 12.5 months; hazard ratio 0.76 (0.58 to 0.97); one sided nominal P=0.01) and overall population (median 14.2 v 12.1 months; hazard ratio 0.80 (0.65 to 0.98); one sided nominal P=0.02). No overall survival benefit was observed with camre+CAPOX followed by camre+apa versus camre+CAPOX followed by camre. Treatment related adverse events of grade ≥3 occurred in 239 of 352 (67.9%) patients in the camre+CAPOX followed by camre+apa group, 158 of 349 (45.3%) in the CAPOX alone group, and 83 of 177 (46.9%) in the camre+CAPOX followed by camre group. Conclusions Initial treatment with camrelizumab plus CAPOX followed by camrelizumab based maintenance was associated with longer overall survival than CAPOX alone in human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Exploratory comparisons between the two camrelizumab based regimens showed no additional survival benefit, with higher rates of treatment related adverse events of grade ≥3 and treatment discontinuations when apatinib was added during maintenance. Trial registration ClinicalTrials.gov NCT03813784