Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial
Mené au Japon, en Corée et à Taïwan sur 724 patients atteints d'un cancer de l'estomac ou d'un cancer de la jonction oesogastrique HER2-, non résécable, de stade avancé ou récidivant (durée médiane de suivi : 11,6 mois), cet essai de phase III évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de l'ajout du nivolumab à une chimiothérapie de première ligne à base d'oxaliplatine
Background : The additive or synergistic sustained antitumour effect of immune checkpoint inhibitorsin combination with oxaliplatin-based chemotherapy has previously been reported. Weinvestigated the efficacy of nivolumab plus oxaliplatin-based chemotherapy versusplacebo plus oxaliplatin-based chemotherapy as first-line therapy for patients withHER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junctioncancer. Methods : We did a randomised, multicentre, double-blind, placebo-controlled, phase 2–3 trial(ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) acrossJapan, South Korea, and Taiwan. We enrolled patients aged 20 years and older withpreviously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180days before recurrence), HER2-negative, unresectable, advanced or recurrent gastricor gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least onemeasurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance statusof 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenousoxaliplatin 130 mg/m2 on day 1 plus either oral S-1 40 mg/m2 [SOX] or oral capecitabine 1000 mg/m2 [CAPOX], twice daily on days 1–14), in addition to either 360 mg nivolumab intravenouslyevery 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapygroup). Randomisation was done using an interactive web response system with blocksizes of four and stratified by intensity of PD-L1 expression, ECOG performance statusscore, disease status, and geographical region. Patients, investigators, and the studysponsor were masked to treatment assignment. The primary endpoints were centrallyassessed progression-free survival and overall survival in the intention-to-treatpopulation, which included all randomly assigned patients. Safety was assessed inall patients who received at least one dose of the assigned treatment. This trialis registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing. Findings : Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo pluschemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7–14·1), median progression-free survival at a prespecifiedinterim analysis was 10·45 months (95% CI 8·44–14·75) in the nivolumab plus chemotherapygroup and 8·34 months (6·97–9·40) in the placebo plus chemotherapy group (hazard ratio[HR] 0·68; 98·51% CI 0·51–0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020,with a median follow-up of 26·6 months (IQR 24·1–29·0), median overall survival atthe final analysis was 17·45 months (95% CI 15·67–20·83) in the nivolumab plus chemotherapygroup and 17·15 months (15·18–19·65) in the placebo plus chemotherapy group (HR 0·90;95% CI 0·75–1·08; p=0·26). The most common treatment-related grade 3–4 adverse eventswere neutrophil count decreased (71 [20%] of 359 patients in the nivolumab plus chemotherapygroup vs 57 [16%] of 358 patients in the placebo plus chemotherapy group) and platelet countdecreased (34 [9%] vs 33 [9%]). Treatment-related serious adverse events of any grade were observed in88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in theplacebo plus chemotherapy group, of which the most common was decreased appetite (18[5%] vs ten [3%]). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapygroup (one each of febrile neutropenia, hepatic failure, and sudden death) and threein the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, andinterstitial lung disease). Interpretation : Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-freesurvival, but not overall survival, in Asian patients with untreated, HER2-negative,unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer,and could potentially be a new first-line treatment option for these patients.