A Phase 3 randomised controlled trial has found that the combination of regorafenib and nivolumab — known as RegoNivo — does not produce a statistically significant improvement in overall survival compared with chemotherapy in patients with refractory gastro-oesophageal adenocarcinoma, ending an exploration that began with striking but ultimately misleading Phase 1b data.

INTEGRATE IIb enrolled 462 patients across multiple countries who had progressed on at least two prior lines of therapy for gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Participants were randomised to regorafenib plus nivolumab or active chemotherapy. The primary endpoint was overall survival. Results presented at ESMO 2025 (LBA80) showed a hazard ratio of 0.88 (95% CI 0.71–1.09; p=0.23) — a numerical trend favouring the combination that did not meet statistical significance.

The objective response rate was 7.4% for RegoNivo versus 2.6% for the control arm. A higher response rate that does not translate into survival benefit is a pattern seen before in this tumour type, and it does not justify the combination as a new standard of care. The OS primary endpoint is the clinically decisive finding.

The result is a significant setback for a regimen that generated substantial interest after a Phase 1b study (REGONIVO) published in the Journal of Clinical Oncology in 2020 reported a 44% objective response rate — a figure that, in retrospect, reflects the optimism-selection bias endemic to small, open-label, single-arm dose-escalation studies. The Phase 3 trial enrolled a more representative patient population with an active comparator, conditions that routinely reveal smaller effects than early-phase data predict.

Gastro-oesophageal adenocarcinoma remains one of the most therapeutically challenged malignancies. Refractory-line options are limited to regorafenib, trifluridine/tipiracil, and — in select PD-L1-positive or MSI-H populations — pembrolizumab. The INTEGRATE IIb result adds nothing to that list, leaving the field to look toward emerging options including claudin 18.2-targeting agents and bispecific antibodies now in Phase 2 development.