The phase 3 INTEGRATE IIa trial has demonstrated that regorafenib offers a modest but statistically significant survival advantage for patients with refractory advanced gastric or gastroesophageal junction (GEJ) cancer. The findings, published in the Journal of Clinical Oncology, represent a meaningful advancement in treating this challenging disease.
At a median follow-up of 48 months, patients receiving regorafenib achieved a median overall survival of 4.5 months compared to 4.0 months in the placebo group (HR, 0.68; 95% CI, 0.52-0.90; P = .006). The survival benefit remained consistent across all prespecified subgroups, regardless of geographic region.
Trial Design and Patient Population
The randomized, double-blind study enrolled patients with metastatic or locally recurrent gastric/GEJ adenocarcinoma who had received at least two prior lines of therapy. Participants were randomized 2:1 to receive either 160 mg oral regorafenib or placebo daily on days 1-21 of each 28-day cycle.
The study population included 251 patients, with a median age of 63 years in the regorafenib arm and 64 years in the placebo arm. Most participants were male (72% regorafenib, 84% placebo) and from Asia (63% regorafenib, 62% placebo), with the stomach being the primary disease site in approximately 72% of cases.
Efficacy Outcomes
Beyond overall survival, regorafenib demonstrated improvements in several secondary endpoints:
- Progression-free survival reached 1.8 months versus 1.6 months for placebo (HR, 0.53; P < .0001)
- Disease control rate was 21.3% for regorafenib compared to 4.9% for placebo
- Objective response rate was 2.4% in the regorafenib group versus 0% in the placebo group
Quality of life measurements showed significant benefits, with regorafenib patients experiencing a longer time to deterioration in global quality of life scores (HR, 0.68; P = .0043).
Safety Profile
The safety analysis revealed manageable but notable adverse events in the regorafenib group:
- 96% of regorafenib patients experienced adverse events compared to 87% in the placebo group
- Most common side effects included palmar-plantar erythrodysesthesia (40%), oral mucositis (21%), and diarrhea (22%)
- Three grade 5 adverse events occurred in the regorafenib arm, including one treatment-related hepatic failure
Lead investigator Dr. Nick Pavlakis of Royal North Shore Hospital and the University of Sydney emphasized the trial's significance: "The results of INTEGRATE IIa confirmed clinical benefit of regorafenib in patients with refractory advanced gastric/GEJ cancer by delaying disease progression and quality-of-life deterioration, leading to prolonged survival."
Future Directions
The positive results support regorafenib's potential as a platform for combination therapies. Currently, investigations are underway in the phase 3 INTEGRATE IIb study and a phase 2 trial combining regorafenib with nivolumab and chemotherapy, potentially opening new treatment avenues for patients with advanced gastric cancer.
