mFOLFIRINOX vs mFOLFOX6 in Gastric/GEJ
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mFOLFIRINOX (irinotecan plus oxaliplatin, leucovorin, and fluorouracil [5-FU]) significantly improved objective response rate (ORR) but not progression-free survival (PFS) or overall survival (OS) vs mFOLFOX6 (oxaliplatin, leucovorin, and 5-FU) in patients when used as a frontline treatment of patients with HER2-negative metastatic gastric and gastroesophageal adenocarcinoma, according to data from the phase 3 IRIGA trial (NCT04442984) presented at the 2025 ESMO Gastrointestinal Cancers Congress.1
The median PFS was numerically improved with mFOLFIRINOX (triplet; n = 157) vs mFOLFOX6 (doublet; n = 161), at 7.20 months (95% CI, 6.82-7.58) and 6.83 months (95% CI, 5.76-7.90), respectively (HR, 0.81; 95% CI, 0.63-1.04; P = .266). However, a significant improvement was observed in those with grade 1 or 2 disease, at a median of 9.9 months (95% CI, 5.6-14.2) vs 8.4 months (95% CI, 7.5-9.2), respectively (HR, 0.55; 95% CI, 0.30-0.99). The median OS with mFOLFIRINOX vs mFOLFOX6 was 13.40 months (95% CI, 11.76-15.04) and 13.23 months (95% CI, 10.86-15.60; HR, 0.87; 95% CI, 0.66-1.15; P = .322).
The partial response rates in the mFOLFIRINOX and mFOLFOX6 arms were 31.2% vs 19.3% (P = .014), the stable disease rates were 43.3% vs 47.8% (P = .419), disease control rates were 74.5% vs 67.1% (P = .144), and the progressive disease rates were 20.4% vs 31.7% (P = .022); 4.5% and 1.2% of patients in the respective arms were not evaluable for response.
“Despite improved response, no significant benefit in OS or PFS was observed in the overall population. A significant improvement in PFS was seen in patients with grade 1 or grade 2 gastric adenocarcinoma treated with mFOLFIRINOX,” Daria Gavrilova, MD, of Russian Federation, said in a presentation of the data. “mFOLFIRINOX was associated with a higher incidence of treatment-related toxicities.”
A Spotlight on IRIGA
The single-center, open-label, randomized phase 3 study enrolled patients with advanced gastric or gastroesophageal HER2-negative adenocarcinoma who had an ECOG performance status of 0 to 2 and who had not previously received systemic therapy for advanced disease. Adjuvant therapy was permitted if received longer than 6 months before the study.
Study participants were randomly assigned 1:1 to mFOLFIRINOX vs mFOLFOX6. Those in the mFOLFIRINOX arm received 180 mg/m2 of irinotecan, 85 mg/m2 of oxaliplatin, 200 mg/m2 of leucovorin, and 250 mg/m2 of 5-FU plus 2200 mg/m2 every 2 weeks. Those in the mFOLFOX6 arm received 85 mg/m2, 400 mg/m2 of leucovorin, and 400 mg/m2 of 5-FU plus 2400 mg/m2 every 2 weeks. Patients received 9 cycles of chemotherapy and then underwent observation. They did not receive maintenance treatment.
Patients were stratified based on age (under 65 years vs 65 years or older), primary tumor (present vs resected), histological differentiation (G1 to G2 vs G3 to signet ring cell carcinoma), number of metastatic sites (1 to 2 vs 3 or more), tumor location (gastroesophageal junction vs stomach), and ECOG performance status (0 to 1 vs 2).
The primary end point of the study was PFS, and secondary end points included OS, ORR, toxicity, efficacy across Lauren subtypes, and efficacy by tumor grade. Investigators also sought to detect a hazard ratio of 0.73 with 82% power, 1-sided α = 0.05, and a 10% dropout rate, which translates to 163 patients per group.
A total of 326 patients were enrolled in the study, and the median follow-up was 22.4 months. The median patient age was 57 years (range, 20-75) with mFOLFIRINOX vs 58 years (range, 34-74) with mFOLFOX6, with 24.2% and 29.8% of patients aged 65 years or older. Slightly more than half of the patients were male (57.3% vs 55.3%). Most patients had an ECOG performance status of 1 (87.9% vs 83.2%), had a primary tumor site of the stomach (87.3% vs 85.7%), histological grade 3 plus signet-ring cell (78.9% vs 72.1%), and 1 to 2 metastatic sites (73.2% vs 75.8%). Moreover, 5.7% and 7.5% of those in the mFOLFIRINOX and mFOLFOX6 arms had prior primary tumor resection.
Additional Subgroup Analysis Data
The hazard ratio (HR) for PFS in women was 0.83 (95% CI, 0.59-1.16) and 0.79 (95% CI, 0.55-1.16) in men. In those under 65 years, the HR for PFS was 0.77 (95% CI, 0.58-1.03); in those aged 65 years or older, the HR for PFS was 0.79 (95% CI, 0.46-1.36). In those with an ECOG performance status of 0 to 1 or 2, the HRs for PFS were 0.81 (95% CI, 0.63-1.05) and 0.83 (95% CI, 0.25-2.79), respectively. In those with histological grade 3 plus signet ring cell disease, the HR for PFS was 0.83 (95% CI, 0.62-1.10). In those with GEJ or stomach cancer, the HRs for PFS were 0.90 (95% CI, 0.46-1.79) and 0.79 (95% CI, 0.60-1.04), respectively.
Moreover, in those with Lauren classifications of intestinal, diffuse, or mixed, the respective HRS for PFS were 0.78 (95% CI, 0.50-1.22), 0.72 (95% CI, 0.49-1.04), and 0.99 (95% CI, 0.58-1.69). In those with no more than 2 organs with metastases, the HR for PFS was 0.81 (95% CI, 0.60-1.08); in those with 3 or more organs with metastases, the HR for PFS was 0.73 (95% CI, 0.45-1.19). The HRs for PFS in those who had prior tumor resection vs those who did not were 0.69 (95% CI, 0.24-1.92) and 0.79 (95% CI, 0.61-1.02).
Safety Revelations
The most common grade 1 to 2 adverse effects (AEs) reported in the mFOLFIRINOX and mFOLFOX6 arms were asthenia (88.1% vs 87.4%; P = .736), nausea (41.4% vs 24.5%; P = .001), diarrhea (40% vs 10.1%; P < .001), hepatotoxicity (36.6% vs 31.5%; P = .333), thrombocytopenia (25.3% vs 24.5%; P = .869), neutropenia (23.3% vs 23.6%; P = .907), peripheral neuropathy (18.7% vs 20.1%; P = .746), vomiting (16% vs 3.8%; P < .001), mucositis (7.3% vs 2.5%; P = .069). The most common grade 3 or 4 AEs in the respective arms were neutropenia (38.7% vs 26.4%; P = .280), asthenia (6.6% vs 0.6%; P = .019), febrile neutropenia (4% vs 1.3%; P = .168), thrombocytopenia (2.7% vs 1.3%; P = .439), diarrhea (2.7% vs 0% P = .057), nausea (1.3% vs 0%; P = .238), hepatotoxicity (0.7% vs 0.6%; P = 1.000), and vomiting (0.7% vs 0%; P = .487).
Disclosures: All authors have declared no conflicts of interest.
Reference
Gavrilova D, Besova N, Obarevich E, et al. IRIGA: Phase III randomized trial of mFOLFIRINOX versus mFOLFOX6 as first-line treatment for HER2-negative metastatic gastric and gastroesophageal adenocarcinoma. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 391MO.