As reported in JAMA Oncology by Stein et al, the German phase II INTEGA trial showed improved survival with the addition of modified FOLFOX6 (fluorouracil, leucovorin, oxaliplatin) vs the addition of ipilimumab to trastuzumab/nivolumab in the first-line treatment of patients with advanced or metastatic HER2-positive esophagogastric adenocarcinoma.
In the multicenter trial, 88 patients were randomly assigned between March 2018 and March 2020 to the FOLFOX group (n = 44) or the ipilimumab group (n = 44). The FOLFOX group received trastuzumab at 4 mg/kg (loading dose of 6 mg/kg), nivolumab at 240 mg, and mFOLFOX6 (consisting of oxaliplatin at 85 mg/m2, fluorouracil at 400 mg/m2 bolus, leucovorin at 400 mg/m2, and fluorouracil at 2,400 mg/m2 over 46 hours) every 2 weeks. The ipilimumab group received trastuzumab at 6 mg/kg (loading dose of 8 mg/kg), nivolumab at 1 mg/kg, and ipilimumab at 3 mg/kg every 3 weeks for a total of 12 weeks; from week 13, patients received trastuzumab at 4 mg/kg and nivolumab at 240 mg every 2 weeks. The primary endpoint was survival improvement, with a targeted increase in 12-month overall survival rate to 70% in both groups vs a historical control rate of 55% observed with current the standard of care fluoropyrimidine, platinum, and trastuzumab (the ToGA trial regimen).
12-Month Overall Survival
Central post hoc biomarker analysis showed that 59 patients (72%; 28 in the FOLFOX group and 31 in the ipilimumab group) had a PD-L1 combined positive score of ≥ 1 and 46 (56%; 22 and 24 patients) had a combined positive score of ≥ 5; 76 patients (90%; 36 and 40 patients) had confirmed HER2 positivity.
Median follow-up was 14.3 months. Overall survival at 12 months was 70% (95% confidence interval [CI] = 54%–81%) in the FOLFOX group vs 57% (95% CI = 41%–71%) in the ipilimumab group. Median overall survival was 21.8 months (95% CI = 12.7–30.8 months) vs 16.4 months (95% CI = 8.3–25.9 months).
Median progression-free survival was 10.7 months (95% CI = 6.6–13.1 months) in the FOLFOX group vs 3.2 months (95% CI = 2.0–6.5 months) in the ipilimumab group. Overall response rates were 56% vs 32%, with median response durations of 9.2 months (95% CI = 8.1–13.5 months) vs 5.8 months (95% CI = 2.4 months–not estimable).
Treatment-related grade ≥ 3 adverse events were observed in 67% of patients in the FOLFOX group vs 46% of the ipilimumab group; the most common were leukopenia (23%), infection (16%), and fatigue (14%) in the FOLFOX group, and diarrhea (14%), anemia (11%), and infection (11%) in the ipilimumab group. Treatment-related serious adverse events occurred in 35% vs 39% of patients. Grade 3 or 4 immune-mediated adverse events were more common in the ipilimumab group (hepatitis in 9% vs 0%, colitis in 7% vs 0%, pneumonitis in 7% vs 0%, and endocrine disorders in 7% vs 2%). Grade 3 or 4 neuropathy was more common in the FOLFOX group (11% vs 0%).
The investigators concluded, “In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in [HER2]-positive esophagogastric adenocarcinoma. The ipilimumab arm yielded similar overall survival compared with the ToGA regimen.”
Alexander Stein, MD, of Hematology-Oncology Practice Eppendorf and University Cancer Center Hamburg, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit jamanetwork.com.
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