FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers: A Phase 2 Nonrandomized Clinical Trial.

Importance Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers. Objective To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. Design, Setting, and Participants This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with alpha of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX. Interventions Starting doses were fluorouracil, 400 mg/m(2)bolus, followed by 2400 mg/m(2)over 46 hours; leucovorin, 400 mg/m(2); irinotecan, 180 mg/m(2); and oxaliplatin, 85 mg/m(2). Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. Main Outcomes and Measures The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. Results From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. Conclusions and Relevance The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. Question What is the clinical activity of FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) as first-line treatment for advanced gastroesophageal adenocarcinoma? Findings In this single-arm phase 2 study, 41 patients with ERBB2-negative gastroesophageal cancer were treated with FOLFIRINOX alone, and 26 patients with ERBB2-positive disease were treated with FOLFIRINOX and trastuzumab. An objective response occurred in 61% of the ERBB2-negative group and 85% of the ERBB2-positive group. Meaning In patients with advanced gastroesophageal cancer, the FOLFIRINOX regimen appears to be an effective first-line treatment. This phase 2 nonrandomized clinical trial evaluates the clinical activity and safety of the FOLFIRINOX regimen (leucovorin, fluorouracil, irinotecan, and oxaliplatin) as first-line treatment for patients with advanced gastroesophageal adenocarcinoma.