FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers
Authors: Haeseong Park, Ramon U. Jin, Andrea Wang-Gillam, Rama Suresh, Caron Rigden, Manik Amin, Benjamin R. Tan, Katrina S. Pedersen, Kian-Huat Lim, Nikolaos A. Trikalinos, Abhilasha Acharya, Megan L. Copsey, Katherine A. Navo, Ashley E. Morton, Feng Gao, A. Craig Lockhart
Journal: JAMA Oncology (2020)

<h3>Importance</h3> 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. <h3>Objective</h3> To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. <h3>Design, Setting, and Participants</h3> 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 α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX. <h3>Interventions</h3> Starting doses were fluorouracil, 400 mg/m<sup>2</sup>bolus, followed by 2400 mg/m<sup>2</sup>over 46 hours; leucovorin, 400 mg/m<sup>2</sup>; irinotecan, 180 mg/m<sup>2</sup>; and oxaliplatin, 85 mg/m<sup>2</sup>. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01928290