In the phase II portion of a French phase II/III trial (PRODIGE 38 AMEBICA) reported in the Journal of Clinical Oncology, Phelip et al found that modified (m) FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) did not improve 6-month progression-free survival vs the combination of cisplatin and gemcitabine as first-line treatment for advanced biliary tract cancer.
As stated by the investigators, “Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer is unknown.”
In the open-label multicenter trial, 190 patients with locally advanced or metastatic disease were randomly assigned between November 2015 and June 2018 to receive mFOLFIRINOX (n = 94) or cisplatin/gemcitabine (n = 96). The mFOLFIRINOX regimen consisted of oxaliplatin at 85 mg/m2, irinotecan at 180 mg/m2, leucovorin at 400 mg/m2, and infusional fluorouracil at 2,400 mg/m2 over 46 hours on day 1 every 2 weeks for 12 cycles (24 weeks). Cisplatin/gemcitabine consisted of cisplatin at 25 mg/m2 and gemcitabine at 1,000 mg/m2 on days 1 and 8 every 21 days for 8 cycles (24 weeks). The primary endpoint was 6-month progression-free survival in the modified intent-to-treat population, which consisted of 92 patients in the mFOLFIRINOX group and 93 in the cisplatin/gemcitabine group who received at least one treatment dose.
It was hypothesized for the phase II part of the study that a 20% increase in 6-month progression-free survival with mFOLFIRINOX—from 59% observed in a prior study of cisplatin/gemcitabine to 73%—would indicate clinically meaningful benefit and provide rationale for moving to phase III evaluation.
Median follow-up was 21 months. Progression-free survival at 6 months was 44.6% (90% confidence interval [CI] = 35.7%–53.7%) in the mFOLFIRINOX group vs 47.3% (90% CI = 38.4%–56.3%) in the cisplatin/gemcitabine group (hazard ratio in favor of cisplatin/gemcitabine = 0.78, 95% CI = 0.57–1.05, P = .11), with the primary study objective thus not being met. Median progression-free survival was 6.2 months (95% CI = 5.5–7.8 months) vs 7.4 months (95% CI = 5.6–8.7 months).
Median overall survival was 11.7 months (95% CI = 9.5–14.2 months) vs 13.8 months (95% CI = 10.9–16.1 months), with 6- and 12-month rates of 77.4% (95% CI = 67.5%–84.6%) vs 79.1% (95% CI = 69.6%–86.0%) and 47.9% (95% CI = 37.3%–57.6%) vs 55.7% (95% CI = 45.2%–65.1%).
Objective responses were observed in 23 patients (25.0%) vs 18 patients (19.4%), with complete response in 3 vs 1.
Grade ≥ 3 adverse events occurred in 72.8% of patients in the mFOLFIRINOX group and 72.0% of the cisplatin/gemcitabine group, with the most common in the mFOLFIRINOX group being neutropenia (20.7% vs 39.8%), fatigue (20.7% vs 10.8%), and diarrhea (19.6% vs 4.3%); grade ≥ 3 peripheral neuropathy (11.9% vs 2.2%) and anorexia (9.8% vs 2.2%) were more common with mFOLFIRINOX.
Adverse events led to treatment discontinuation in 5.4% vs 2.1% of patients. Adverse events led to death in two patients in the mFOLFIRINOX group, due to infection and respiratory failure, and one patient in the cisplatin/gemcitabine group, due to jaundice and bowel obstruction.
The investigators concluded, “mFOLFIRINOX triplet chemotherapy did not meet the primary study endpoint. Cisplatin-gemcitabine doublet chemotherapy remains the first-line standard in advanced biliary tract cancer.”
Jean Marc Phelip, MD, PhD, of Université Jean Monnet, CHU de Saint-Etienne, Saint-Etienne, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Institut National du Cancer. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.