In a French phase III trial (PRODIGE 51-FFCD-GASTFOX) reported in The Lancet Oncology, Zaanan et al found that a modified FLOT (fluorouracil, oxaliplatin, and docetaxel) regimen known as TFOX (docetaxel, folinic acid, oxaliplatin, and fluorouracil) improved outcomes vs FOLFOX (folinic acid, oxaliplatin, fluorouracil) in patients with previously untreated, advanced, HER2-negative gastric or gastroesophageal junction adenocarcinoma.
Study Details
In the open-label multicenter trial, 507 patients with locally advanced unresectable or metastatic disease were randomly assigned between December 2016 and December 2022 to receive TFOX (n = 254) or FOLFOX (n = 253). TFOX consisted of docetaxel at 50 mg/m², folinic acid at 400 mg/m², and oxaliplatin at 85 mg/m² followed by fluorouracil at 2,400 mg/m² as a continuous 46-hour infusion every 2 weeks. FOLFOX consisted of folinic acid at 400 mg/m², oxaliplatin at 85 mg/m², and a fluorouracil bolus at 400 mg/m² followed by fluorouracil at 2,400 mg/m² as a continuous 46-hour infusion every 2 weeks. The primary endpoint was progression-free survival, defined as time from randomization to the first radiologic or clinical disease progression or death from any cause. If proportional hazards assumptions were violated, restricted mean survival time was used to estimate treatment effect size.
Key Findings
At median follow-up of 42.8 months (interquartile range = 25.8–49.9 months), median progression-free survival was 7.6 months (95% confidence interval [CI] = 7.1–8.0 months) in the TFOX group vs 6.0 months (95% CI = 5.7–7.0 months) in the FOLFOX group. The assumption of proportional hazards was violated (P = .013); the 12-month restricted mean progression-free survival was 7.5 months (95% CI = 7.1–8.0 months) in the TFOX group vs 6.6 months (95% CI = 6.2–7.1 months) in the FOLFOX group (P = .0072).
Median overall survival was 15.1 months (95% CI = 13.7–16.7 months) in the TFOX group vs 12.7 months (95% CI = 10.9–14.0 months) in the FOLFOX group (proportional hazards assumption confirmed; hazard ratio = 0.82, 95% CI = 0.68–0.99, P = .048). Objective response rate was 62.3% (95% CI = 56.0%–68.3%) vs 53.4% (95% CI = 47.0%–59.8%; P = .045).
The most common grade 3 or 4 adverse events were diarrhea (15% in the TFOX group vs 7% in the FOLFOX group), peripheral neuropathy (32% vs 20%), neutropenia (27% vs 18%), and fatigue (16% vs 8%). Serious treatment-related adverse events occurred in 27% vs 13% of patients. Treatment-related death occurred in two patients in the TFOX group (from septic shock and gastrointestinal perforation) and one patient in the FOLFOX group (from septic shock).
The investigators concluded: “The modified FLOT/TFOX regimen significantly improved progression-free survival, overall survival, and objective response rate compared with FOLFOX in previously untreated patients with advanced HER2-negative gastric and [gastroesophageal] junction adenocarcinoma. The modified FLOT/TFOX regimen might represent a new first-line treatment option for patients eligible for this docetaxel triplet chemotherapy.”
Aziz Zaanan, MD, PhD, of the European Georges Pompidou Hospital, Assistance Publique Hopitaux de Paris, University of Paris Cite, Paris, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by the Fédération Francophone de Cancérologie Digestive. For full disclosures of all study authors, visit The Lancet Oncology.
