First-Line TFOX Regimen for Patients With HER2-Negative Advanced Gastric/Gastroesophageal Junction Adenocarcinoma

According to results from the phase 3 PRODIGE 51-FFCD-GASTFOX trial, TFOX, a modified version of the FLOT chemotherapy regimen, in the first-line setting improved survival and response outcomes compared to FOLFOX among patients with human epidermal growth factor (HER2)-negative advanced gastric and gastroesophageal junction adenocarcinoma. 

“Perioperative FLOT (fluorouracil, oxaliplatin, and docetaxel) triplet chemotherapy is the standard of care for localised and resectable gastric and gastro-oesophageal junction adenocarcinoma,” stated Aziz Zaanan, MD PhD, European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris, France, and coauthors. “We aimed to compare a modified FLOT regimen (also known as TFOX) with FOLFOX as first-line treatment for patients with HER2-negative advanced gastric and gastro-oesophageal junction adenocarcinoma.”

This study enrolled 507 previously untreated patients with locally advanced, unresectable, or metastatic HER2-negative gastric and gastroesophageal junction adenocarcinoma. Patients were allotted on a 1-to-1 basis, using the minimization method, to receive either FOLFOX (folinic acid, oxaliplatin, and 5-fluorouracil followed by 5-fluorouracil) or TFOX (50 mg/m² of docetaxel plus 400 mg/m² of folinic acid and 85 mg/m² of oxaliplatin 85 mg/m² followed by 2400 mg/m2 of 5-fluorouracil as a continuous 46 hour infusion every 2 weeks). The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS), objective response rate (ORR), and safety. 

At a median follow-up of 42.8 months, the median PFS was 7.59 months in the TFOX arm and 5.98 months in the FOLFOX arm (P = .013). The 12-month restricted mean PFS was 7.52 months in the TFOX arm and 6.62 months in the FOLFOX arm (P = .0072). The median OS was 15.08 months in the TFOX arm and 12.65 months in the FOLFOX arm (hazard ratio [HR] 0.82; P = .048). The ORR was 62.3% and 53.4% (P = .045), respectively. 

The most common grade 3/4 treatment-emergent adverse events included diarrhea, peripheral neuropathy, neutropenia, and fatigue. Serious treatment-related adverse events occurred in 27% of patients in the TFOX arm and 13% of patients in the FOLFOX arm. Two treatment-related deaths occurred in the TFOX arm (due to septic shock and gastrointestinal perforation) and 1 treatment-related death occurred in the FOLFOX arm (due to septic shock).

“The modified FLOT/TFOX regimen might represent a new first-line treatment option for patients eligible for this docetaxel triplet chemotherapy,” concluded Dr Zaanan et al. 

Source:

Zaanan A, Bouche O, de la Fouchardiere C, et al. TFOX versus FOLFOX in first-line treatment of patients with advanced HER2-negative gastric or gastro-oesophageal junction adenocarcinoma (PRODIGE 51- FFCD-GASTFOX): An open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. Published online: April 23, 2025. doi:10.1016/S1470-2045(25)00130-5