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.

Background: Perioperative FLOT (fluorouracil, oxaliplatin, and docetaxel) triplet chemotherapy is the standard of care for localised and resectable gastric and gastro-oesophageal junction adenocarcinoma. 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.

Methods: PRODIGE 51-FFCD-GASTFOX is an open-label, multicentre, randomised, phase 3 trial conducted at 96 medical centres in France. Eligible individuals were aged 18 years or older, had histologically confirmed, HER2-negative adenocarcinoma of the stomach or gastro-oesophageal junction that was locally advanced unresectable or metastatic and previously untreated, measurable disease per Response Evaluation Criteria in Solid Tumours, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were randomly assigned (1:1), using the minimisation method, to receive FOLFOX (folinic acid 400 mg/m, oxaliplatin 85 mg/m, and 5-fluorouracil bolus 400 mg/m then 5-fluorouracil 2400 mg/m as a continuous 46 h infusion every 2 weeks) or TFOX (docetaxel 50 mg/m, folinic acid 400 mg/m, and oxaliplatin 85 mg/m then 5-fluorouracil 2400 mg/m as a continuous 46 h infusion every 2 weeks). Randomisation was stratified by centre, ECOG performance status, (neo)adjuvant chemotherapy or chemoradiotherapy, tumour stage, tumour location, and pathological histological subtype. The primary endpoint was progression-free survival (assessed in the intention-to-treat population), defined as time from randomisation to the first radiological or clinical progression (or both), or death due to any cause, whichever occurred first. Secondary endpoints included overall survival (defined as time from randomisation to death due to any cause) and objective response rate (defined as the proportion of patients with a best overall complete or partial response). Hazard ratio and 95% CIs were estimated using an unstratified Cox proportional hazards model. When the proportional hazards assumption was violated, the restricted mean survival time was used to estimate the treatment effect size. This study is registered with ClinicalTrials.gov, NCT03006432, and EudraCT, 2016-002331-16.

Findings: Between Dec 19, 2016, and Dec 26, 2022, 507 patients were randomly assigned (254 to the TFOX group and 253 to the FOLFOX group [intention-to-treat population]). The median age was 64·2 years (IQR 56·7-70·8), and 399 (79%) participants were male and 108 (21%) were female. At median follow-up of 42·8 months (25·8-49·9), the median progression-free survival was 7·59 months (95% CI 7·06-7·95) in the TFOX group versus 5·98 months (5·65-6·97) in the FOLFOX group. The assumption of proportional hazards was violated (p=0·013); therefore, the 12-month restricted mean progression-free survival was calculated: 7·52 months (7·06-7·97) in the TFOX group versus 6·62 months (6·16-7·09) in the FOLFOX group (p=0·0072). The median overall survival was 15·08 months (13·70-16·72) in the TFOX group versus 12·65 months (10·94-14·00) in the FOLFOX group (proportional hazards assumption was confirmed; HR 0·82 [0·68-0·99]; p=0·048) and the objective response rate was 62·3% (56·0-68·3) versus 53·4% (47·0-59·8; p=0·045). The most common grade 3 and 4 treatment-emergent adverse events were diarrhoea (37 [15%] in the TFOX group vs 18 [7%] in the FOLFOX group), peripheral neuropathy (80 [32%] vs 49 [20%]), neutropenia (67 [27%] vs 44 [18%]), and fatigue (40 [16%] vs 20 [8%]). Serious treatment-related adverse events occurred in 66 (27%) participants in the TFOX group and 33 (13%) in the FOLFOX group. There were two (<1%) treatment-related deaths in the TFOX group (one due to septic shock and one due to gastrointestinal perforation) and one (<1%) in the FOLFOX group (due to septic shock).

Interpretation: 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 gastro-oesophageal junction adenocarcinoma. The modified FLOT/TFOX regimen might represent a new first-line treatment option for patients eligible for this docetaxel triplet chemotherapy.

Funding: Fédération Francophone de Cancérologie Digestive.