A modified chemotherapy regimen has demonstrated significant survival benefits for patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, according to results from a major French clinical trial published in The Lancet Oncology.
The phase III PRODIGE 51-FFCD-GASTFOX trial found that TFOX—a modified FLOT regimen containing docetaxel, folinic acid, oxaliplatin, and fluorouracil—improved multiple clinical outcomes compared to the standard FOLFOX regimen in previously untreated patients with HER2-negative advanced disease.
Improved Survival Outcomes
After a median follow-up of 42.8 months, patients receiving TFOX achieved a median progression-free survival (PFS) of 7.6 months compared to 6.0 months with FOLFOX. The study's primary endpoint was met with statistical significance, with a 12-month restricted mean PFS of 7.5 months versus 6.6 months (P = .0072).
More importantly, the TFOX regimen demonstrated a meaningful improvement in overall survival, with a median of 15.1 months versus 12.7 months in the FOLFOX group (hazard ratio = 0.82, 95% CI = 0.68–0.99, P = .048). The 12-month overall survival rates were 59.7% and 52.6% for TFOX and FOLFOX, respectively.
"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," said lead investigator Dr. Aziz Zaanan from the European Georges Pompidou Hospital in Paris.
Study Design and Patient Population
The open-label multicenter trial enrolled 507 patients with locally advanced unresectable or metastatic disease between December 2016 and December 2022. Patients were randomly assigned to receive either TFOX (n = 254) or FOLFOX (n = 253).
The TFOX regimen 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. The FOLFOX arm received 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.
Most participants were male (approximately 80%), with a majority having an ECOG performance status of 1. About 56% had primary tumors located at the gastroesophageal junction, and approximately half had metastases in the liver and lymph nodes.
Enhanced Response Rates
The objective response rate was significantly higher in the TFOX group at 62.3% (95% CI = 56.0%–68.3%) compared to 53.4% (95% CI = 47.0%–59.8%) in the FOLFOX group (P = .045). Disease control rates also favored TFOX at 86.9% versus 77.7% (P = .0072).
Exploratory subgroup analyses revealed that overall survival particularly favored TFOX in patients younger than 70 years (HR, 0.76), those with an ECOG performance status of 0 (HR, 0.65), and those with diffuse histological subtype (HR, 0.59).
Safety and Tolerability Considerations
The improved efficacy of TFOX came with an increased toxicity profile. The most common grade 3 or 4 adverse events were peripheral neuropathy (32% with TFOX vs 20% with FOLFOX), neutropenia (27% vs 18%), fatigue (16% vs 8%), and diarrhea (15% vs 7%).
Dose reductions were more frequent in the TFOX arm (77% vs 65%), and serious treatment-related adverse events occurred in 27% of TFOX patients compared to 13% in the FOLFOX group. Treatment-related deaths occurred in two patients receiving TFOX (from septic shock and gastrointestinal perforation) and one patient in the FOLFOX group (from septic shock).
Clinical Implications
The findings suggest that TFOX could represent a new standard first-line treatment option for patients with advanced HER2-negative gastric or GEJ adenocarcinoma who are eligible for triplet chemotherapy.
"The modified FLOT/TFOX regimen might represent a new therapeutic option for selected patients not eligible for immune checkpoint inhibitors or targeted agents," Dr. Zaanan noted. "This docetaxel triplet chemotherapy deserves to be investigated in future trials encompassing PD-1 or claudin 18.2 inhibitors in biomarker selected populations."
The results are particularly significant given the challenging prognosis for patients with advanced gastric cancer, where treatment options remain limited. The TFOX regimen provides a meaningful improvement in survival outcomes, albeit with increased toxicity that requires careful patient selection and management.
Future Directions
Researchers suggest that future studies should explore combining TFOX with emerging targeted therapies and immunotherapies to potentially further improve outcomes for patients with advanced gastric cancer.
The PRODIGE 51-FFCD-GASTFOX trial results add an important treatment option to the therapeutic landscape for advanced gastric and GEJ adenocarcinoma, particularly for patients with good performance status who can tolerate the increased toxicity profile of the triplet regimen.
