First-Line mFLOT/TFOX Regimen Boosts PFS For Advanced Gastric Adenocarcinoma

medwireNews: Phase III study findings support the addition of docetaxel to 5-fluorouracil (5-FU) and oxaliplatin for the first-line treatment of HER2-negative, advanced gastric or gastro-oesphageal junction adenocarcinoma. 

The GASTFOX-PRODIGE 51 study demonstrated a “statistically significant and clinically meaningful improvement” in outcomes in this patient population, the presenting author told delegates at the ESMO Congress 2023 in Madrid, Spain. 

Patients with treatment-naïve locally advanced and unresectable or metastatic disease without prior experience of docetaxel were randomly assigned to receive a modified (m)FLOT regimen (also known as TFOX; n=254) every 2 weeks, consisting of docetaxel, oxaliplatin, folinic acid and 5-FU or to receive FOLFOX (oxaliplatin, folinic acid and 5-FU; n=252). 

Aziz Zaanan, from Hospital European Georges Pompidou in Paris, France, explained FOLFOX includes a 5-FU bolus plus 5-FU continuous therapy whereas the mFLOT/TFOX regimen has only the continuous 5-FU element. 

The primary endpoint of intention-to-treat progression-free survival (PFS) was a median 7.59 months with mFLOT/TFOX and 5.98 months with FOLFOX. This gave a nonproportional hazard for PFS analysis with a p value of 0.01, triggering restricted mean survival time (RMST) analysis  at 12 months, a duration that was chosen to reflect the median follow-up. 

This RMST was a median 7.52 months with mFLOT/TFOX, significantly longer than the 6.62 months achieved with FOLFOX, the investigator said. 

mFLOT/TFOX was also associated with a significant gain in the per-protocol PFS, at a median duration of 7.66 months versus 5.88 months with FOLFOX; the corresponding RMST values at 12 months were 7.78 and 6.55 months. 

In addition, intention-to-treat overall survival (OS) was significantly longer with mFLOT/TFOX than FOLFOX, at 15.08 versus 12.65 months and a hazard ratio (HR) for death of 0.82. The corresponding values for per-protocol OS were 15.31 and 12.12 months, and 0.76. 

Subgroup analysis confirmed OS was better with mFLOT/TFOX across all subgroups but especially among patients with an ECOG performance status of 0 (HR=0.65), commented Aziz Zaanan. 

Session discussant Radka Obermannova, from the Masaryk Memorial Cancer Institute in Brno, Czech Republic, noted that patients aged less than 65 years, those with locally advanced disease and those with diffuse disease as per the Lauren classification also appeared more likely to benefit from mFLOT/TFOX.  

The objective response rate among 237 evaluable patients given mFLOT/TFOX was 66.2%, significantly higher than the rate of 57.5% among 235 evaluable patients treated with FOLFOX, the presenter said. This included complete response in 6.7% and 8.1% of patients, respectively, and a significantly improved disease control rate of 92.4% versus 83.0%.  

Discussing the safety profile, the investigator highlighted an increased rate of neutropenia with mFLOT/TFOX than FOLFOX at grade 3 (18.1 vs 13.3%) and grade 4 (8.0 vs 4.4%) but there was no difference in the rates of febrile neutropenia (2.8 vs 1.6%). 

Patients given mFLOT/TFOX were also more likely than those given FOLFOX to have grade 3 peripheral neuropathy (31.7 vs 18.9%), fatigue (15.3 vs 7.2%) and diarrhoea (12.9 vs 6.4%). 

Nevertheless, mFLOT/TFOX was associated with a significantly longer time to deterioration of health-related quality of life, as assessed using the EORTC QLQ-C30 measure (median 17.02 vs 13.67 months; HR=0.75). 

Aziz Zaanan concluded that the mFLOT/TFOX regimen “can be considered as a new first-line treatment option for patients eligible for a triplet regimen, at least for patients with PD-L1- and claudin-negative tumours.” 

However, Radka Obermannova highlighted that a doublet regimen is the current standard of care for first-line HER2-negative disease with a PD-L1 score of 1 or less, and taxane-based chemotherapy is not currently recommended because of “higher levels of toxicity and uncertain survival benefit”, especially in older patients. 

She, therefore, suggested that for patients without biomarkers for targeted therapy or immunotherapy, the choice of platinum fluoropyrimidine doublet or mFLOT/TFOX should be individualised, “based on clinical context and patient’s preference”. 

The presenter added that the GASTFOX-2 trial will now investigate the combination of mFLOT/TFOX with immunotherapy or zolbetuximab for patients whose tumours were positive for PD-L1 or CLDN18.2, respectively. 

Reference  

LBA77 - Zaanan A, Bouche O, de la Fouchardiere C, et al. 5-fluorouracil and oxaliplatin with or without docetaxel in the first-line treatment of HER2 negative locally advanced (LA) unresectable or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma (GASTFOX-PRODIGE 51): A randomized phase III trial sponsored by the FFCD. Ann Oncol 2023;34(suppl_2): S1318. DOI: 10.1016/j.annonc.2023.10.078