Sequential alternation of nal-IRI/5-FU and gemcitabine/nab-paclitaxel versus nal-IRI/5-FU versus gemcitabine/nab-paclitaxel in first-line metastatic pancreatic cancer: results of the randomized phase II PRODIGE 61—FUNGEMAX trial (France)
Mené en France sur 288 patients atteints d'un cancer métastatique du pancréas (âge : 18-75 ans ; durée médiane de suivi : 39,2 mois), cet essai multicentrique de phase II évalue l'efficacité, du point de vue de la survie sans progression à 6 mois, de 3 stratégies thérapeutiques de première ligne : nal-IRI/5-FU (irinotécan nanoliposomal, leucovorine, 5-fluorouracile), gemcitabine/nab-paclitaxel ou une alternance de nal-IRI/5-FU et gemcitabine/nab-paclitaxel
Background: New chemotherapeutic approaches are still needed to improve survival and quality of life in metastatic pancreatic ductal adenocarcinoma (mPDAC). In the absence of validated predictive biomarkers, first-line sequential treatment strategies may allow to delay chemoresistance and reduce cumulative side effects.
Methods: PRODIGE 61–FUNGEMAX was an open-label, multicentre, randomised phase II trial conducted in 31 centres in France. Between November 2018 and January 2024, chemotherapy-naive patients aged 18–75 years with histologically confirmed metastatic pancreatic ductal adenocarcinoma (mPDAC) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 were randomly assigned (1:1:1) to receive either nal-IRI (nanoliposomal irinotecan; 70 mg/m2 intravenously [IV] over 90 min) plus leucovorin (400 mg/m2 IV over 30 min) and 5-fluorouracil (5-FU; 2400 mg/m2 IV over 46 h) every 2 weeks (NAPOLI regimen), gemcitabine (1000 mg/m2 IV over 30 min) plus nab-paclitaxel (125 mg/m2 IV over 30 min) on days 1, 8, and 15 of a 28-day cycle (MPACT regimen), or both regimens alternating every 2 months (sequential arm). The primary endpoint was the 6-month progression-free survival (PFS) rate, assessed in the modified intention-to-treat (mITT)/safety population (patients who received at least one dose of study treatment). Secondary efficacy analyses were performed in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov (NCT03693677) and EudraCT (2017-004309-41).
Findings: Between 16 November 2018 and 25 January 2024, 288 patients were enrolled in 31 French centres. Baseline characteristics were well balanced between the three arms. With a median follow-up of 39.2 months, median treatment durations were 6.3/3.3/5.3 months, for sequential, NAPOLI and MPACT arms, respectively. The 6-month PFS rates were 51.6%, 32.3% and 45.3% in the sequential, NAPOLI and MPACT arms, respectively. Neither sequential (HR = 0.76, p = 0.072) nor NAPOLI regimens (HR = 1.20, p = 0.22) lead to a statistically significant improvement of PFS over the MPACT regimen. The 12-month PFS rates were 20·3%, 12·7%, and 11·9%, and the 24-month OS rates were 23·8%, 9·5%, and 12·5% in the sequential, NAPOLI, and MPACT arms, respectively; these differences were not statistically significant. Safety profiles were consistent with previous publications for each regimen and QoL (QLQ-C30 and EQ5D) was preserved in the sequential arm.
Interpretation: The sequential NAPOLI/MPACT regimen seems feasible and tolerable, with higher rates of 12-month PFS and 24-month OS compared with standard MPACT, despite no improvement in median PFS or OS. Future trials should be adequately powered, integrate predictive biomarkers, and include contemporary first-line standards as comparators.
eClinicalMedicine , article en libre accès, 2026