Patients with metastatic pancreatic ductal adenocarcinoma continue to have poor outcomes despite the use of combination chemotherapy. In the first-line setting, treatment aims not only to control disease but also to preserve quality of life, as cumulative toxicity and treatment resistance often limit the duration of therapy.
Sequential chemotherapy is one strategy designed to address these challenges. Instead of continuing a single regimen until progression, this approach alternates active regimens over time, with the goal of exposing tumors to different drugs while limiting overlapping or cumulative toxicity.
The PRODIGE 61–FUNGEMAX trial evaluated whether alternating nal-IRI/5-FU with gemcitabine/nab-paclitaxel could improve outcomes compared with each regimen given continuously in patients with previously untreated metastatic pancreatic cancer. The trial was sponsored by the Fédération Francophone de Cancérologie Digestive and supported by a grant from Servier, France.
The original article, titled “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),” was published in eClinicalMedicine in June 2026.
Authors: Julien Taieb, Simon Pernot, Frédéric Thuillier, Alexis Delattre, Erwan Vo-Quang, Caroline Petorin, Vincent Bourgeois, David Tougeron, Franck Audemar, Carole Vitellius, Laurent Mosser, Jérôme Desrame, Frédéric Di Fiore, Yves Rinaldi, Anna Pellat, Marion Bolliet, Fabienne Watelle, Hervé Perrier, Olivier Dubreuil, Come Lepage, and Jean-Baptiste Bachet.
Rationale Behind the Study
First-line treatment for metastatic pancreatic cancer remains difficult because many patients require active combination chemotherapy, but prolonged exposure to the same regimen can lead to cumulative toxicities, including neuropathy, gastrointestinal adverse events, and hematologic toxicity.
PRODIGE 61–FUNGEMAX tested whether early alternation between two active doublet regimens could maintain disease control while preserving quality of life. The study also explored whether nal-IRI/5-FU, known from the NAPOLI regimen, could be used as a continuous first-line option or as part of a sequential strategy.
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Trial Population and Treatment Arms
PRODIGE 61–FUNGEMAX was an open-label, multicenter, randomized phase 2 trial conducted across 31 centers in France. The trial was registered as NCT03693677 and EudraCT 2017-004309-41.
The study enrolled chemotherapy-naive patients aged 18–75 years with histologically confirmed metastatic pancreatic ductal adenocarcinoma, measurable disease, ECOG performance status 0–1, adequate organ function, and controlled pain. Previous systemic therapy for metastatic disease was not allowed, although prior adjuvant therapy was permitted if completed more than 12 months before study entry.
Between November 16, 2018, and January 25, 2024, 288 patients were randomized equally into three treatment arms. In the sequential arm, patients received nal-IRI/5-FU first for 2 months, followed by gemcitabine/nab-paclitaxel for 2 months, with the regimens alternating every 2 months until progression, unacceptable toxicity, or patient refusal.
In the NAPOLI arm, patients received nal-IRI, leucovorin, and 5-FU every 2 weeks until progression or intolerance. In the MPACT arm, patients received gemcitabine plus nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle until progression or intolerance.
The primary endpoint was the 6-month progression-free survival rate in the modified intention-to-treat/safety population, defined as patients who received at least one dose of treatment. Secondary endpoints included overall survival, best objective response rate, time to treatment failure, treatment compliance, and time to definitive deterioration in quality of life, with safety also assessed throughout the trial.
Efficacy Outcomes
Baseline characteristics were generally balanced across the three arms. The median age was 65.4 years, 57.3% of patients were male, and approximately two-thirds had performance status 1. Median treatment duration was 6.3 months in the sequential arm, 3.3 months in the NAPOLI arm, and 5.3 months in the MPACT arm.
After a median follow-up of 39.2 months, the study did not meet its primary endpoint.
In the modified intention-to-treat/safety population, the 6-month progression-free survival rate was 51.6% with sequential therapy, 32.3% with NAPOLI, and 45.3% with MPACT. Sequential therapy did not significantly improve progression-free survival compared with MPACT, with a hazard ratio of 0.76 and p=0.073. NAPOLI also did not improve progression-free survival compared with MPACT.
Median progression-free survival was 6.2 months with sequential therapy, 3.7 months with NAPOLI, and 5.7 months with MPACT. At 12 months, progression-free survival rates were 20.3% with sequential therapy, 12.7% with NAPOLI, and 11.9% with MPACT.
In the intention-to-treat population, the objective response rate was highest with sequential therapy at 42.7%, compared with 20.8% with NAPOLI and 37.5% with MPACT. Disease control rates were 81.6%, 63.3%, and 77.3%, respectively.
Overall survival did not significantly improve with the sequential strategy. Median overall survival was 11.6 months with sequential therapy, 9.1 months with NAPOLI, and 12.4 months with MPACT.
The 24-month overall survival rate was numerically higher with sequential therapy at 23.8%, compared with 9.5% with NAPOLI and 12.5% with MPACT. These longer-term results are clinically interesting but should be interpreted cautiously because the differences were not statistically significant.
Prespecified subgroup analyses suggested greater progression-free survival benefit with sequential therapy in some groups, including patients younger than 70 years, patients with ECOG performance status 0, patients with neutrophil-to-lymphocyte ratio below 5, and patients who had received prior adjuvant therapy. However, these subgroup findings were exploratory and were not adjusted for multiplicity.
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Treatment-Related Toxicity
The safety profiles were consistent with the known toxicities of the regimens, but grade 3–4 adverse events were more frequent in the sequential arm.
Grade 3–4 adverse events occurred in 85.3% of patients in the sequential arm, 53.8% in the NAPOLI arm, and 69.5% in the MPACT arm. The most common high-grade non-hematologic toxicities were diarrhea and nausea/vomiting. Grade 3–4 diarrhea occurred in 17.9% of patients receiving sequential therapy, 16.1% receiving NAPOLI, and 5.3% receiving MPACT. Grade 3–4 nausea/vomiting occurred in 15.8%, 14.0%, and 4.2% of patients, respectively.
Grade 3–4 neutropenia occurred in 35.8% of patients in the sequential arm, 9.7% in the NAPOLI arm, and 35.8% in the MPACT arm.
Peripheral neuropathy was an important point of comparison. Grade 3–4 peripheral neuropathy occurred in 5.3% of patients in the sequential arm, none in the NAPOLI arm, and 8.4% in the MPACT arm. This supports the rationale that alternating regimens may reduce prolonged exposure to nab-paclitaxel and help limit cumulative neuropathy, although the sequential strategy was still associated with more overall high-grade toxicity.
Patient-Reported Quality of Life
Quality of life was assessed using EORTC QLQ-C30. A definitive deterioration of quality of life of at least 5 points occurred in 32.6% of patients in the sequential arm, 22.6% in the NAPOLI arm, and 31.6% in the MPACT arm.
Median time to definitive deterioration was 8.1 months with sequential therapy, compared with 6.6 months with NAPOLI and 7.0 months with MPACT.
At 6 months, the proportion of patients without definitive quality-of-life deterioration was 63.1% with sequential therapy, 54.1% with NAPOLI, and 57.3% with MPACT. These findings suggest that quality of life was broadly preserved in the sequential arm despite higher rates of grade 3–4 adverse events.
Meaning of the Findings
PRODIGE 61–FUNGEMAX showed that alternating nal-IRI/5-FU with gemcitabine/nab-paclitaxel every 2 months is feasible in selected patients with previously untreated metastatic pancreatic ductal adenocarcinoma.
The sequential arm showed the highest objective response and disease control rates, along with numerically higher 12-month progression-free survival and 24-month overall survival rates. However, the study did not show a statistically significant improvement in median progression-free survival or overall survival compared with standard gemcitabine plus nab-paclitaxel.
Continuous nal-IRI/5-FU did not demonstrate an advantage over gemcitabine plus nab-paclitaxel in this first-line setting and was associated with lower response rates and shorter survival outcomes in this trial.
Important Context
The trial was an exploratory phase 2 study and was not designed to establish definitive superiority or non-inferiority. The findings should therefore be considered hypothesis-generating rather than practice-changing.
The study population was limited to patients aged 75 years or younger with ECOG performance status 0–1, which may limit generalizability to older or frailer patients. The trial was also initiated before newer contemporary first-line standards, including NALIRIFOX, became more established.
In addition, the study did not include predictive biomarkers to identify patients most likely to benefit from sequential chemotherapy.
Final Takeaway
The PRODIGE 61–FUNGEMAX trial supports sequential nal-IRI/5-FU and gemcitabine/nab-paclitaxel as a feasible first-line strategy for selected patients with metastatic pancreatic cancer. The approach produced encouraging response and long-term disease-control signals while preserving quality of life, but it did not significantly improve median progression-free survival or overall survival compared with standard gemcitabine plus nab-paclitaxel.
These results support further evaluation of sequential chemotherapy in adequately powered trials using contemporary comparators and biomarker-driven patient selection.
Read the full article in eClinicalMedicine.
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