5-FU + Naliri, gemcitabine plus nab-paclitaxel or both regimens given sequentially for first line treatment of metastatic pancreatic ductal adenocarcinoma: A randomized phase II comparative study (FUNGEMAX-PRODIGE 61).

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4184 Background: New chemotherapeutic approaches are still needed to improve survival and quality of life in metastatic pancreatic ductal adenocarcinoma (mPDAC). We have previously published results of two randomized phase II of first-line sequential treatment strategies of intensified FOLFIRI regimen followed by gemcitabine-based regimens (FIRGEM and FIRGEMAX-PRODIGE 37 studies) with good efficacy and tolerability results. FUNGEMAX-PRODIGE 61 evaluated 5FU + Naliri (NAPOLI) vs gemcitabine + Nab-paclitaxel (MPACT) vs both regimens sequentially. Methods: Chemotherapy-naive pts with proven mPDAC, bilirubin levels < 1.5 ULN and performance status (PS) 0-1 were randomized to receive either the NAPOLI regimen for 2 months, alternating with the MPACT regimen for 2 months (arm A), NAPOLI alone (arm B) or MPACT alone (arm C) until progression or limiting toxicity. Using the Schoenfeld method, the primary endpoint was the progression-free survival (PFS) rate at 6 months from (H0) 30% over (H1) 45%, requiring 96 patients per arm (assuming 5% lost to follow-up). Results: Between 11/2018 and 01/2024, 288 pts were enrolled in 31 French centers and 283 included in the modified intent to treat population (mITT, patients who received at least one dose of treatment). Database lock was done on the 20/12/2024. Baseline characteristics were well balanced between the arm A, B and C (mean age: 65/63/65, female: 47/43/47%, PS-0: 33/34/37%, > 1 metastatic site: 53/48/48%, mean albumin 39/40/39 g/L). With a median follow-up of 39.2 months, study treatment was discontinued in 89.5%, 96.8% and 93.7% of patients for arms A/B/C; median treatment duration were 6.3/3.3/5.3 months, respectively. In the mITT, neither treatment with MPACT/NAPOLI (HR = 0.76, 95%CI: 0.57-1.02; p = 0.07) nor NAPOLI (HR = 1.20, 95%CI: 0.90-1.60; p = 0.22) lead to a statistically significant improvement of PFS over MPACT. PFS, Overall survival (OS) and safety data are summarized in the table. Conclusions: The study did not show superiority of either the sequence MPACT/NAPOLI or NAPOLI over standard MPACT. However, the sequential MPACT/NAPOLI regimen is feasible, tolerable, and associated with higher rates of 12-mo PFS and 24-mo OS and less neuropathy and can be considered in patients unfit to receive FOLFIRINOX. NCT03693677. Clinical trial information: 2024-518143-38-00 . Arm A (MPACT/NAPOLI) Arm B (NAPOLI) Arm C (MPACT) PFS median (mo) rate at 6-m rate at 12-m 6.2 [4.0;7.8]51.6% [41.1;61.0]20.3% [12.9;29.0] 3.7 [2.2;5.1]32.3% [23.04;41.81]12.7% [6.8;20.3] 5.7 [4.0;6.5]45.3% [35.1;55.0]11.9% [6.3;19.4] OS median (mo) rate at 24-m 11.6 [8.4;15.0]23.8% [15.4;33.2] 9.1 [7.10;10.45]9.5% [4.19;17.36] 12.4 [9.76;14.03]12.5% [6.28;20.93] Grade 3-4 toxicities AE/SAE All Grades Grade 3-4 All Grades Grade 3-4 All Grades Grade 3-4 Neutropenia 25.3% 9.5% 11.8% 0% 26.3% 7.4% Diarrhea 80% 17.9% 69.9% 16.1% 55.8% 5.3% Vomiting 80% 15.8% 72% 14.0% 61.1% 4.2% Peripheral Neuropathy 44.2% 5.3% 10.8% 0% 57.9% 8.4%

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