Is FOLFIRINOX more effective than gemcitabine plus nab-paclitaxel in pancreatic adenocarcinoma? A Decade of Debate! A commentary on the GENERATE, JCOG1611: a randomized, open-label, phase II/III trial

Pancreatic adenocarcinoma (PC) is a disease with guarded prognosis with a 5-year survival rate of only 3.2% in patients with metastatic disease based on data from Surveillance Epidemiology and End Results (SEER), National Cancer Institute (NCI). In addition, the incidence is increasing, including in young patients, and it is predicted to be the second leading cause of cancer mortality in 2030 and after. The development of novel therapeutic modalities to mitigate this cancer is essential. Pancreatic cancer has 3 frontline regimens that have demonstrated efficacy in prospective randomized trials [5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), gemcitabine plus nab-paclitaxel (GA), and [5-fluorouracil, liposomal irinotecan, and oxaliplatin (NALIRIFOX)]. There has been a debate for more than a decade about which one of these regimens is more effective in the frontline setting, FOLFIRINOX or GA? NAPLOI 3 is a more recent trial comparing NALIRIFOX to GA and established its efficacy after meeting pre-established end points. The GENERATE trial is a well-designed trial to potentially provide insight into this question. Herein, I discuss the trial and provide perspective into this dilemma. It is important to note that the treatment landscape in PC is changing with the discovery of effective multi-selective, and selective, RAS (ON) inhibitors and positive data from the PANOVA 3 study demonstrating a role for Tumor Treating Fields in pancreatic cancer.

The GENERATE, JCOG1611 is an exciting, randomized phase II/III trial investigating the efficacy of mFOLFIRINOX and S-IROX (S-1:tegafur/gimeracil/oteracil, irinotecan, and oxaliplatin) when compared to GA in patients with metastatic PC in the frontline setting. Firstly, I would like to congratulate the investigators on addressing this important question, completing the trial, and presenting their data. We also thank the patients who participated in the trial for advancing the therapeutic landscape in this aggressive disease. The trial was conducted from April 2019 to March 2023, and 527 patients were enrolled.

Current approved regimens in the frontline treatment of PC include FOLFIRINOX, GA, and NALIRIFOX (1-3). The choice of which regimen to utilize and when has been a debate for an exceptionally long time. Factors which providers use to guide therapeutic decision making include functional status with mostly triplet chemotherapy reserved for young patients and those with excellent performance status, platinum-based regimens for patients with germline DNA damage repair mutations (DDRMs), and provider/institution-based preference among many other factors. Subjectively, we always feel that a triplet-based regimen is more efficacious. The PRODIGE trial compared FOLFIRINOX to gemcitabine and the MPACT trial compared GA to gemcitabine (1,2). NAPOLI 3, however, compared NALIRIFOX to GA as opposed to gemcitabine alone. There are several retrospective analyses that compared FOLFIRINOX to GA such as an analysis that evaluated both regimens in patients, all comers, and those with an Eastern Cooperative Oncology Group (ECOG) of 0-1 across all the US Oncology Network. The study demonstrated similar outcomes with time to treatment failure and overall survival among patients treated with both regimens (4). There were no appropriate prospective trial comparing both regimens until recently this year with two trials published sequentially addressing this question which are the GENERATE and PASS-01 trials (5,6). The former is a large, randomized trial assessing the efficacy of both regimens and the second a randomized phase II trial that analyzed efficacy, predictive biomarkers, and patient-derived organoid development. The GENERATE investigators studied if mFOLFIRINOX or S-IROX are more efficacious regimens than GA. The trial was designed by a stratified log-rank to test the superiority of mFOLFIRINOX to GA and S-IROX to GA. GENERATE was a phase II and III trial with primary endpoints of overall response rate (ORR) and overall survival (OS), respectively. Secondary endpoints of the phase III trial included progression-free survival (PFS), ORR (investigator assessed), and adverse events based on the CTCAE v4.0. At a planned interim analysis, unexpectedly the results revealed a higher median OS favoring GA with 17.1 months [95% confidence interval (CI): 14.5–19.2] compared to 14.0 months (95% CI: 11.3–16.2) in the mFOLFIRINOX group [hazard ratio (HR), 1.31, 95% CI: 0.97–1.77] and 13.6 months (95% CI: 12–16.4) in the S-IROX group (HR, 1.35, 95% CI: 1.00–1.82). This data calculated the predictive probability of achieving a superiority for FOLFIRINOX and S-IROX to be <1% and hence the trial was terminated early due to futility. There was also no difference in PFS and more grade 3 and 4 anorexia in the mFOLFIRINOX and S-IROX groups. In the randomized phase II PASS-01 trial PFS and ORR was similar between both groups, but OS favored the GA group with median OS of 8.5 months with FOLFIRINOX and 9.7 months with GA (HR, 1.57; 95% CI: 1.08 to 2.28; P=0.017). Similar outcomes were seen in the SWOG-1505 in the perioperative setting with a higher rate of complete or major response in the GA group (7). Considering the aforementioned data, is FOLFIRINOX truly superior to GA? The data described in a randomized prospective trial argues otherwise. There are some points to consider: (I) the PRODIGE trial conducted a trial with full dose FOLFIRINOX in academic institutions in France with adjustments later. This was a smaller number of patients compared to the MPACT trial that was conducted internationally. Hence, the MPACT trial included a more internationally diverse patient population. Although the GENERATE was conducted exclusively in Japan, the PASS-01 was conducted in the USA and Canada with a diverse patient population. It is important to note that the PASS-01 trial excluded patients with BRCA1/2 and PALB2 germline mutations, in the GENERATE trial 4.4% of patients tested positive for BRCA 1/2 germline mutation. Moreover, the PASS-01 trial enrolled patients with bulky disease to allow for study specific biopsies. (II) The PRODIGE trial included slightly more patients with ECOG of 0-1 than the MPACT and the latter had more geriatric patients (> 65 years of age) enrolled. (III) The regimen studied in the PRODIGE trial was FOLFIRINOX and not mFOLFIRINOX. This also brings an important question of what is mFOLFLIRINOX? Most centers identify this regimen as omitting the 5-Fu bolus from the regimen while others include irinotecan and oxaliplatin dose-reductions, or -20 to 25% dose reductions across the board for example. Hence, a lower dose of chemotherapy is administered, albeit more tolerable, in clinic, and there is relatively no standardization. (IV) It is also important to note that after the PRODIGE trial was published, 5-Fu and nano-liposomal irinotecan was established as a second line regimen and in some patients is used as third line after progression on FOLFIRINOX and GA. This is in addition to early phase clinical trials expanding as an option in the post-PRODIGE era with an evolving role of precision medicine and targeted therapy that might have favored better survival in our current era. One example is treating with immune-check point inhibitors in microsatellite instability high tumors, albeit rare, there are also other targetable mutations now. However, the GENERATE and PASS-01 trials were conducted and presented recently. (V) Stratification of response based on basal and classical subtypes of PC or assessing biomarkers of response were not studied in the old legacy trials of PRODIGE and MPACT and this might have affected outcomes by not identifying subgroups of responders to one regimen or the other. This was studied in the PASS-01 and it revealed a slightly more improved of OS favoring GA in the classical subtype. (VI) It is also important to note that S-IROX is not utilized in the USA for patients with PC. (VII) In the GENERATE, the median OS in the GA arm was 17.1 months which is higher than the data from the MPACT trial of 8.5 months. The potential for improvement in the OS, in addition to the above, can also be secondary to improvement in managing toxicities. Conversely this is an argument that can also be applied to FOLFIRINOX or S-IROX.

However, considering all the above it is important to note that data from the GENERATE trial, a prospective randomized trial, including other trials, indicate that mFOLFIRINOX might not be a superior regimen to GA. The NAPLOI 3 study did demonstrate improved survival of NALIRIFOX when compared to GA, but this is not the same regimen as FOLFIRINOX as it incorporates a liposomal formulation of irinotecan that alters the pharmacokinetics of the drug potentially allowing for a higher concentration and more targeted approach for the active metabolite SN38. I congratulate the investigators for conducting a well-designed trial and reporting their data. Designing a trial with an interim analysis for assessing benefit prior to expanding into a larger study was very fruitful in this trial. It will be essential to develop biomarkers of response to identify patients who can benefit from a gemcitabine versus a 5-Fu based regimens in the frontline setting. It is occasionally difficult to obtain adequate tissue for NGS in pancreatic cancer and hence it is important to consider ctDNA testing to identify targetable driver mutations and ctDNA and tissue NGS correlate in identifying driver mutations (8). Although we investigate which is the more efficacious regimen in the frontline setting, the treatment landscape is changing where in the future there is potential role for combining multi-select RAS (ON) or select KRAS inhibitors in PC with or without chemotherapy in the frontline setting (9,10). In addition, there are other targeted therapies emerging in PC that can change the therapeutic landscape in the future. In addition, the PANOVA 3 study demonstrated a survival benefit of Tumor Treating Fields with GA in patients with locally advanced unresectable PC (11). This is a disease with guarded prognosis, and we are currently witnessing a burgeoning era for drug development in pancreatic cancer which is exciting.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-988/prf

Funding: This work was supported by the K-12 grant program (K12CA090628) of the Mayo Clinic Cancer Center, at which H.B. is a Paul Calabresi Scholar.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-988/coif). H.M.B. reports consultation with Ipsen, Guardant360, Moderna, and Novocure (to institution), unrelated to this work. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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