Insights from the NEOPAN trial: FOLFIRINOX vs. gemcitabine in locally advanced pancreatic cancer

NEOPAN and current landscape of locally advanced pancreatic cancer (LAPC)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with the subset of LAPC, defined as unresectable disease within the pancreas, accounting for over 30% of new diagnoses and associated with a median overall survival (OS) of between 10–16 months (1,2). LAPC is a unique clinical scenario in which the tumor appears localized but unresectable due to anatomic features, mainly involving significant vasculature (2). Optimal management for LAPC is controversial and combination treatments are extrapolated from treatment guidelines for borderline resectable and metastatic disease. Although surgery offers the potential for curative-intent treatment for a small subset of LAPC who respond to therapy, gaps in our knowledge and understanding of the disease remain (2). Many questions remain unanswered throughout the current literature, including the selection of specific chemotherapeutic agents, duration of therapy, the role of radiotherapy, prediction of those who may become resectable and accurate and real-time assessments of responses to therapies. Furthermore, the biological underpinnings of LAPC remain unclear (3).

Historically, gemcitabine monotherapy has served as the standard of care, providing modest benefits in both symptom control and survival (4). The LAPC population was excluded from the key combination chemotherapy trials for metastatic PDAC in order to evaluate a more homogeneous population (5,6). Against this backdrop, Ducreux et al. in the PRODIGE 29-UCGI 26 (NEOPAN) phase III trial (7) sought to evaluate whether the multi-agent regimen FOLFIRINOX [combining 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin] could offer superior outcomes compared to gemcitabine alone in LAPC. In this randomized study, 171 patients with histologically confirmed, unresectable LAPC were allocated 1:1 to either FOLFIRINOX or gemcitabine for 6 months across 30 French centres (7). After 6 months of therapy, at the discretion of the investigators, there was the option to continue on maintenance gemcitabine in that group or switch to a 5-FU maintenance regimen in the FOLFIRININOX group. Additionally, after 6 months of therapy on either arm investigators were permitted to close the 6-month period of chemotherapy with radiation (conventional or stereotactic). After a median follow-up of approximately 59.6 months, the trial achieved its primary endpoint: progression-free survival (PFS) was significantly improved with FOLFIRINOX, reaching a median of 9.7 vs. 7.7 months with gemcitabine [hazard ratio (HR), 0.70; P=0.04]. This translated into notable differences in PFS‑rate landmarks—at 12 months, 36.5% of patients on FOLFIRINOX remained progression-free vs. 17.4% on gemcitabine; at 36 months, 3.5% vs. 1.2% respectively (7).

Despite these PFS gains, the study found no significant difference in median OS: FOLFIRINOX achieved 15.7 vs. 15.4 months for gemcitabine (HR, 1.02, P=0.95). The absence of an OS benefit likely reflects substantial crossover to subsequent therapies: 77% of patients progressing on FOLFIRINOX and 64% progressing on gemcitabine received second-line chemotherapy. These are higher crossover rates than generally seen with metastatic PDAC and suggests a reasonable benefit of second-line chemotherapy in LAPC.

The safety profile warranted attention but was manageable. In the FOLFIRINOX arm, grade 3–4 adverse events included diarrhea (18%) and fatigue (18%), while neutropenia (13%) was most common with gemcitabine. Treatment-related discontinuation rates were similar (7% FOLFIRINOX vs. 8% gemcitabine). Treatment-related deaths were fewer in the FOLFIRINOX cohort (1 vs. 7), this is a higher than expected number in the single agent gemcitabine group and the reason is unclear. Patients receiving gemcitabine experienced earlier disease progression, which is associated with increased mortality, despite similar OS between the two arms. This difference in the timing of progression potentially led to a higher number of deaths in the gemcitabine group during the study period, as FOLFIRINOX provided a longer PFS and delayed progression-related mortality. While protocol-specific treatment modifications and supportive care including filgrastim or pegfilgrastim were permitted, details of these in each arm was not provided. Thus, FOLFIRINOX demonstrated a more favorable risk-benefit profile in terms of PFS, though with similar tolerability and safety. Despite an objective response rate of 42.4% in the FOLFIRINOX group compared to 15.1% in the gemcitabine group only 9 patients (4 in gemcitabine group and 5 in FOLFIRINOX group) responded to the extent that they were able to undergo curative intent surgery, of these only 2 are reported to be alive without progression (7). All 9 patients achieved a R0 resection. However, this low but not un-expected conversion rate speaks to the vascular complexity of LAPD and need for more active treatments.

In the broader context of pancreatic cancer management, these findings reinforce a growing shift towards more aggressive cytotoxic multi-agent regimens in fit patients with advanced disease. For metastatic disease, FOLFIRINOX had already shown dramatic survival advantages over gemcitabine: median OS of 11.1 vs. 6.8 months and PFS of 6.4 vs. 3.3 months (5). In resectable disease, adjuvant modified-FOLFIRINOX improved disease-free survival (median 21.6 vs. 12.8 months) and median OS (54.4 vs. 35.0 months) compared to gemcitabine (8). NEOPAN now extends the potential value of FOLFIRINOX into the LAPC space by offering a meaningful PFS benefit, though OS remains unaltered by trial maturity and crossover (7).

One criticism from NEOPAN, put in context in 2025, is the use of single agent gemcitabine without a combination. Gemcitabine plus nab-paclitaxel is an accepted standard of care in the metastatic setting, having shown superiority over gemcitabine alone, with excellent tolerability (6,9). Additionally, the GENERATE JCOG1611 demonstrates superiority of this regimen in terms of OS over modified FOLFIRINOX and S-IROX (S-1, irinotecan and oxaliplatin) (10) in a metastatic Japanese population. Furthermore, when BRCA-mutated patients were excluded in the PASS-01 trial where the doublet gemcitabine/nab-paclitaxel out-performed the triplet modified FOLFIRINOX in terms of PFS (11,12). More recently, other regimens have emerged in the metastatic setting. NALIRIFOX (liposomal irinotecan combined with 5-FU, leucovorin, and oxaliplatin), demonstrated a first-line survival advantage over gemcitabine/nab-paclitaxel in metastatic disease (median OS 11.1 vs. 9.2 months; HR, 0.83) (13). However, this regimen has not been compared head to head with FOLFIRINOX to select one over the other. Additionally, exploring biomarkers and next-generation sequencing (11,12) have further refined therapeutic decision-making. Direct comparisons between these more recent approaches and FOLFIRINOX remain lacking in LAPC.

Taken together, NEOPAN’s demonstration that FOLFIRINOX improves PFS in unresectable LAPC without compromising safety confirms the regimen’s potency beyond metastatic and adjuvant settings (7). Yet, the absence of an OS advantage underscores the impact of subsequent therapies, crossover effects, and perhaps the need for combination strategies—such as integrating chemoradiation, incorporating KRAS-targeted agents, or exploring immunotherapeutic options that might extend survival further (1).

The recently published randomized PANOVA-3 study is the first positive study demonstrating a modest survival benefit with a novel approach: investigating tumor treating fields therapy in addition to gemcitabine and nab-paclitaxel, in the first-line setting in unresectable locally advanced PDAC. Tumor treating fields therapy is a non-invasive, locoregional antimitotic treatment that utilizes low-intensity, intermediate-frequency (typically 150 kHz) alternating electric fields delivered via transducer arrays placed on the skin over the abdomen. A total of 571 patients were enrolled. Median OS: 16.2 vs. 14.2 months (HR, 0.819; P=0.039) (14). It also demonstrated an improved pain-free survival and quality of life with a manageable toxicity profile with only 8% discontinuation due to skin reactions, related to the tumor treating fields therapy device (14).

The use of radiation in LAPC remains somewhat controversial with variable outcomes regarding the addition of radiation being reported, and it is generally extrapolated from borderline resectable settings (2). The Alliance A021501 trial, which compared OS after neoadjuvant-modified FOLFIRINOX alone vs. modified FOLFIRINOX followed by stereotactic body radiation therapy (SBRT) in patients with borderline resectable disease, did not demonstrate improved survival among those who received radiation (15). Complete pathologic response, however, was observed in two patients who received it, leading to the overall recommendation that radiation may be an effective treatment option after a response or stability of disease is achieved with a FOLFIRINOX approach. Based on this and other evidence where LAPC and borderline resectable disease have been grouped together in early phase II studies, it has become an accepted standard approach after a time on systemic therapy with stability of disease or response to consider chemoradiation in LAPC with the objective to still achieve a chance of exploring surgical intervention (16). Chemoradiation is this setting also allows time for a “treatment-break” from combination more toxic chemotherapy regimens (16,17).

Future directions

During the last decade, molecular biology advances have greatly contributed to our understanding of the intricate pathways involved in the development of PDAC (18). These discoveries have not only deepened our knowledge but also have identified several potential therapeutic targets that have generated substantial interest. Due to the localized nature of LAPC, adequate tissue is not always easily obtained for sequencing of the tumor. The COMPASS trial for whole genomic sequencing after laser microdissection, included a subset of LAPC (n=37) and compared with metastatic patients (3). Driver alternations were similar amongst LAPC and metastatic cases. However, LAPC exhibited a significantly lower burden of single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) than metastatic PDAC. Major imbalances in mutant KRAS were absent in the LAPC group and there were no basal-like subtypes, both suggested to have a worse prognosis (3,18,19). In comparison to metastatic disease, LAPC therefore may demonstrate less genomic instability and maybe predominantly classical RNA subtype disease, which in itself infers for improved survival. Having these molecular insights could be pivotal in tailoring better treatment strategies for LAPC and directing better trial stratifications and/or adaptive designs that account for differential treatment responses. Another limitation of NEOPAN is certainly the lack of tissue availability for sequencing and RNA-subtyping (7).

PDAC is largely driven (>90%) by activating KRAS mutations—notably G12D, G12V, and G12R variants. Until recently, KRAS was considered “undruggable”, but advances have yielded inhibitors even targeting rare G12C mutations in PDAC, showing modest efficacy in heavily pretreated patients with metastatic disease (20). Preclinical studies with KRAS G12D inhibitor MRTX1133 show strong anti-tumor activity in cell lines and mouse models. Notably, combining MRTX1133 with chemotherapy significantly improved tumor control compared to either therapy alone in preclinical PDAC models (21). This synergistic effect appears to stem from chemotherapysensitive “classical-state” cells becoming dominant after KRAS inhibition, suggesting combination regimens may prevent relapse/progression and more effectively suppress tumor growth (22). Currently, clinical trials are underway: KRAS G12D inhibitors and broader pan-KRAS agents have entered phase I/II/III trials in metastatic disease. It is likely that integrating these targets with chemotherapy combinations will be the next steps to move the needle forward in LAPC.

Conclusions

In summary, from NEOPAN, in fit patients it is clear that FOLFIRINOX emerges as a viable and more effective first-line option vs. gemcitabine alone in unresectable, LAPC, delivering a clinically meaningful PFS increase with acceptable safety. Although OS remains equivalent, these results align with evolving standards in pancreatic cancer treatment approaches. Extrapolating from the PANOVA-3 results the alternative of gemcitabine plus nab-paclitaxel may also provide an equally good option to patients with LAPC unable to tolerate the triplet combination. Ultimately NEOPAN paves the way for KRAS/chemotherapy combination regimens. Personalized approaches with innovative combinations, incorporating RNA subtyping and KRAS directed therapies into the paradigm, should now follow into this setting to truly move the needle on survival. NEOPAN contributes a vital piece of evidence supporting the broadening use of intensive cytotoxic regimens and neatly frames the landscape within which next-generation directed treatments must now prove their value.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article has undergone external peer review.

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-25-21/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-25-21/coif). J.J.K. received research grants from AZ, Roche, Merck, Ibsen, and consulting fees from Astellis, Incyte, AZ, Roche, Merck, Ibsen, Jazz, Nucana, outside the submitted work. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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