NALIRIFOX Remains Effective Despite Dose Modification in First-Line PDAC

The effects of dose reductions and a regimen’s safety profile can be used to properly inform frontline treatment selection between irinotecan liposome (Onivyde) plus oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (NALIRIFOX), and the established regimen of FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) for patients with metastatic pancreatic adenocarcinoma (PDAC).

“It’s great to have choices. For a long time, we did not have choices, and now we do,” Axel Grothey, MD, explained. “We don’t expect that much of a difference in efficacy, but do see differences in toxicity profiles, which allows us to individualize treatment. That is where we as oncologists come into play [and need to] talk to patients [about] expectations, comorbidities, and [perform a] holistic assessment…patients and choose the appropriate regimen. I honestly do not believe that every patient should receive NALIRIFOX [nor that] every patient should receive FOLFIRINOX.”

“NALIRIFOX [and] FOLFIRINOX are both very active regimens in this disease space, [but] the key difference [in terms of] treatment selection comes down to the adverse effect [AE] profiles. The doses of the individual drugs in triplets are different, most notably the oxaliplatin dose in NALIRIFOX is a little bit lower than in FOLFIRINOX, and that is a regimen I would favor in a patient that may have baseline neuropathy,” Jonathan W. Lee, MD, MSc, added.

In an OncLive Peer Exchange filmed during the 2026 Gastrointestinal Cancers Symposium (ASCO GI), expert investigators participated in a discussion which aimed to further tease out the optimal dosing approach for patients who are selected for first-line NALIRIFOX, the selection process of frontline NALIRIFOX vs FOLFIRINOX in metastatic PDAC in light of data released throughout 2025, and touched on treatment sequencing approaches in the second-line setting.

How can NALIRIFOX dosing be optimized?

In February 2024, the FDA approved NALIRIFOX for the frontline treatment of patients with metastatic pancreatic adenocarcinoma.¹ The approval was supported by data from the phase 3 NAPOLI 3 study (NCT04083235), which demonstrated that treatment with NALIRIFOX led to a significant overall survival (OS) benefit compared with gemcitabine plus nab-paclitaxel (Abraxane; HR, 0.84; 95% CI, 0.71-0.99; P = .0403). Patients in the investigational arm also experienced a 30% reduction in the risk of disease progression or death compared with those in the control arm (HR, 0.70; 95% CI, 0.59-0.85; P = .0001).

Notably, data from a post-hoc analysis of NAPOLI 3 showed that dose modifications of NALIRIFOX allowed for prolonged treatment exposure, which ultimately increased long-term OS.² Specifically, the objective of the analysis was to determine the effect of dose reductions of liposomal irinotecan and oxaliplatin on OS in the study.

Data from the post-hoc analysis showed that patients in the safety population of NAPOLI 3 who had a dose reduction of liposomal irinotecan (n = 194) had a median OS of 12.6 months (95% CI, 11.0-14.5) compared with 9.4 months (95% CI, 7.6-11.5) among patients who did not have a dose reduction (n = 176). Those who experienced a dose reduction of oxaliplatin (n = 217) achieved a median OS of 13.5 months (95% CI, 11.7-15.2) vs 7.7 months (95% CI, 6.2-10.2) in patients who did not (n = 153).

“These findings support the potential for treatment optimization in patients who receive first-line NALIRIFOX for the [management] of metastatic PDAC,” the study authors wrote in their conclusion.

“[These findings are] confounded by the fact that the longer [a patient is] on treatment, the more likely you are going to have to make those reductions,” Grothey commented. “But [these data can] more or less guide our clinical practice and our interaction with patients, because in [giving] therapy we will have to perform those reductions. We have data now that show us that we can safely do that, [and] survival won’t be compromised. [We] don’t have to afflict adverse effects [AEs] too much on patients who are already suffering from a devastating disease. These data give us ways to talk to patients and reassure us and them that we’re not harming them by lowering the doses.”

Moreover, in another post-hoc analysis of NAPOLI 3, investigators sought to elucidate the clinical and pathological characteristics of long-term survivors who received NALIRIFOX in North America during the trial.³ Long-term survivors were defined as patients who achieved an OS of at least 18 months.

Findings from the analysis revealed that 15 patients (12.5%) in the intention-to-treat population (n = 120) experienced an OS of at least 18 months. The median age of these patients at baseline was 61.0 years (IQR, 49.0-70.5), 46.7% were female, and 66.7% were White. Most long-term survivors had an ECOG performance status of 0 (53.3%), had metastatic disease at diagnosis (86.7%), and had at least 3 metastatic sites at baseline (53.3%).

The median OS among the long-term survivors was 19.5 months (IQR, 18.8-22.6). Notably, a majority of the long-term survivors had dose reductions and delays, respectively, with liposomal irinotecan (66.7% and 86.7%) and oxaliplatin (80% and 80%). Most long-term survivors were also UGT1A1*28 nonhomozygous (73.3%).

In another analysis that examined UGT1A1*28 in NAPOLI 3, the study authors aimed to assess the effect of UGT1A1*28 (genotype 7/7) homozygosity on the incidence and profile of treatment-emergent AEs (TEAEs).⁴ The exploratory end point of the post-hoc analysis of NAPOLI 3 compared the safety outcomes of patients with UGT1A1*28 status vs nonhomozygous patients (other genotypes).

Findings from the analysis showed that patients who received NALIRIFOX with UGT1A1*28 homozygous disease (n = 39) and those with nonhomozygous disease (n = 328) experienced any-grade TEAEs at respective rates of 100.0% and 99.7%. The rates of any-grade treatment-related AEs (TRAEs) were 100.0% and 94.5%, respectively. Patients in both groups experienced grade 3 or higher TEAEs (79.5% vs 87.8%), grade 3 or higher TRAEs (69.2% vs 70.7%), serious TEAEs (61.5% vs 53.7%), and TEAEs leading to death (5.1% vs 6.1%) at similar rates.

“There was not a lot of [added] toxicity related to [UGT1A1*28] homozygosity,” Hani M. Babiker, MD, noted. “That makes you feel comfortable saying, ‘I can prescribe the drug and keep an eye on [a patient who] has homozygosity.’ It makes me feel a little more comfortable. That may be related to the mechanism of the drug and the drug formulation of having the liposomal formulation that can deliver an effective dosage and mitigate some of the AEs.”

What is the influence of patient-centric care and practical management on NALIRIFOX vs FOLFIRINOX selection in frontline PDAC?

Although NALIRIFOX and FOLFIRINOX have not been compared head-to-head in a randomized clinical trial, there have been external control arm and real-world studies comparing the regimens.^5,6 In an external control arm study which included patients treated with NALIRIFOX in NAPOLI 3 and external controls treated with FOLFIRINOX, patients who received NALIRIFOX experienced a reduction in the risk of death of 21% (HR, 0.79; 95% CI, 0.64-0.96; P = .02); these results were deemed to be statistically significant.⁵ The study authors noted that the baseline characteristics were well balanced between the 2 groups following the application of inverse probability of treatment weighting.

Moreover, in a retrospective, longitudinal cohort study, investigators sought to describe the real-world OS for patients with metastatic PDAC who received frontline FOLFIRINOX in 3 cohorts: all-comers (cohort 1); those who met the eligibility criteria of NAPOLI 3 (cohort 2); and a subgroup of cohort 2 who received a modified FOLFIRINOX regimen (cohort 3).⁵ The modified regimen examined in cohort 3 consisted of an initial dose of liposomal irinotecan at 150 mg/m² or less or an initial cumulative dose of 5-FU at 2720 mg/m² or less during the first treatment cycle. The study authors used de-identified, patient-level data from the Flatiron Health Electronic Health Record from January 1, 2014, to February 29, 2024, to build the retrospective study cohorts.

Findings from the retrospective study showed that patients in cohort 1 (n = 3271) experienced a median OS of 9.0 months (95% CI, 8.5-9.3). Those in cohorts 2 (n = 219) and 3 (n = 154) had a median OS of 9.1 months (95% CI, 7.8-10.9) and 8.6 months (95% CI, 7.3-10.5), respectively.

“Real-world analyses don’t have the same level of evidence as prospective, randomized clinical trials,” Grothey said. “The outcomes and data are probably very similar [between NALIRIFOX and FOLFIRINOX]. We have the benefit having choices and adjusting our selection of treatments based on patient characteristics [such as] pre-existing conditions, comorbidities, and [treatment] expectations. Education of providers and patients is critical here.”

“The outcome may be similar, but there are small differences in the toxicity profiles [according to] the data we have right now. It seems like the NALIRIFOX regimen might have significantly lower rates of thrombocytopenia compared with the FOLFIRINOX regimen,” Dan Zhao, MD, PhD, noted.

Which novel agents could affect treatment sequencing in the second line?

The panelists concluded their discussion by outlining factors that influence their treatment sequencing decisions in the second-line setting. “It’s unfortunate that we don’t have a lot of options for pancreatic cancer and that we only have 2 lines of therapy that we use. Hopefully, in the future, things will get better. I have not had difficulties with prescribing NALIRIFOX for patients. It happens to me [very infrequently] given the data [and the fact] that it’s approved and is [listed] in the NCCN [National Comprehensive Cancer Network] guidelines,⁷ so that’s not an issue that I’ve had lately with this regimen,” Babiker said.

Zhao noted that historically, approximately 50% of patients with pancreatic cancer do not reach a second line of therapy.⁸ However, she noted that novel agents such as KRAS and PRMT5 inhibitors have displayed promising data in early-phase studies.

“We need to have a chemotherapy backbone that allows for the addition of these targeted agents,” Grothey said. “I hope that, at some point, we’ll see iterations of FOLFIRINOX and that NALIRIFOX will also be used as a backbone for the addition of targeted agents, because it can really make a difference. There might even be some biological and pharmacodynamic approach [that] benefits from having a liposomal, reformulated irinotecan plus a targeted agent. This is exciting for patients with pancreatic cancer. I hope that patients will eventually benefit from these advances within the next year or 2.”

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. Updated February 16, 2024. Accessed January 22, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
2. Patel AJ, Laursen AA, Cockrum P, et al. Effect of dose adjustments on overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX: a post hoc analysis of NAPOLI 3. J Clin Oncol. 2025;43(suppl 4):716. doi:10.1200/JCO.2025.43.4_suppl.716
3. Chung V, Kochenderfer MD, Natarajan N, et al. NAPOLI 3, a phase 3 study of NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): final overall survival (OS) analysis and characteristics of the long-term survivors. J Clin Oncol. 2025;43(suppl 17):LBA4175. doi:10.1200/JCO.2025.43.17_suppl.LBA4175
4. Abdelrahim M, Khan G, Hatoum H, et al. Impact of UGT1A1*28 polymorphism on tolerability in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX in NAPOLI 3. J Clin Oncol. 2025;43(suppl 4):717. doi:10.1200/JCO.2025.43.4_suppl.717
5. Duh MS, Chang R, Cockrum P, et al. Overall survival (OS) with NALIRIFOX (NFX) compared to FOLFIRINOX (FFX) in patients not previously treated for metastatic pancreatic ductal adenocarcinoma (mPDAC): an external control arm study. J Clin Oncol. 2025;43(suppl 16):e16383. doi:10.1200/JCO.2025.43.16_suppl.e16383
6. Cockrum P, Chang R, Yu LH, et al. Overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line (1L) FOLFIRINOX (FFX): bridging the gap between the NAPOLI 3 trial and real-world practice. J Clin Oncol. 2025;43(suppl 4):690. doi:10.1200/JCO.2025.43.4_suppl.690
7. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 2.2025. Accessed January 16, 2026. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
8. Lambert A, Schwarz L, Borbath I, et al. An update on treatment options for pancreatic adenocarcinoma. Ther Adv Med Oncol. Published online September 25, 2019. doi:10.1177/1758835919875568