NALIRIFOX Approval Revitalizes Pancreatic Cancer Management


Zev A. Wainberg, MD, discusses the FDA approval of NALIRIFOX in patients with metastatic pancreatic adenocarcinoma and key data from the NAPOLI 3 trial.

Zev A. Wainberg, MD

Zev A. Wainberg, MD

The FDA approval of NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-fluouroracil, and leucovorin) for patients with metastatic pancreatic adenocarcinoma has expanded the treatment armamentarium for this population, although this addition to the paradigm also necessitates further research to improve outcomes, according to Zev A. Wainberg, MD.

On February 13, 2024, the FDA approved NALIRIFOX for the frontline treatment of patients with metastatic pancreatic adenocarcinoma.1 The regulatory decision was supported by findings from the phase 3 NAPOLI 3 trial (NCT04083235), in which patients who received NALIRIFOX (n = 383) achieved a median overall survival (OS) of 11.1 months (95% CI, 10.0-12.1) vs 9.2 months (95% CI, 8.3-10.6) in those who received gemcitabine plus nab-paclitaxel (Abraxane; n = 387; HR, 0.84; 95% CI, 0.71-0.99; = .0403).2

“Here, we sit in early 2024, when there still have not been the kinds of changes we want to see in this disease, but it’s now nice to have a new treatment option at our disposal,” said Wainberg, who is a professor of medicine at the University of California, Los Angeles (UCLA), as well as codirector of the UCLA Gastrointestinal Oncology Program.

In an interview with OncLive®, Wainberg discussed the significance of the approval, key efficacy and safety data from NAPOLI 3, and how the role of NALIRIFOX in pancreatic cancer may continue to evolve.

OncLive: What were the rationale and design of the NAPOLI 3 trial, and how did NALIRIFOX improve OS in this study?

Wainberg: The approval was based on [findings from] the NAPOLI 3 trial, which were published [in 2023. This trial] randomly assigned patients with newly diagnosed pancreatic cancer to receive either NALIRIFOX in the investigational arm or standard dosing of gemcitabine and nab-paclitaxel. [NAPOLI 3 employed] 1:1 randomization and had a primary end point of OS. The study results showed a [2-month] improvement in OS [with NALIRIFOX], going from 9.2 [months with gemcitabine plus nab-paclitaxel] to 11.1 months [with NALIRIFOX], with an HR of 0.84 that met statistical significance. In accordance with [those data], the FDA decided to approve this regimen [for this patient population].

What other key efficacy findings from NAPOLI 3 are important to note?

It’s hard to show improvement in OS in a randomized phase 3 trial in pancreatic cancer. [That] hasn’t been done since the emergence of nab-paclitaxel and the FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin] regimens at around the same time [for patients with this disease]. Since then, many studies that have been done in pancreatic cancer failed to meet their end points.

The fact that [NAPOLI 3] met its primary end point of OS is significant. [This trial] also met its end point of progression-free survival [PFS], which was improved to 7.4 months in the NALIRIFOX arm, which is the highest PFS we’ve ever seen in a randomized trial in metastatic pancreatic cancer. The response rates were not statistically significantly different between the 2 arms.

What is the safety profile of NALIRIFOX in this population?

The safety profile of NALIRIFOX is similar to [that of] what most of us have been using, FOLFIRINOX, which [is associated with noticeable] gastrointestinal [GI] toxicities. [In NAPOLI 3], there was an increase in GI toxicities in the experimental arm vs the control arm. Interestingly, there was less peripheral neuropathy [with NALIRIFOX] than we typically see [in pancreatic cancer treatment regimens] because lower doses of oxaliplatin were used in this regimen. In addition, there were similar rates of other typical adverse effects, such as fatigue, [as seen with other regimens]. We tend to assume [patients will] have less neuropathy with gemcitabine plus nab-paclitaxel, but that regimen [is associated with] some neuropathy, as well.

Based on this approval, where does NALIRIFOX fit into the metastatic pancreatic cancer treatment paradigm?

It’ll be interesting to see how [NALIRIFOX is] incorporated into different treatments. We now have a [treatment] option that we didn’t have before. More options are better, and we now have a new option to treat patients with metastatic pancreatic cancer.

[The NAPOLI 3] trial was done for the community [oncologists] to answer questions that are important for the treating oncologists who are not necessarily going to enroll their patients in academic center studies. It was a community-driven trial that now offers the community a new regimen that was not available before. [Community oncologists need] to gain experience with [NALIRIFOX] and make decisions on their own regarding whether this a regimen they would like to use moving forward in this disease. It’s always important to keep trying in this disease to offer new therapies for patients. Accordingly, I am glad the FDA issued this approval because it offers a new treatment option for these patients.

What unmet needs remain for patients with metastatic pancreatic cancer, and how might those needs be addressed in the future?

There are still huge unmet needs in this disease. I don’t think [the NAPOLI 3] trial satisfies those needs by any stretch of the imagination. We need to make significant improvements in [the treatment of] this disease both in early and late stages. We need to do a much better job of incorporating new drugs into existing treatment regimens. We need to do a better job of finding appropriate biomarkers. We need to do a better job with patient selection and recognizing that different patients have different treatment needs. There is simply no shortage of important needs in this disease, [and it is] incumbent upon us in the community to try to answer these questions moving forward.

We’ve got more coming. This is just the beginning of new drug development in pancreatic cancer. We have a host of new drugs that will come down the pike in the next few years.


  1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed February 14, 2024.
  2. Onivyde. Prescribing information. Ipsen Biopharmaceuticals, Inc.; 2024. Accessed February 14, 2024.
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