NALIRIFOX Expands Frontline Options in Metastatic Pancreatic Cancer

Next-generation sequencing (NGS) results, treatment flexibility, and patient age must be carefully weighed to determine whether irinotecan liposome (Onivyde) plus oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (NALIRIFOX) is an appropriate first-line treatment for patients with metastatic pancreatic cancer, according to Dong Kim, MD. The regimen received FDA approval for this population in February 2024.¹

“One of the themes you often hear is how much things have changed with NGS, molecular testing, and all of the targeted therapies,” Kim said in an interview with OncLive®. “There’s still a lot of basic research, in addition to clinical trials, that needs to be done to better understand what other therapies could be effective. Now that we know more about the genetic predisposition for pancreatic cancer, it’s important that everyone is aware of this and knows to ask about genetic testing.”

Kim is an oncologist and hematologist at Maryland Oncology Hematology in Silver Spring and Hyattsville.

In the interview, which took place during Pancreatic Cancer Awareness Month in November, Kim discussed his decision-making process when selecting a frontline chemotherapy regimen, the real-world uptake of NALIRIFOX, and other notable research areas in pancreatic cancer.

OncLive: What factors do you weigh when selecting a frontline chemotherapy regimen for patients with metastatic disease and how do you tie patient treatment goals into this decision?

Kim: There used to be a more traditional paradigm, and now there’s a more modern one. Traditionally, we focused on [factors including] the patient’s age, performance status, and how aggressive they wanted to be, with the general idea that gemcitabine/nab-paclitaxel [Abraxane] might be more tolerable. Those [factors] are still relevant, but I believe we’ve learned that age is a wide spectrum and doesn’t always tell us how fit a patient is. Sometimes we’re surprised by what patients can tolerate.

The more modern way of thinking is: what’s the probability that this patient may have some platinum sensitivity? How long do we need to wait for the NGS results to figure that out? Some patients seem more sensitive to gemcitabine/nab-paclitaxel. Do we really know how to determine that? Probably not.

It’s interesting timing for this discussion because [data from] the [phase 2] PASS-01 trial [NCT04469556] just came out. I think even community oncologists would say we’ve noticed that some patients are more sensitive to gemcitabine/nab-paclitaxel. The test they ran isn’t ready for clinical use yet, but it’s something we’re learning from.

Overall, I think the more modern view is that you don’t necessarily want to exclude someone from a platinum-based regimen like FOLFIRINOX [leucovorin, 5-FU, irinotecan, and oxaliplatin] or NALIRIFOX just because of age.

[Another] thing to consider is how long you can afford to wait for the NGS results. Typically, we can wait, but pancreatic cancer is such a time-sensitive disease and for many patients, we only get 1 line of therapy if we can’t get them into a clinical trial.

I [consider] the pretest probability that a patient may have a homologous recombination repair deficiency. You can’t tell for sure, but if there’s a family history, you might suspect a germline mutation that could influence the approach.

I also like to have an upfront conversation with the patient. [A certain therapy] might be better for a patient if they are platinum sensitive. We’re not always sure, but it’s worth considering.

Another important point is flexibility [because] you can pivot quickly if toxicity becomes an issue. Although gemcitabine/nab-paclitaxel is often seen as the less aggressive option, I don’t believe that’s the only way to view it. A lot depends on how aggressive the patient wants to be and their potential for platinum sensitivity. Finally, although the toxicities with modified FOLFIRINOX or NALIRIFOX are real, they’re not prohibitive.

How have you seen NALIRIFOX adopted in practice and what do you think it will take for its use to increase in the real-world setting?

One justified point is the cost. Switching to something that may not offer a dramatic benefit over modified FOLFIRINOX can be hard to justify. That said, people are slowly adopting it, and I’ve certainly used it.

Another way to think about it is that we don’t have a lot of options in pancreatic cancer. Even if the difference is small, for a patient, those extra months can matter. I also think NALIRIFOX has a slightly better toxicity profile. The data suggest that’s the case, and my experience supports it.

The slow adoption is partly because it’s not a huge or exciting change, but I’d encourage more oncologists to consider it. Since many patients with metastatic pancreatic cancer only receive 1 line of therapy, a regimen with a slight efficacy or toxicity advantage could meaningfully improve quality of life.

How do the safety profiles of the various regimens contribute to your frontline decision-making?

One factor I’ve been thinking about more is pharmacogenomics, specifically irinotecan metabolism. Theoretically, that could influence how patients tolerate these regimens, although we don’t yet have clear dosing guidance from that.

The gemcitabine/nab-paclitaxel every-other-week regimen is generally well tolerated and a good option for patients you’re concerned about. But with proper dose adjustments, the gastrointestinal [GI] toxicities from modified FOLFIRINOX or NALIRIFOX can also be manageable.

Upfront supportive care is critical [and that means] addressing pancreatic enzyme insufficiency, nutrition, and weight loss early. Just because a patient is cachectic or has GI issues doesn’t necessarily mean you should avoid those regimens.

An abstract [presented during] the 2025 ASCO Annual Meeting showed that a dose reduction with the liposomal irinotecan component in NALIRIFOX didn’t affect long-term outcomes, so starting at a reduced dose is very reasonable.² That’s my personal practice. Being flexible early with dosing is key.

What’s the potential of RAS-targeted therapies in the frontline setting, either as monotherapy or in combination with chemotherapy regimens?

Over 90% of pancreatic cancers have some form of KRAS mutation. Right now, the trials with KRAS-targeted therapies, or agents targeting that broader pathway, are what we’re most excited about. There are some preliminary, encouraging data showing responses, and I’ve personally enrolled patients on those studies. It’s early but promising.

Historically, therapies that have worked in other malignancies haven’t translated well to pancreatic cancer, so we have to be more creative, whether that’s CAR T approaches for solid tumors, KRAS inhibitors, or targeting MTAP deletions. We need to cast a wide net and see what sticks.

What would you tell colleagues about the current state of frontline treatment in pancreatic cancer and where the paradigm is headed?

Even though our treatment options are limited right now, that doesn’t mean there aren’t important steps we can take. Beyond trying to get patients on clinical trials, it’s critical to address the genetic component. Sending NGS as early as possible and talking with families about germline testing [is critical].

I’m comfortable ordering [NGS] right away. It not only helps with family counseling and screening but also ensures we’re selecting the right therapy. If you start with gemcitabine/nab-paclitaxel and later find a homologous recombination pathway mutation, you may have missed an opportunity to use a more responsive regimen.

Part of the reason gemcitabine/nab-paclitaxel performed better in the PASS trial wasn’t just because of the new molecular subtype identified—it’s because they excluded patients with certain mutations, which earlier studies didn’t do. That likely made a difference.

I’d encourage all of us to raise awareness that there are still meaningful things we can do, even within standard frontline treatment, to make a difference for patients.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. Updated February 16, 2024. Accessed November 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
2. 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