How Does NALIRIFOX Fit Into the Metastatic PDAC Treatment Paradigm?

In February 2024, the FDA approved irinotecan liposome (Onivyde) plus oxaliplatin, fluorouracil (5-FU), and leucovorin (NALIRIFOX) for the first-line treatment of metastatic pancreatic adenocarcinoma.¹ The decision was supported by results from the phase 3 NAPOLI 3 trial (NCT04083235), where NALIRIFOX was compared with gemcitabine/nab-paclitaxel.²

Topline results from the NAPOLI 3 trial showed a median progression-free survival (PFS) of 7.4 months in the NALIRIFOX arm compared with 5.6 months in the nab-paclitaxel/gemcitabine arm (HR, 0.69; 95% CI, 0.58-0.83; P <.0001). The median overall survival (OS) was 9.2 months in the gemcitabine/nab-paclitaxel arm vs 11.1 months in the NALIRIFOX arm (HR, 0.83; 95% CI, 0.70-0.99; P = .036). The overall response rate was 36.2% in the gemcitabine arm vs 41.8% in the NALIRIFOX arm.

CancerNetwork® spoke with Martin F. Dietrich, MD, PhD, regarding results from the trial, and how the NALIRIFOX regimen measures up to others in the space, and even the comparator regimen. While adverse effects were noted, they weren’t as intense as expected.

Dietrich is an assistant professor of Internal Medicine at the University of Central Florida College of Medicine, and a medical oncologist at The US Oncology Network Cancer Care Centers.

CancerNetwork: What is the mechanism of action of liposomal irinotecan?

Dietrich: Liposomal irinotecan banks on the original topoisomerase inhibitor inhibiting capacity of irinotecan, but it has a unique mechanism of delivery by having a liposomal membrane surrounding the individual treatment particles and thereby allowing for deeper tissue penetration and coverage of the microenvironment. It is an old agent that we’ve been using for quite some time with great success, and it’s been the standard of care in the first line for pancreatic adenocarcinomas. We refined the agent by giving an active membrane around the drug that is nanoparticle-bound and thereby able to cross some of those lipophilic barriers. This is particularly important in pancreatic cancer, where we see these desmoplastic overreactions in the background, where tissue penetration is always a concern and obstacle for treatment efficacy. By refining this agent, we were able to see an improvement in delivery into the microenvironment in pre-clinical studies and also in the clinical trial data.

Liposomal irinotecan was assessed in the NAOPOLI 3 trial. Can you discuss the efficacy observed and the long-term overall survival results?

Just to start out with a little bit of an overview of NAPOLI 3. It was a global, randomized, open-label phase 3 study that evaluated NALIRIFOX, which is essentially a dose-defined triplet regimen with liposomal irinotecan, 5-FU, and leucovorin against nab-paclitaxel and gemcitabine, a standard FDA-approved regimen. It was a very large study. About 800 patients were evaluated here, with a performance status of 0 to 1. It was a very broad eligibility. We always had concerns, previously, that our data for FOLFIRINOX [leucovorin, 5-FU, irinotecan, and oxaliplatin] were age restricted, and there were other criteria that made it applicable only to a small subset of patients.

In our readouts, NALIRIFOX provided a statistically significant improvement in PFS. The median increased here from 7.4 months [for NALIRIFOX] vs 5.6 months for gemcitabine and nab-paclitaxel. When we looked at the OS, we saw an improvement from 9.2 months [in the gemcitabine arm] to 11.1 months [in the NALIRIFOX arm], and there was a higher response rate, which is important for us. We look at response rate, not only as a short-term marker of efficacy, but also as a correlate of symptom relief by reducing tumor dimensions. We saw an increase here from 36% to 41.8%, so across the board, we had better efficacy; it was obviously highly statistically significant across the different readouts for our patients.

When needed, how do you handle dose modifications? Have you found it safe to do so?

Dose modifications depend on the [adverse] effects that we are experiencing in patients. Obviously, in a triplet regimen, we would expect higher rates of neutropenia, and surprisingly, compared with nab-paclitaxel, we saw lower levels. For grade 3/4 toxicities, we see a [neutropenia] level [of 24.5%] with nab-paclitaxel and gemcitabine, which was almost cut in half [to 14.1%] when we used NALIRIFOX. I mentioned this when I talked about the clinical study design. One of the features of this study was that the FOLFIRINOX model was [broader] and individualized, and there was never a registrational dose that was defined. It had very clearly defined numbers. Here we see an improvement in the hematologic toxicities. The dose adjustments depend on the [adverse] effects that we’re experiencing. Focusing on irinotecan, and when it comes to gastrointestinal [adverse] effects, diarrhea, nausea, and vomiting, those were typically in the low 1-digit range. Not necessarily a big problem, but even the lower grades can result in impairment for patients. Dose adjustments here are certainly an important feature. When it comes to hematologic toxicity, both oxaliplatin and liposomal irinotecan were considered for adjustment, and when we look at neuropathy here, [it’s] the main culprit on the side of oxaliplatin. I do want to say that we want to incorporate the dosing here and the pharmacogenomic testing now. DPYD and UGT1A1, in my practice, are now standard of care to understand that the doses delivered are actually the doses that the patients are safely receiving and processing appropriately. [We’re] getting those up front. But the dose modifications demonstrated similar outcomes. This is a regimen that, and you can see this in the progression-free survival, has oftentimes been given consecutively for many, many months, which is difficult in a very sick patient population. Dose adjustments didn’t seem to interfere with outcomes here.

Are there any significant adverse effects from treatment with liposomal irinotecan?

The main columns of [adverse] effects here are gastrointestinal and hematologic [adverse] effects. It’s important to understand that the hematologic toxicity looked significantly better compared with gemcitabine and nab-paclitaxel, especially with the concerning [adverse] effects of neutropenia and neutropenic fever. Those looked favorable here compared with treatment. We had less growth factor use, which is important. We’ve seen some cumulative anemia, which is unfortunately difficult to manage, other than dose adjustments. We don’t have a good handle on the long-term toxicity. Then the [gastrointestinal adverse] effects are highly dependent on supportive care. We want to use anti-motility agents and anti-emetics, and be very generous with those. For patients who experience spasmodic diarrhea, that is a cholinergic mechanism of activation that’s been well-described for irinotecan; we sometimes have to add atropine here as well for a patient’s control of symptoms.

Looking at the mPDAC space, how do the results from the NAPOLI trials and the use of liposomal irinotecan measure against other available treatment options?

We have a data gap here. The head-to-head study against gemcitabine/[nab-paclitaxel] was clear. This is an easier-to-give regimen when it comes to the schedule, so the logistics are better. We’ve seen improved efficacy on all efficacy markers—response rate, PFS, and also OS. What we don’t have is a direct head-to-head comparison against modified FOLFIRINOX. We had a French study over a decade ago, the [phase 2/3 PRODIGE 4 study (NCT00112658)], which looked at FOLFIRINOX in the first-line setting against gemcitabine and [nab-paclitaxel]. There were a number of limitations. We want to point out that modified FOLFIRINOX is not an FDA-approved regimen for first-line use in metastatic pancreatic cancer, but we’ve adopted it as a standard of care. We extrapolated some of the experiences from colorectal cancer here as well, but we have had very strict patient selection, with a cut-off at age 70. We had a very good performance status, and it was also a 1-country experience that tested against gemcitabine alone, not gemcitabine/[nab-paclitaxel]. There were a number of difficult factors, and for me, it was the highest level of evidence. The NALIRIFOX level of evidence and the FDA support here is highest.

Is there anything else you would like to highlight?

NALIRIFOX has established itself as a preferred first-line regimen for metastatic pancreatic adenocarcinoma. The [adverse] effects that we’re seeing here are very well characterized. One of the achievements here was the definition of doses; there was no longer any ambiguity. We know exactly what we’re giving. We have a level of oxaliplatin which is potentially lower than what has been given here, with the starting dose of 60 mg/m². That’s very important when we think about the impact on neuropathy, which is a dose-limiting and impairing [adverse] effect that can be seen. The same is true for liposomal irinotecan at 50 mg/m², the starting dose that we are very comfortable handling. What’s going to be exciting is that we’re going to be seeing evolutions in the first line space. The genetic understanding of pancreatic cancer is very good. KRAS is a central alteration that’s present in almost 100% of patients; it’s the absolute exception to see pancreatic cancer that’s not KRAS mutant. We always have to think about whether we have the right diagnosis. Could this be an adjacent tumor, a cholangiocarcinoma? There are some fusions that may be present in pancreatic adenocarcinoma. Obviously, the excitement comes when we have a defined standard with NALIRIFOX and consider the addition of some of the other agents that are coming—the KRAS inhibitors, some of the subtype-specific inhibitors for KRAS G12C and G12D that are in development, and there are some adjacent pathways that are being looked at. For the time being, the triplet regimen, for eligible patients, and those are typically patients who have a better performance status, will remain the standard of care, but we’ll augment it with targeted therapies and hopefully see even better efficacy.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. News release. FDA. February 13, 2024. Accessed November 14, 2025. https://tinyurl.com/5yhhuan9
2. Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1
3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364;1817-1825. doi:10.1056/NEJMoa1011923