Managing the Dosing and Toxicity of NALIRIFOX in Pancreatic Cancer

EP: 1.First-Line Treatment Options for Metastatic Pancreatic Adenocarcinoma

EP: 2.Insights From The NAPOLI-3 and PRODIGE4 Trials In Metastatic Pancreatic Adenocarcinoma

EP: 3.Managing AEs Associated With the FOLFIRINOX and NALIRIFOX Regimens in Pancreatic Cancer

EP: 4.NAPOLI-3 in Real World Practice: Expert Insights on Data From ASCO GI 2025

EP: 5.Evaluating the Impact of UGT1A128 Status on Tolerability Of NALIRIFOX in mPDAC

EP: 6.NALIRIFOX In Practice: Treatment Strategies for Patients With mPDAC

EP: 7.NALIRIFOX Shows Survival Benefit Vs Gemcitabine/Nab-Paclitaxel in Metastatic PDAC

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EP: 8.Managing the Dosing and Toxicity of NALIRIFOX in Pancreatic Cancer

The phase 3 NAPOLI 3 trial (NCT04083235) established the novel triplet regimen NALIRIFOX (liposomal irinotecan [Onivyde], fluorouracil [5-FU], and leucovorin) as a first-line treatment option for patients with metastatic pancreatic ductal adenocarcinoma (PDAC), significantly improving overall survival (11.1 months vs 9.2 months) and progression-free survival (7.4 months vs 5.6 months) compared with the standard nab-paclitaxel/gemcitabine. While a triplet regimen may raise concerns about heightened toxicity, Martin F. Dietrich, MD, PhD, highlighted that NALIRIFOX’s safety profile proved to be manageable.1

A key finding related to the study’s design—which featured broad eligibility unlike the more restrictive leucovorin, 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX) study—was the significant reduction in anticipated hematologic toxicity. Dietrich noted that grade 3/4 neutropenia rates occurred in 14.1% of patients in the NALIRIFOX arm and 24.5% in the gemcitabine/nab-paclitaxel regimen. Historical data from a 2011 study showed neutropenia rates of 45.7% in the FOLFIRINOX arm vs 21.0% in the gemcitabine arm.2

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.

Transcript:

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, and those were typically in the low 1-digit range. Not necessarily a big problem, but even the lower grades they 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.

References

1. 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
2. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364;1817-1825.