The Favorable Toxicity Profile of NALIRIFOX Focuses on Hematologic/GI AEs in mPDAC

The phase 3 NAPOLI 3 trial (NCT04083235) established the triplet regimen of liposomal irinotecan (Onivyde), fluorouracil (5-FU), and leucovorin (NALIRIFOX) as a first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The study was randomized after enrolling 770 patients, featuring broad eligibility to address prior limitations of intensive regimens like leucovorin, 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX). Efficacy results were encouraging, showing an improvement in overall survival (OS) from 9.2 months in the gemcitabine/nab-paclitaxel arm to 11.1 months in the NALIRIFOX arm, and an increase in progression-free survival (PFS) from 5.6 months to 7.4 months.

Addressing the toxicity profile, Martin F. Dietrich, MD, PhD, focused on the main adverse effects associated with NALIRIFOX: gastrointestinal (GI) and hematologic. Despite being a triplet regimen, NALIRIFOX presented a favorable hematologic toxicity profile when compared directly against standard nab-paclitaxel and gemcitabine. Specifically, the highly concerning adverse effects of neutropenia and neutropenic fever were observed less frequently in the NALIRIFOX arm, translating into less need for growth factor support.

The primary GI adverse effects—diarrhea, nausea, and vomiting—are common with irinotecan-based treatments. Dietrich emphasized the importance of aggressive and generous supportive care using anti-motility agents and antiemetics. While some cumulative anemia was noted, which is primarily managed by dose adjustments, the overall safety data, particularly the reduced incidence of severe neutropenia, support the use of NALIRIFOX as a manageable and highly effective first-line therapy.

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:

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.

Reference

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