Mitigating NALIRIFOX-Related Diarrhea May Extend Survival in Metastatic PDAC

Post hoc analysis of the NAPOLI 3 trial suggests that proactively managing NALIRIFOX-induced diarrhea could allow patients with PDAC to remain on treatment longer.

Findings from a post hoc, exploratory analysis of the phase 3 NAPOLI 3 trial (NCT04083235), presented at the 2025 Oncology Nursing Society (ONS) Congress, indicate that proactive management of diarrhea, a common adverse effect (AE) of NALIRIFOX (liposomal irinotecan [Onivyde], 5-fluorouracil [5-FU]/leucovorin, and oxaliplatin), may allow patients with metastatic pancreatic ductal adenocarcinoma (PDAC) to remain on treatment for extended periods, potentially improving survival.¹

Among 120 total patients in North America from the intention-to-treat population who were randomly assigned to receive NALIRIFOX in the trial, 54.2% (n = 65) had an overall survival (OS) lasting 12 months or less, and 45.8% (n = 55) had an OS lasting longer than 12 months. In the safety population of the North America subgroup (n = 112), diarrhea occurred in 82.5% (n = 47/57) of evaluable patients in the shorter OS subgroup and 76.4% (n = 42/55) of evaluable patients in the longer OS subgroup. In the shorter OS subgroup, 18, 12, and 17 patients experienced grades 1, 2, and 3 diarrheal AEs, respectively. Among patients in the longer OS subgroup, 15, 17, and 10 experienced grades 1, 2, and 3 diarrheal AEs, respectively. Of note, no patients from either subgroup experienced grade 4 diarrheal AEs.

Similar proportions of patients in the shorter OS subgroup and the longer OS subgroup experienced at least 1 event of acute diarrhea (OS ≤ 12 months, 29.8%, n = 17/57; OS > 12 months, 30.9%, n = 17/55). A numerically higher number of patients had delayed diarrhea in the shorter OS subgroup (n = 30/57) compared with the longer OS subgroup (n = 25/55).

“Assessing the signs and symptoms of chemotherapy-induced diarrhea, providing accurate and timely patient education, and consulting with the medical team regarding appropriate prevention and treatment may reduce complications and optimize survival outcomes for patients,” lead study author Pareshkumar B. Patel, MD, of Florida Cancer Specialists and Research Institute in Tallahassee, and coauthors wrote in the poster.

Background and NAPOLI 3 Design

In February 2024, the FDA approved NALIRIFOX for the frontline treatment of patients with metastatic PDAC.² The regulatory decision was based on data from the NAPOLI 3 trial, which demonstrated that diarrhea is a known dose-limiting AE related to irinotecan-based chemotherapy.

The randomized, open-label study included patients aged 18 years or older who had confirmed PDAC that was treatment naive in the metastatic setting, were diagnosed with metastatic disease within 6 weeks before screening, had at least 1 measurable metastatic lesion by CT/MRI per RECIST 1.1 criteria, and had an ECOG performance status of 0 or 1.¹ Patients were stratified based on an ECOG performance status of 0 or 1, geographical region, and the presence of liver metastases. Patients (n = 770) were randomly assigned 1:1 to the NALIRIFOX arm or the gemcitabine plus nab-paclitaxel (Abraxane) arm. Patients treated with NALIRIFOX received 5-FU at 2400 mg/m² plus leucovorin at 400 mg/m² and oxaliplatin at 60 mg/m² on days 1 and 15 of 28-day cycles. Those in the gemcitabine/nab-paclitaxel arm were treated with gemcitabine at 1000 mg/m² and nab-paclitaxel at 125 mg/m² on days 1, 8, and 15 of 28-day cycles. Every 8 weeks, patients underwent tumor assessment per RECIST 1.1 criteria and had follow-ups until death or the end of the study. Patients received treatment until disease progression, unacceptable toxicity, or study withdrawal.

Pharmacological management of diarrhea during the trial was permitted but not required according to institutional or international guidelines. However, antidiarrheal initiation was recommended after the first event of poorly formed stools or the earliest onset of bowel movements that were more frequent than normal. The prophylactic and therapeutic use of atropine was recommended to manage diarrhea that occurred due to cholinergic syndrome, and loperamide was recommended as first-line pharmacological therapy for chemotherapy-induced diarrhea.

The present analysis evaluated the use of atropine as prophylaxis or treatment for diarrhea. Prophylaxis was defined as atropine treatment starting on the day of or 1 day before NALIRIFOX initiation or within 2 days before or after NALIRFOX initiation with a stated indication of “prophylaxis” or similar language. Of note, the use of loperamide and other antidiarrheal medications was not defined as prophylaxis or treatment.

Because an analysis of gastrointestinal (GI) AE management from the trial has not yet been reported, the objective of the present post hoc, exploratory analysis was to describe GI AEs and management strategies used to mitigate chemotherapy-induced diarrhea in patients treated with NALIRIFOX in NAPOLI 3 across centers in North America.

Baseline Patient Characteristics

In the shorter OS subgroup, the median age was 65.0 years (IQR, 60.0-71.0), 36.9% of patients were female, and most patients were White (86.2%). Patients had an ECOG performance status of 0 (30.8%) or 1 (69.2%). Most patients had liver metastases in the electronic case report form (eCRF; 86.2%). Patients had 1 (32.3%), 2 (36.9%), or 3 or more (30.8%) metastatic sites.

In the longer OS subgroup, the median age was 65.0 years (IQR, 53.5-69.0), 45.5% of patients were female, and most patients were White (78.2%). Patients either had an ECOG performance status of 0 (47.3%) or 1 (52.7%). Existing liver metastases in the eCRF were reported in 69.1% of patients. Patients had 1 (23.6%), 2 (27.3%), or 3 or more (49.1%) metastatic sites.

“Generally, in the longer OS subgroup, a higher proportion of patients were female and had an ECOG performance status of 0 [compared with those in] the shorter OS subgroup,” the authors wrote in the poster.

Antidiarrheal Medication Use

Of all the patients who experienced diarrhea (n = 89), atropine, loperamide, and other antidiarrheal medications were given as treatment for diarrhea or as prophylaxis in 71.9% (n = 64), 75.3% (n = 67), and 13.5% (n = 12), respectively. Among patients in the shorter OS subgroup, 68.1% were treated with atropine, 78.7% received loperamide, and 10.6% were treated with other antidiarrheal medications; in the longer OS subgroup, 76.2%, 71.4%, and 16.7% of patients received these respective medications. Atropine was used for prophylaxis in 53.2% of patients in the shorter OS subgroup and 59.5% of patients in the longer OS subgroup. Atropine was given as a treatment in 38.3% and 31.0% of patients in these subgroups, respectively.

Disclosures: Patel reported receiving honoraria from Pfizer for participating in advisory/reviewing activities.

References

1. Patel PB, Laursen A, Lieb C, et al. Mitigation of gastrointestinal side effects among patients receiving NALIRIFOX for metastatic pancreatic ductal adenocarcinoma. Presented at: 50th Annual Oncology Nursing Society Congress; April 9-13, 2025; Denver, Colorado. Abstract I9.
2. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. Updated February 16, 2024. Accessed April 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma