NALIRIFOX improved overall survival and progression-free survival in patients with metastatic pancreatic ductal adenocarcinoma.
Treatment with liposomal irinotecan (Onivyde), 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (NALIRIFOX) led to improvements in overall survival (OS) and progression-free survival (PFS) compared with nab-paclitaxel (Abraxane) plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).1
These findings come from the phase 3 NAPOLI 3 trial (NCT04083235), presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Data showed that at a median follow-up of 16.1 months, patients in the intent-to-treat (ITT) population administered liposomal irinotecan plus NALIRIFOX (n=383) experienced a median OS of 11.1 months (95% CI, 10.0-12.1) compared with 9.2 months (95% CI, 8.3-10.6) for those given nab-paclitaxel plus gemcitabine (n=387; HR, 0.83; 95% CI, 0.70-0.99 P=.04).
"These results support the NALIRIFOX regimen as a new regimen for the first-line treatment of patients with metastatic PDAC. The regimen represents something we can hopefully build on in the future," lead study author Zev A. Wainberg, MD, a professor of medicine at UCLA and codirector of the UCLA GI Oncology Program, said in a presentation of the data.
Based on the findings of NAPOLI 3, the drug's manufacturer Ipsen plans to file a supplemental new drug application seeking the approval of liposomal irinotecan plus NALIRIFOX in this patient population in the United States.2
In October 2015, the FDA approved liposomal irinotecan plus 5-FU/leucovorin for the treatment of patients with metastatic PDAC after progression with gemcitabine-based treatment.3
The randomized, open-label NAPOLI 3 study evaluated the efficacy and safety of liposomal irinotecan plus NALIRIFOX vs nab-paclitaxel plus gemcitabine in patients with confirmed metastatic PDAC who were previously untreated in the metastatic setting. Patients were required to have metastatic disease diagnosed no more than weeks prior to screening, at least 1 metastatic lesion measurable by MRI or CT scan per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1. Enrolled patients were randomly assigned 1:1 to 50 mg/m2 of liposomal irinotecan plus 2400 mg/m2 of 5-FU, 400 mg/m2 of leucovorin, and 60 mg/m2 of oxaliplatin on days 1 and 15 of each 28-day cycle, or 1000 mg/m2 of gemcitabine plus 125 mg/m2 of nabpaclitaxel on days 1, 8, and 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal. Tumor assessment was conducted every 8 weeks per RECIST 1.1 criteria, and follow-up continued until death or study conclusion.
Stratification factors included ECOG performance status (0 vs 1), region, and presence or absence of liver metastases.
OS served as the trials primary end point. Secondary end points comprised investigatorassessed PFS and overall response rate (ORR) per RECIST 1.1 criteria and safety. Health-related quality of life and biomarker assessments were exploratory end points.
At the July 23, 2022, data cutoff, 85.1% of patients in the experimental arm had discontinued treatment compared with 96.1% in the control arm. The primary reasons for discontinuation in the liposomal irinotecan/NALIRIFOX arm were progressive disease (48%), adverse events (AEs; 14.1%), death (8.4%), or other (14.7%). In the nab-paclitaxel/gemcitabine arm, those rates were 45.7%, 23.8%, 6.7%, and 19.9%, respectively.
Baseline characteristics were similar across both treatment arms. The median age of patients was 64 years (range, 20-85) and 65 years (range, 36-82) in the liposomal irinotecan/NALIRIFOX and nab-paclitaxel/gemcitabine arms, respectively. The majority of patients in both arms were male (53.3% and 59.4% for the experimental and control arms, respectively), White (82.2%) and (83.7%), and had an ECOG performance status of 1 (58.0% and 56.6%), at least 3 metastatic sites (38.9% and 36.4%), and liver metastases (80.2% and 80.4%).
The median time from metastatic diagnosis at study entry was 3.0 weeks (range, 0.6-9.1) for the liposomal irinotecan/NALIRIFOX group and 3.6 weeks (range, 0.4-10.9) for the nab-paclitaxel/gemcitabine group.
Additional data showed the patients in the liposomal irinotecan/NALIRIFOX arm achieved a median PFS of 7.4 months (95% CI, 6.0-7.7) compared with 7.4 months (95% CI, 5.3-5.8) for the nab-paclitaxel/gemcitabine arm (HR, 0.69; 95% CI, 0.58-0.83; P < .0001).
Liposomal irinotecan/NALIRIFOX elicited an ORR of 41.8% (95% CI, 36.8-46.9) vs 36.2% (95% CI, 31.4%-41.2%) for nab-paclitaxel gemcitabine. The complete response rate was 0.3% in both arms (TABLE1).
Among patients evaluable for safety, those treated with liposomal irinotecan/NALIRIFOX (n=370) had a median treatment duration of 24.29 weeks (range, 0.4-100.9) compared with 17.57 weeks (range, 0.7-81.7) for those in the nab-paclitaxel/gemcitabine arm (n=379).
Any-grade treatment-emergent AEs (TEAEs) occurred in 99.7% and 99.2% of patients in the experimental and control arms, respectively, and 95.1% and 92.9% had any-grade TEAEs related to the treatment regimen.
Serious TEAEs occurred in 54.3% of patients who received liposomal irinotecan/NALIRIFOX, and 26.5% experienced a serious TEAE related to treatment.
“When one looks at the nuances in the patients and the toxicity profiles, we can see these regimens have very different toxicity profiles," Wainberg said.
The most common hematologic TEAEs in the experimental and control arms, respectively, included neutropenia (any grade, 29.5% vs 31.9%; grade 3/4, 14.1% vs 24.5%), decreased neutrophil count (any grade, 20.5% vs 18.7%; grade 3/4, 9.7% vs 13.5%), and febrile neutropenia (any grade, 2.4% vs 2.6%; grade 3/4, 2.4% vs 2.4%.)
In a discussion of the presentation, Laura Goff, MD, MSCI, an associate professor of medicine, and executive medical director for the Cancer Patient Care Center at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, referenced the phase SWOG S1505 trial (NCT02562716) that evaluated (m)FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin) vs nab-paclitaxel/gemcitabine in patients with resectable PDAC. She noted that the resectable setting is clinically different from the metastatic setting, and although the randomized SWOG S1505 study was not designed as a head-to-head trial, the similar outcomes between the arms led to the belief that there was not a difference between the regimens of the 2 trials.
“I would argue that [the data from] this randomized trial of NAPOLI 3 should supersede our opinion about the efficacy of these regimens mFOLFIRINOX and nabpaclitaxel/gemcitabine] in the metastatic setting," Goff said.
Goff also pointed to safety findings observed with both liposomal irinotecan/ NALIRIFOX and nab-paclitaxel/gemcitabine during NAPOLI 3.
“High rates of toxicity were seen in both arms, despite the reputation [of] gemcitabine/nab-paclitaxel [being] a significantly easier regimen to tolerate. I would argue that the data do not necessarily support that," Goff said.