In the phase III NAPOLI-3 trial in previously untreated patients with metastatic pancreatic cancer, the ­NALIRIFOX regimen significantly improved overall survival and progression-free survival over nab-paclitaxel plus gemcitabine.¹ NALIRIFOX, which contains liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin, could become a new reference standard in this setting.

At the median follow-up of 16.1 months, NAPOLI-3 met its primary endpoint, demonstrating a statistically significant improvement in overall survival with NALIRIFOX. Median overall survival was 11.1 months with the NALIRIFOX regimen compared with 9.2 months with nab-paclitaxel and gemcitabine (hazard ratio [HR] = 0.83; P = .04). Progression-free survival and objective response rates were also improved, although the improvement in response rate did not reach statistical significance, according to Zev A. Wainberg, MD, Professor of Medicine at UCLA and Co-Director of the UCLA GI Oncology Program, who presented the findings at the 2023 ASCO GI Cancers Symposium.

Zev A. Wainberg, MD

“For the first time, a clinical study in the first-line setting for metastatic pancreatic ductal adenocarcinoma demonstrated superior overall survival and progression-free survival for an investigational regimen when compared to standard-of-care treatment with nab-paclitaxel and gemcitabine” said Dr. Wainberg. “These results support the NALIRIFOX regimen as a new reference regimen for the first-line treatment of patients with metastatic pancreatic ductal carcinoma.”

Liposomal irinotecan is an investigational, long-circulating topoisomerase inhibitor that has been approved, in combination with fluorouracil and leucovorin, in patients with metastatic pancreatic adenocarcinoma who have disease progression after gemcitabine-based therapy. Previous early-phase studies showed its benefit in the first-line setting when oxaliplatin was added to the regimen, and this approach was further evaluated in the open-label randomized NAPOLI-3 trial of 770 patients with previously untreated metastatic pancreatic ductal adenocarcinoma.

Approximately 80% of patients in both arms had liver metastases; 31% were enrolled in North America, approximately 3% in Southeast Asia, and 66% from Eastern and Western Europe, South America, and Australia. The primary tumor location was the head of the pancreas in approximately 40%, and 83% of patients had elevated CA 19-9 at baseline.

Patients were randomly assigned to receive the NALIRIFOX regimen or nab-paclitaxel plus gemcitabine. The NALIRIFOX regimen consisted of liposomal irinotecan at 50 mg/m² combined with fluorouracil (infusion) at 2,400 mg/m², leucovorin at 400 mg/m², and oxaliplatin at 60 mg/m² on days 1 and 15 of a 28-day cycle. The control regimen was standard nab-paclitaxel at 125 mg/m² and gemcitabine at 1,000 mg/m² on days 1, 8, and 15 of a 28-day cycle.

Additional Endpoints Met

“Beginning at about 3 months, the overall survival curves separated slightly and stayed slightly separated for the duration…. The subgroup analyses generally favored NALIRIFOX over gemcitabine and nab-paclitaxel…. The overall survival and progression-free survival benefits with NALIRIFOX vs nab-paclitaxel/gemcitabine were generally consistent regardless of performance status, region, or presence of liver metastases,” Dr. Wainberg said.

In addition to the significant improvement in overall survival, patients treated with NALIRIFOX also had a statistically significant improvement in median progression-free survival, which was 7.4 months vs 5.6 months for nab-paclitaxel/gemcitabine (HR = 0.69; P < .0001). Objective response rates were also numerically higher with NALIRIFOX—41.8% vs 36.2%, respectively—and progressive disease as best response was documented for 9.9% vs 23.3%, respectively, he reported.

Subsequent anticancer therapy was received by 50.5% of the experimental arm and 54.4% of the control arm, with similar proportions treated with systemic agents, surgery, and radiotherapy.

No Safety Signals

“The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. There were no significant differences in the two arms with respect to treatment-emergent adverse events, grade ≥ 3 or all grades,” he said. Serious treatment-emergent adverse events or treatment-emergent adverse events attributed to death, caused by any of the components of the regimen, also affected similar proportions of patients, though as Dr. Wainberg pointed out, there are “nuanced” differences in the toxicity profiles of the regimens.

The most common grade 3 or 4 treatment-emergent adverse events for NALIRIFOX vs nab-paclitaxel/gemcitabine were diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%), and neutropenia (14.1% vs 24.5%). Peripheral neuropathy appeared to be less prevalent with ­NALIRIFOX (3.2% vs 5.8%), he added.

Other Thoughts and Considerations

During the discussion period, Dr, Wainberg was questioned about the dosages used for the NALIRIFOX regimen—in particular, the 60 mg/m² dose of oxaliplatin. He said the dosing was determined from the phase I dose-escalation study that found higher doses to be associated with toxicity, “some meeting the criteria for dose-limiting toxicity and essentially making the regimen nontolerable…. More practically speaking, we were satisfied with the efficacy seen with the 60 mg/m² dose in the small feasibility study.”

He was also asked how he would place NALIRIFOX in context with the more traditionally used FOLFIRINOX (leucovorin, fluorouracil, [nonliposomal] irinotecan, oxaliplatin). “Obviously, that’s a good question, and the truth is, we haven’t done the head-to-head study of FOLFIRINOX vs gemcitabine/nab-paclitaxel…. I will say that the NALIRIFOX and FOLFIRINOX regimens have slightly different toxicity profiles. I think with NALIRIFOX, we are seeing a little less neuropathy than we associate with traditional FOLFIRINOX,” he said. 

DISCLOSURE: Dr. Wainberg has served as a consultant or advisor to Amgen, Arcus Biosciences, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Daiichi Sankyo/AstraZeneca, Ipsen, Lilly, Merck KGaA, Novartis, Pfizer, PureTech, QED Therapeutics, and Seattle Genetics; has received institutional research funding from Five Prime Therapeutics, Merck, Novartis, Pfizer, and Plexxikon; and has received reimbursement for travel, accommodations, and other expenses from Bayer, Lilly, and Merck.

REFERENCE

1. Wainberg ZA, Melisi D, Macarulla T, et al: NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma. 2023 ASCO GI Cancers Symposium. Abstract LBA661. Presented January 20, 2023.