Frontline NALIRIFOX Regimen Demonstrates Promising Activity in Advanced PDAC

Long-term follow-up results from the study were presented in a poster at the virtual 2020 European Society of Medical Oncology World Congress on Gastrointestinal Cancer meeting.

Promising disease control and survival was achieved with the use of liposomal irinotecan (Onivyde) in combination with fluorouracil (5-FU), leucovorin, and oxaliplatin (NALIRIFOX) as a frontline treatment for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), according to the results of a phase 1/2 trial.

Long-term follow-up results from the study were presented in a poster at the virtual 2020 European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer meeting.1

“Pancreatic cancer is aggressive, and we continue to investigate opportunities to improve outcomes for more patients that can extend survival. Unfortunately, current treatments, including immunotherapies that are transforming outcomes for patients with other solid tumors, have not demonstrated similar success in pancreatic cancer,” said lead investigator Zev Wainberg, MD, associate professor of medicine, University of California Los Angeles, in a statement.2 “The initial median progression-free and overall survival data from our phase 1/2 trial are promising and we look forward to seeing how this investigational first-line treatment compares to gemcitabine + nab-paclitaxel in the phase 3 trial now underway.”

The phase 1/2 trial was an open-label, dose-exploration, and dose-expansion study exploring the safety, tolerability, and efficacy of the frontline NALIRIFOX regimen in patients with locally advanced or metastatic PDAC (NCT02551991). Patients had been diagnosed at least 6 weeks before screening and were not previously treated in the metastatic setting, they also had to have an ECOG performance status of 0 or 1, adequate organ function, and a Karnofskyperformance status score of at least 70 for the dose-expansion phase.

In the dose-exploration phase, patients were treated in 1 of 4 cohorts with varying doses of liposomal irinotecan and oxaliplatin: 70 mg/m2 of liposomal irinotecan and 60 mg/m2 of oxaliplatin (cohort A); 50 mg/m2 and 60 mg/m2, respectively (cohort B); 50 mg/m2 and 85 mg/m2 (cohort C); and 55 mg/m2 and 70 mg/m2 (cohort D). In each cohort patients received treatment on days 1 and 15 of each 28-day cycle plus 2400 mg/m2 of 5-FU and 400 mg/m2 of leucovorin.

The primary end point was safety in terms of treatment-emergent adverse events (TEAEs) and dose-limiting toxicities. The primary efficacy end point was progression-free survival (PFS). Secondary end points included overall survival (OS), best overall response, overall response rate (ORR), disease control rate (DCR) at week 16, and duration of response (DOR).

The presentation focused on the pooled population of patients who were treated with 50 mg/m2 of liposomal irinotecan and 60 mg/m2 of oxaliplatin between the dose-exploration and -expansion phases, as cohort B was selected for expansion (n = 32).1

In this pooled population, the median age was 58 years (range, 39-76), and the majority of patients were female (56.2%), white (87.5%), had stage IV disease at diagnosis (87.5%), and had a performance status of 1 (56.3%).

The median PFS was 9.2 months (95% CI, 7.69-11.96), and the median OS was 12.6 months (95% CI, 8.74-18.69). ORR was 34.4% (95% CI, 18.6%-53.2%), consisting of 1 complete response and 10 partial responses. An additional 15 patients had stable disease, resulting in a DCR of 71.9% (95% CI, 53.3%-86.3%) at week 16. The median DOR was 9.4 months (95% CI, 3.52-not estimable).

Investigators also looked to survival according to subtype and of 9 patients with evaluable subtype and tumor response data, 8 had classical subtype and 1 had basal-like subtype. The PFS in the classical group ranged from 7.7 months to 17.8 months and the PFS for the 1 patient with basal-like subtype was 9.6 months.

Dose-limiting toxicities were observed in 2 patients in cohort A, due to neutropenia infection and neutropenia sepsis, 1 case of febrile neutropenia in cohort B, and in cohort C, 2 patients experienced diarrhea, vomiting, anal fissure, anal inflammation, and/or proctalgia. No dose-limiting toxicities were observed in cohort 4.

TEAEs were observed in all patients in the pooled population and grade ≥3 events were seen in 68.8% of patients, with the most common being neutropenia (31.3%), febrile neutropenia (12.5%), and hypokalemia (12.5%). No cases of grade ≥3 peripheral sensory neuropathy or fatigue were observed in the pooled population but were observed in cohort C and A, respectively.

Serious treatment-related TEAEs were observed in 31.3%, which was most frequently due to febrile neutropenia and nausea.

TEAEs led to death in 3 patients—due to malignant gastrointestinal obstruction, upper gastrointestinal hemorrhage, and disease progression—but were not considered treatment related.

These positive findings led to the initiation of an international, open-label, randomized phase 3 trial (NAPOLI-3; NCT04083235) exploring the use of frontline NALIRIFOX compared with gemcitabine and nab-paclitaxel (Abraxane) in patients with metastatic PDAC.2

The phase 3 trial is looking to enroll about 750 patients with previously untreated metastatic adenocarcinoma of the pancreas, an ECOG performance status of 0 or 1, and adequate organ function and biological parameters. OS is the primary end point and PFS and ORR are the secondary end points.

In June 2020, the FDA granted a fast track designation to the NALIRIFOX regimen for the frontline treatment of patients with unresectable, advanced PDAC.3 The combination of liposomal irinotecan and 5-FU/leucovorin are also FDA approved for the treatment of patients with PDAC after disease progression following gemcitabine-based treatment. 


1. Wainberg ZA, Bekaii-Saab T, Boland PM, et al. First-line liposomal irinotecan 5 fluorouracil/leucovorin oxaliplatin in patients with pancreatic ductal adenocarcinoma: Primary analysis from a phase 1/2 study. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 1-4, 2020. Abstract LBA-001.

2. Ipsen presents Phase I/II clinical data evaluating liposomal irinotecan (Onivyde®) as an investigational first-line combination treatment for metastatic pancreatic cancer at the ESMO World Congress on Gastrointestinal Cancer. News release. Ipsen. July 1, 2020. Accessed July 2, 2020.

3. Ipsen Receives FDA Fast Track Designation for Liposomal Irinotecan (ONIVYDE®) as a First-Line Combination Treatment for Metastatic Pancreatic Cancer. News release. Ipsen. June 17, 2020. Accessed July 2, 2020.