FDA Grants Liposomal Irinotecan Fast Track Status for Frontline Metastatic Pancreatic Cancer

The FDA has granted a fast track designation to liposomal irinotecan for use in combination with 5-fluorouracil/leucovorin and oxaliplatin as a treatment for patients with previously untreated, unresectable, locally advanced or metastatic pancreatic ductal adenocarcinoma.

The FDA has granted a fast track designation to liposomal irinotecan (Onivyde) for use in combination with 5-fluorouracil (5-FU)/leucovorin and oxaliplatin as a treatment for patients with previously untreated, unresectable, locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).1

Data with the regimen, which is known as NALIRIFOX, is slated to be virtually presented as part of a final analysis from a multicenter, open-label, phase 1/2 study (NCT02551991) at the 2020 ESMO World Congress on Gastrointestinal Cancer in July. In the trial, investigators assessed the safety, tolerability, and efficacy of NALIRIFOX in patients with previously untreated, metastatic, pancreatic adenocarcinoma.

Additionally, patient enrollment has also been initiated on the international, phase 3 NAPOLI-3 study (NCT04083235), which is evaluating the efficacy and safety of NALIRIFOX compared with gemcitabine and nab-paclitaxel (Abraxane) as a first-line treatment for patients with metastatic pancreatic cancer, according to Ipsen, the manufacturer of liposomal irinotecan.

“Since the initial approval of Onivyde in metastatic pancreatic cancer, we have continued to dedicate our research efforts to better understand the needs of pancreatic cancer patients. Through ongoing clinical investigations and exploratory real-world analyses, we have sought to determine whether patients who receive active treatment early have an improvement in survival,” Howard Mayer, MD, executive vice president, head of Research and Development at Ipsen, the manufacturer of liposomal irinotecan, stated in a press release. “As we continue to enroll additional patients in the ongoing phase 3 NAPOLI-3 clinical study, we look forward to working closely with the FDA to potentially bring Onivyde to more pancreatic cancer patients earlier in the disease.”

To be eligible for enrollment on the phase 1/2 study, investigators had to have histologically or cytologically confirmed pancreatic adenocarcinoma that had not been previously treated in the metastatic setting; had unresectable, locally advanced or metastatic disease; at least 1 measurable tumor lesion; an ECOG performance status of 0 or 1; adequate hematological, hepatic, renal, and cardiac function; and a Karnofsky performance status of at least 70 at screening.

Those who had prior adjuvant chemotherapy, uncontrolled central nervous system metastases, a clinically significant gastrointestinal disorder, a history of a second malignancy in the last 3 years, any contradictions for NALIRIFOX, and who had neuroendocrine or acinar pancreatic carcinoma were excluded from enrollment.

Part 1a of the trial was designed as a safety run-in as initial dose exploration, while part 1b was dose expansion of NALIRIFOX. The expected enrollment was 56 patients.

Primary endpoints include safety and dose-limiting toxicities; secondary outcome measures include pharmacokinetics, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and additional safety assessments.

The liposomal irinotecan regimen is currently approved by the FDA, as well by the European Commission, for the treatment of patients with metastatic pancreatic adenocarcinoma following disease progression on gemcitabine-based therapy.

The October 2015 approval was based on findings from the phase 3 NAPOLI-1 trial, which demonstrated a 1.9-month improvement in OS with NALIRIFOX versus leucovorin. In the combination arm, the median OS was 6.1 months compared with 4.2 months with 5-FU/leucovorin alone (HR, 0.57; 95% CI, 0.41-0.80; P = .0009).2

Additionally, the median progression-free survival was 3.1 months for the NALIRIFOX combination versus 1.5 months with the control arm (HR, 0.56; 95% CI, 0.41-0.75; P = .0001). At 12 weeks, 57% of patients treated with the combination were alive and progression-free compared with 26% with 5-FU and leucovorin alone.

Longer-time follow-up of NAPOLI-1 showed that NALIRIFOX maintained the OS benefit over leucovorin alone at 6.2 months and 4.2 months, respectively (HR, 0.75; 95% CI, 0.57-0.99).3 The median PFS, ORR, and DCR also favored the NALIRIFOX arm.

Fast track designations facilitate the development and expedites the review of drugs that treat patients with serious conditions and have the potential to address an unmet medical need.


  1. Ipsen receives FDA Fast Track designation for liposomal irinotecan (ONIVYDE®) as a first-line combination treatment for metastatic pancreatic cancer [news release]: Paris, France. Ipsen. Published June 17, 2020. Accessed June 17, 2020. https://bit.ly/2BkyKbG.
  2. Chen L-T, Von Hoff DD, Li C-P, et al. Expanded analyses of NAPOLI-1: phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. J Clin Oncol. 2015;33(suppl 3; abstr 234). doi:10.1200/jco.2015.33.3_suppl.234
  3. Wang-Gillam A, Hubner RA, Siveke JT, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78-87. doi: 10.1016/j.ejca.2018.12.007