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First-line liposomal irinotecan plus 5-FU and oxaliplatin has promising antitumor activity in patients with previously untreated pancreatic ductal adenocarcinoma

A primary analysis of a phase I/II trial evaluating a combination of liposomal irinotecan with 5-fluorouracil/leucovorin (5-FU) and oxaliplatin (NALIRIFOX) as a first-line treatment option for patients with pancreatic ductal adenocarcinoma indicates that this regimen is well tolerated and comes with substantial antitumor activity. In fact, with this regimen a median progression-free survival (PFS) of 9.2 months was obtained with a median overall survival (OS) of 12.6 months, which represents a promising finding in this poor-prognosis setting.


Patients with pancreatic ductal adenocarcinoma (PDAC) typically present with metastatic disease and face a poor prognosis. As such, these patients urgently need novel therapies that are able to prolong their survival with a minimal impact on their quality of life. To date, non-liposomal irinotecan is an established component of the FOLFIRINOX combination, one of the approved first-line treatment options for metastatic PDAC (mPDAC). Unfortunately, non-liposomal irinotecan has a complex and rapid metabolism, a short half-life and dose-limiting toxicity. Liposomal irinotecan may overcome some of these disadvantages as 95% of irinotecan remains contained within the liposome during circulation and the active metabolite persists for a longer time within the tumour.

At the 2020 ESMO World Congress on Gastrointestinal Cancer, Prof. Wainberg presented the primary analysis of a phase 1/2 study that assessed liposomal irinotecan in combination with 5-FU and oxaliplatin (NALIRIFOX) in treatment-naïve patients with locally advanced or mPDAC. In the dose exploration part of the study (1A), a safety run-in with 31 patients was performed to identify an appropriate dose for NALIRIFOX in the dose-expansion part (1B).  Finally, the ‘pooled 50/60 population’ included 32 patients (N= 7 from the dose exploration and N= 25 from the dose expansion cohorts) who all received liposomal irinotecan 50 mg/m2 (free base), 5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2 and oxaliplatin 60 mg/m2. All patients were at least 18 years old, had histologically or cytological confirmed PDAC with unresectable, locally advanced or metastatic disease, adequate hematologic parameters and liver function and an ECOG performance status of 0 or 1.  Mean age of the study participants was 58 years with 44% being male and 88% with tumour stage IV at diagnosis.


As mentioned before, the ‘50/60 population’ was ultimately selected for further expansion, not only because of its low rate of dose-limiting toxicities, which included one case of febrile neutropenia, but also for less cumulative adverse events and less hospitalisations as compared to the other cohorts. In the final pooled population (N= 32), there were ten patients with neutropenia, including four with febrile neutropenia. In addition, the standard toxicity profile that one could expect from a modified FOLFIRINOX regimen, was observed with this protocol. Kaplan-Meier estimates for PFS and OS indicate a median of 9.2 months and 12.6 months, respectively. One patient had a complete response to NALIRIFOX while ten other patients experienced a partial response, adding up to an overall response rate (ORR) of 34.4%. At week 16, a disease control rate of 71.9% was reported. The median duration of the response among the eleven responders, was 9.4 months.


Results from this phase 1/2 study suggest that NALIRIFOX is tolerable for patients with previously untreated locally advanced or metastatic pancreatic ductal adenocarcinoma. No new safety signals were identified and antitumour activity was promising. Nevertheless, the observed antitumour activity warrants further investigation and efficacy of this regimen will therefore be the primary objective of the ongoing phase III NAPOLI-3 study in adults with previously untreated mPDAC.


Wainberg ZA, Bekali-Saab T, Boland PM, et al. First-line liposomal irinotecan + 5-fluorouracel/leucovorin + oxaliplatin in patients with pancreatic ductal adenocarcinoma: long-term follow-up results from a phase 1/2 study. Presented at ESMO World GI 2020; Abstract LBA1.

Spreker Zev Wainberg

Sylvie Lorenzen

Zev A. Wainberg, MD, University of California Los Angeles, Los Angeles, CA, USA


Zie: Keyslides

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