Frontline NALIRIFOX Regimen Shows Promising Activity, Tolerability in Pancreatic Cancer

The regimen of liposomal irinotecan plus 5-fluorouracil/leucovorin plus oxaliplatin demonstrated a tolerable safety profile with promising antitumor activity when used as frontline treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.

The regimen of liposomal irinotecan plus 5-fluorouracil (5-FU)/leucovorin plus oxaliplatin (NALIRIFOX) demonstrated a tolerable safety profile with promising antitumor activity when used as frontline treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), according to updated data from a phase 1/2 study presented during the 2020 ESMO World Congress on Gastrointestinal Cancer Virtual Meeting.1

Safety results showed that treatment-related, treatment-emergent adverse events (TEAEs) of grade 3 or higher reported in 68.8% of patients (n = 22), and the most commonly reported toxicities included neutropenia (31.3%), febrile neutropenia (12.5%), and hypokalemia (12.5%). Notably, no patients in the pooled population who received a 50 mg/m2 and 60 mg/m2 dose of the regimen experienced treatment-related grade 3 or higher peripheral neuropathy or fatigue. However, these events were reported in 1 patient in cohort C (50 mg/m2 and 85 mg/m2) and 1 patient in cohort A (70 mg/m2 and 60 mg/m2).

With regard to efficacy, the regimen led to a median progression-free survival (PFS) of 9.2 months (95% CI, 7.69-11.96) and an overall survival (OS) of 12.6 months (95% CI, 8.74-18.69). The overall response rate (ORR) with NALIRIFOX was 34.4% (95% CI, 18.6%-15.3%).

The best overall responses included a complete response in 1 patient (3.1%) who had locally advanced PDAC and stable disease in 15 patients (46.9%). Partial responses were reported in 10 patients (31.3%). The median duration of response (DOR) was 9.4 months (95% CI, 3.52–not estimable). Additionally, at week 16, the disease control rate (DCR) was 71.9% (95% CI, 53.3%-86.3%).

Although FOLFIRINOX (non-liposomal irinotecan plus 5-FU plus leucovorin plus oxaliplatin) has long been established as the standard frontline treatment for this patient population,2 non-liposomal irinotecan has a rapid metabolism, and thus, a short half-life; its associated toxicities have also proven to be dose-limiting.3

Investigators have hypothesized that liposomal irinotecan could potentially offer additional benefits over non-liposomal irinotecan. Previous research has shown that, in a preclinical setting, the active metabolite persisted in tumors for a longer duration following treatment with liposomal irinotecan compared with the non-liposomal formulation, of 168 hours versus <48 hours, respectively.4 Preclinical data also indicate that prolonged exposure could be more significant than high concentrations with regard to cytotoxic activity.5

To this end, Zev A. Wainberg, MD, assistant professor of medicine and co-director of the GI Oncology Program at UCLA, and colleagues, set out to examine the safety and efficacy of frontline NALIRIFOX in patients with locally advanced or metastatic PDAC.

The open-label, phase 1/2 (NCT02551991) was conducted in 2 phases: a dose exploration and a dose expansion. To be eligible enrollment, patients had to be aged ≥18 years with unresectable, locally advanced or metastatic PDAC and have been diagnosed ≤6 weeks prior to screening; they could not have received previous treatment in the metastatic setting. Additionally, patients had to have an ECOG performance status score of 0 to 1, a Karnofsky performance status score of ≥70 for the dose-expansion portion of the trial, and acceptable organ function in order to enroll.

In the dose exploration phase of the trial, patients were separated into 4 cohorts and received treatment on days 1 and 15 of each 28-day treatment cycle with 5-FU at 2400 mg/m2 and leucovorin mg/m2 in combination with liposomal irinotecan and oxaliplatin at the following doses, respectively: cohort A received 70 mg/m2 and 60 mg/m2, cohort B received 50 mg/m2 and 60 mg/m2, cohort C was given 50 mg/m2 and 85 mg/m2, and cohort D was given 55 mg/m2 and 70 mg/m2. Investigators identified the dose for the expansion phase of the trial based on dose-limiting toxicities and cumulative safety data collected from the dose exploration phase.

The primary end point of the trial is safety, specifically TEAEs and lose-limiting toxicities. Secondary end points include efficacy, namely PFS (a primary efficacy end point), OS, best overall response, ORR, DCR at week 16, and DOR. Investigators assessed disease using the RECIST v1.1 criteria at the time of screening, every 8 weeks thereafter, and at the end of the study. Assessments continued until radiologically progressive disease was identified. An exploratory objective of the trial was response data per tumor subtype, and this was assessed by conducting genomic profiling of archival samples.

A total of 31 patients were treated during the dose exploration phase of the trial, and the pooled population of patients was composed of 32 patients who received the 50 mg/m2 and 60 mg/m2 dose; of these 32 patients, 7 patients came from cohort B (50 mg/m2 and 60 mg/m2) in the dose-exploration phase of the trial and 25 came from the dose-expansion phase. At the time of the data cutoff, 1 patient was still receiving treatment.

The median age of participants in the pooled population was 58 years and just under half, or 43.8%, were men. The majority of the patients examined (87.5%) had metastatic disease at baseline and 56.3% had an ECOG performance status of 1. The pooled population received a mean duration of treatment of 223.4 days with liposomal irinotecan, 209.3 days with oxaliplatin, 225.5 days with 5-FU, and 223.4 days with leucovorin.

The tolerability assessment during the dose exploration portion of the trial revealed that the doses explored in cohorts A, C, and D were not tolerable. The reason cited for cohorts A and
C was that dose-limited toxicities occurred in >1 patient. In cohort D, the dose was not considered to be tolerable because of results from an assessment of cumulative safety data, including TEAEs of grade 3 or higher.

Additional safety results showed that 3 TEAEs resulted in death (1 each in cohorts B, C, D), but none of these events were determined to be related to the study treatment. Serious treatment-related TEAEs were experienced by 31.3% of patients (n = 10) in the pooled population, and the most commonly reported events were febrile neutropenia and nausea; these events were reported in 3 patients (9.4% each case).

Investigators also conducted genomic profiling, and tumor subtype and tumor-response data were available for a total of 9 patients; 8 had a classical subtype and 1 had the basal-like subtype of disease. The PFS values reported for the classical and basal-like subtypes were 7.7 months-17.8 months and 9.6 months, respectively.

“No new safety signals were observed with first-line NALIRIFOX in patients with locally advanced or metastatic PDAC, and antitumor activity was promising,” the investigators concluded.

In the ongoing phase 3 NAPOLI-3 trial (NCT04083235), investigators are comparing the NALIRIFOX regimen with gemcitabine plus nab-paclitaxel (Abraxane) in the frontline treatment of adult patients with metastatic PDAC.


  1. Wainberg Z, Bekaii-Saab T, Boland PM, et al. First-line liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin in patients with pancreatic ductal adenocarcinoma: long-term follow-up results from a phase 1/2 study. Presented at: 2020 ESMO World Congress on Gastrointestinal Cancer Virtual Meeting; July 1-4, 2020; Virtual. Poster LBA-001.
  2. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923
  3. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015;(suppl 5):v56-v68. doi:10.1093/annonc/mdv295
  4. Kalra AV, Kim J, Klinz SG, et al. Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. Cancer Res. 2014;74(23):7003-7013. doi:10.1158/0008-5472.CAN-14-0572
  5. Gerrits CJ, de Jonge MJ, Schellens JH, et al. Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development. Br J Cancer. 1997;76(7):952-962. doi:10.1038/bjc.1997.491