In a randomised, open-label, phase III NAPOLI 3 study, the NALIRIFOX regimen demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) compared with nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma who had not previously received treatment in the metastatic setting. The observed improvements in OS and PFS were generally consistent regardless of baseline ECOG performance status (0 or 1), region (North America or the rest of the world), or presence of liver metastasis based on prespecified subgroup analyses.
Before NAPOLI 3, the last study to meet the primary endpoint of OS in patients with metastatic pancreatic ductal adenocarcinoma was the MPACT in 2013, which led to the approval of first-line nab-paclitaxel plus gemcitabine. The findings from NAPOLI 3 study are published by Prof. Zev A Wainberg of the David Geffen School of Medicine, University of California Los Angeles in Los Angeles, CA, US, and colleagues on 11 September 2023 in The Lancet.
The authors wrote in the background that in the past decade, two combination chemotherapy regimens, a quadruplet of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and a doublet, nab-paclitaxel plus gemcitabine, have emerged as first-line standard of care. However, these regimens have never been compared directly. Except for microsatellite instability-high pancreatic cancer, immune checkpoint inhibitors have demonstrated only partial benefits and relatively few patients are eligible to receive molecularly targeted agents.
Encapsulation allows irinotecan to remain in circulation for longer than unencapsulated (free) irinotecan before conversion to SN-38. At equivalent doses, liposomal irinotecan demonstrates higher and sustained intratumoural levels of irinotecan and SN-38 relative to free irinotecan.
In the phase III NAPOLI 1 study, liposomal irinotecan in combination with fluorouracil and leucovorin significantly prolonged OS versus fluorouracil and leucovorin in patients with metastatic pancreatic ductal adenocarcinoma whose disease had progressed following gemcitabine-based therapy. A phase I/II study demonstrated promising antitumour activity with liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin (NALIRIFOX) in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma. Median PFS was 9.2 months and OS was 12.6 months.
Building on these findings, the phase III NAPOLI 3 study aimed to compare NALIRIFOX with nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma not previously treated in the metastatic setting. It was a randomised, open-label, phase III study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with metastatic pancreatic ductal adenocarcinoma and ECOG performance status score 0 or 1 were randomly assigned 1:1 to receive NALIRIFOX or nab-paclitaxel plus gemcitabine. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system.
The primary endpoint was OS in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. Between 19 February 2020 and 17 August 2021, 770 patients were randomly assigned, 383 to NALIRIFOX and 387 to nab-paclitaxel plus gemcitabine with a median follow-up 16.1 months. Median OS was 11.1 months (95% confidence interval [CI] 10.0–12.1) with NALIRIFOX versus 9.2 months (95% CI 8.3-10.6) with nab-paclitaxel plus gemcitabine (hazard ratio 0.83, 95% CI 0.70-0.99; p = 0.036).
Grade 3 or higher treatment-emergent adverse events occurred in 322 of 370 patients (87%) receiving NALIRIFOX and 326 of 379 patients (86%) receiving nab-paclitaxel plus gemcitabine. Treatment-related deaths occurred in 6 patients (2%) in the NALIRIFOX group and 8 patients (2%) in the nab-paclitaxel plus gemcitabine group.
The safety profile of NALIRIFOX could be related to several factors. One possibility is the use of lower doses of oxaliplatin, which help to reduce toxicities such as in cumulative peripheral neuropathy. Additional factors that include the use of the liposomal formulation of irinotecan, which was designed to maximise tumour exposure while minimising systemic toxicity, might also play a role.
The authors commented that the cost of treatment and its impact on health-related quality of life are important factors in treatment decision making. Future research will be conducted to evaluate cost implications, and analyses of patient-reported quality of life outcomes from NAPOLI 3 are ongoing. Furthermore, ongoing genomic profiling evaluations on tissue and serum collected in the NAPOLI 3 study might answer additional questions that could inform patient selection, such as whether patients with BRCA-mutated pancreatic cancer could have benefited from platinum exposure in the NALIRIFOX group.
In an accompanied comment, Drs. Marc G Besselink and Johanna W Wilmink of the Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam in Amsterdam, Netherlands wrote that NAPOLI 3 is clearly a pivotal study as it presents the first major development for patients with metastatic pancreatic ductal adenocarcinoma in more than a decade. However, several issues should be addressed when assessing the NAPOLI 3 findings. First, does the 1.9-month benefit in OS hold clinical relevance? The ASCO Cancer Research Committee determined that a 3–4-month improvement would be clinically meaningful. The ESMO Magnitude of Clinical Benefit Scale identified a minimum 3-month benefit in OS. WHO states a 4–6-month threshold for benefit in OS without detriment to quality of life. These requirements were not met in NAPOLI-3.
The NAPOLI 3 has confirmed the superiority of quadruplet chemotherapy over the doublet nab-paclitaxel plus gemcitabine, but the commentators questioned how the efficacy and safety profiles compare between NALIRIFOX and FOLFIRINOX regimens which both reported an OS of 11.1 months in patients with treatment-naïve metastatic pancreatic ductal adenocarcinoma. The safety profiles are comparable, although less neutropenia was reported with NALIRIFOX than FOLFIRINOX. However, in clinical practice most patients receive modified FOLFIRINOX (mFOLFIRINOX) that includes a dose reduction aiming to improve tolerability without compromising efficacy, which could be seen as the current reference standard. A 2018 systematic review of mFOLFIRINOX reported a neutropenia rate of 23%, and a 1-year OS rate of 47.6%, both highly like NALIRIFOX.
When compared with mFOLFIRINOX, NALIRIFOX is probably not cost-effective, although a formal cost analysis is not available yet. In the US setting, the cost of liposomal irinotecan (50 mg/m2) is 2852 USD for 43 mg. In an average patient with a body surface area of 1.7m2, costs would amount to 5638 USD, whereas the costs of regular irinotecan (180 mg/m2) in FOLFIRINOX would amount to 84 USD, a 67 times price differential. In the European setting, the costs of NALIRIFOX are more than 25 times higher than FOLFIRINOX. This difference in cost is mainly driven by the availability of several low-cost generic irinotecan products.
The commentators concluded that NAPOLI 3 demonstrated the superiority in OS of NALIRIFOX over nab-paclitaxel plus gemcitabine in patients with treatment-naïve metastatic pancreatic ductal adenocarcinoma. However, data are lacking to suggest superiority of NALIRIFOX over mFOLFIRINOX in this setting. Data on quality of life and costs are needed before a final comparison with nab-paclitaxel plus gemcitabine can be made.
The study was funded by Ipsen.
