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. 2024 Jan 2;7(1):e2350756.
doi: 10.1001/jamanetworkopen.2023.50756.

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis

Federico Nichetti  1   2 , Simone Rota  1 , Paolo Ambrosini  1 , Chiara Pircher  1 , Eleonora Gusmaroli  1 , Michele Droz Dit Busset  3 , Sara Pusceddu  1 , Carlo Sposito  3   4 , Jorgelina Coppa  3 , Federica Morano  1 , Filippo Pietrantonio  1 , Maria Di Bartolomeo  1 , Luigi Mariani  5 , Vincenzo Mazzaferro  3   4 , Filippo de Braud  1   4 , Monica Niger  1
Affiliations

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis

Federico Nichetti et al. JAMA Netw Open. .

Abstract

Importance: The NAPOLI 3 trial showed the superiority of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) over the combination of gemcitabine and nab-paclitaxel (GEM-NABP) as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Analyses comparing NALIRIFOX and GEM-NABP with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) have not yet been reported.

Objective: To derive survival, response, and toxic effects data from phase 3 clinical trials and compare NALIRIFOX, FOLFIRINOX, and GEM-NABP.

Data sources: After a systematic search of PubMed, Scopus, Embase, and American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, Kaplan-Meier curves were extracted from phase 3 clinical trials conducted from January 1, 2011, until September 12, 2023.

Study selection: Phase 3 clinical trials that tested NALIRIFOX, FOLFIRINOX, or GEM-NABP as first-line treatment of metastatic PDAC and reported overall survival (OS) and progression-free survival (PFS) curves were selected. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses of Individual Participant Data reporting guidelines.

Data extraction and synthesis: Individual patient OS and PFS data were extracted from Kaplan-Meier plots of original trials via a graphic reconstructive algorithm. Overall response rates (ORRs) and grade 3 or higher toxic effects rates were also collected. A pooled analysis was conducted, and results were validated via a network meta-analysis.

Main outcomes and measures: The primary end point was OS. Secondary outcomes included PFS, ORR, and toxic effects rates.

Results: A total of 7 trials with data on 2581 patients were analyzed, including 383 patients treated with NALIRIFOX, 433 patients treated with FOLFIRINOX, and 1756 patients treated with GEM-NABP. Median PFS was longer in patients treated with NALIRIFOX (7.4 [95% CI, 6.1-7.7] months) or FOLFIRINOX (7.3 [95% CI, 6.5-7.9] months; [HR], 1.21 [95% CI, 0.86-1.70]; P = .28) compared with patients treated with GEM-NABP (5.7 [95% CI, 5.6-6.1] months; HR vs NALIRIFOX, 1.45 [95% CI, 1.22-1.73]; P < .001). Similarly, GEM-NABP was associated with poorer OS (10.4 [95% CI, 9.8-10.8]; months) compared with NALIRIFOX (HR, 1.18 [95% CI, 1.00-1.39]; P = .05], while no difference was observed between FOLFIRINOX (11.7 [95% CI, 10.4-13.0] months) and NALIRIFOX (11.1 [95% CI, 10.1-12.3] months; HR, 1.06 [95% CI, 0.81-1.39]; P = .65). There were no statistically significant differences in ORR among NALIRIFOX (41.8%), FOLFIRINOX (31.6%), and GEM-NABP (35.0%). NALIRIFOX was associated with lower incidence of grade 3 or higher hematological toxic effects (eg, platelet count decreased 1.6% vs 11.8% with FOLFIRINOX and 10.8% with GEM-NABP), but higher rates of severe diarrhea compared with GEM-NABP (20.3% vs 15.7%).

Conclusions and relevance: In this systematic review and meta-analysis, NALIRIFOX and FOLFIRINOX were associated with similar PFS and OS as first-line treatment of advanced PDAC, although NALIRIFOX was associated with a different toxicity profile. Careful patient selection, financial toxic effects consideration, and direct comparison between FOLFIRINOX and NALIRIFOX are warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Pusceddu reported receiving personal fees from Novartis, Merck Serono, and Advanced Accelerator Applications and grants from Ipsen and Pfizer outside the submitted work. Dr Morano reported receiving personal fees from Pierre Fabre, Servier, and Lilly and grants from Incyte outside the submitted work. Dr Pietrantonio reported receiving grants from Amgen, Agenus, AstraZeneca, BMS, Incyte, and Lilly and personal fees from Bristol Myers Squibb, MSD, Amgen, Merck Serono, Servier, Bayer, Takeda, Pierre Fabre, Johnson and Johnson, Astellas, GSK, and Ipsen outside the submitted work. Dr Mazzaferro reported serving on an advisory board for Roche Pharma outside the submitted work. Dr de Braud reported receiving personal fees from Bristol Myers Squibb, Roche, Merck, Bayer, Ignyta, Dephaforum, Biotechespert, Prime Oncology, Pfizer, Nadirex, Ambrosetti, Incyte, Motore Sanità, Fare Comunicazione, Itanet, European School of Oncology, Accmed, Idea-z, Dynamicom Education, Pierre Fabre, Mattioli 1885, MCCann Health, MSD, IQVIA, Celgene, Amgen, and Sanofi; grants from Novartis, Roche, Bristol Myers Squibb, Celgene, Incyte, Nerviano Medical Sciences, Merck, Darmstadt, Kymab, Pfizer, Tesaro, and Kenilworth; serving on advisory boards for Tiziana Life Sciences, Bristol Myers Squibb, Celgene, Novartis, Servier, Pharm Research Associated, Daiichi Sankyo, Ignyta, Amgen, Pfizer, Octimet Oncology, Incyte, Pierre Fabre, Eli Lilly, Roche, AstraZeneca, Gentili, Dephaforum, Merck, Kenilworth, Bayer, Fondazione Menarini, Sanofi, Taiho; serving as principal investigator for studies by Novartis Farma, AstraZeneca, F. Hoffmann-La Roche, Bristol Myers Squibb, AnHeart Therapeutics, and Apollomics outside the submitted work. Dr Niger reported receiving personal fees from AstraZeneca, Incyte, Accademia della Medicina, Sandoz, Medpoint, Servier, EMD Serono, Basilea Pharmaceutica, MSD Italia, and Taiho outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Selection Flowchart
ASCO indicates American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; FOLFIRINOX, irinotecan, oxaliplatin, folinic acid, and fluoruracil; GEM-NABP, gemcitabine and nab-paclitaxel; NALIRIFOX, liposomal irinotecan, oxaliplatin, folinic acid, and fluoruracil.
Figure 2.
Figure 2.. Reconstructed Kaplan-Meier Plots for Progression-Free Survival and Overall Survival According to First-Line Regimen
FOLFIRINOX indicates irinotecan, oxaliplatin, folinic acid, and fluoruracil; GEM-NABP, gemcitabine and nab-paclitaxel; NALIRIFOX, liposomal irinotecan, oxaliplatin, folinic acid, and fluoruracil. Dotted lines indicate median survival.
Figure 3.
Figure 3.. Reporting Incidence of Grade 3 or Higher Toxic Effects According to the Pooled Treatment Regimens
P values of adjusted logistic regression models are plotted for each comparison. FOLFIRINOX indicates irinotecan, oxaliplatin, folinic acid, and fluoruracil; GEM-NABP, gemcitabine and nab-paclitaxel; NALIRIFOX, liposomal irinotecan, oxaliplatin, folinic acid, and fluoruracil. aEquivalent terms reported separately in original reports were pooled before the analysis, including neutrophil count decreased and neutropenia, peripheral neuropathy and peripheral sensory neuropathy, and fatigue and asthenia. bThe following toxic effects were not detailed in all trials: platelet count decreased and fatigue rates were not available in CanStem111P trial results; diarrhea rates were not available in HALO trial results; peripheral neuropathy rates were not available in CanStem111P, HALO, and AVENGER500 trial results; vomit rates were not available in CanStem111P, MPACT, HALO, and AVENGER500 trial results.
See this image and copyright information in PMC

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