Nalirifox in the Treatment of Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC): A Comprehensive Review
DOI:
https://doi.org/10.52783/jns.v14.2383Keywords:
Nalirifox, metastatic pancreatic cancer, nanoliposomal irinotecan, chemotherapy, drug resistance, FOLFIRINOXAbstract
Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a highly aggressive malignancy with limited treatment options and poor survival rates. While standard chemotherapy regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel have improved clinical outcomes, their use is often restricted due to severe toxicities.
Objective: This review examines the therapeutic potential of Nalirifox, a novel combination of nanoliposomal irinotecan (nal-IRI), 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin, in the management of mPDAC.
Methods: A comprehensive evaluation of Nalirifox is provided, covering its pharmacological properties, clinical efficacy, safety profile, and comparative advantages over existing therapies. Additionally, mechanisms of resistance and potential strategies to optimize treatment outcomes are discussed.
Results: Clinical evidence suggests that Nalirifox offers a promising alternative to conventional regimens, demonstrating comparable or superior efficacy with a more favorable toxicity profile. This makes it a viable option for patients who may not tolerate more aggressive chemotherapy. However, challenges such as acquired resistance and tumor microenvironment factors necessitate further investigation.
Conclusion: Nalirifox represents a significant advancement in mPDAC treatment by balancing therapeutic efficacy with improved tolerability. Future research should focus on overcoming resistance mechanisms and exploring combination strategies to enhance patient outcomes.
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Ntukidem OL, Ogedegbe OJ, Bai S. Updated trends in incidence and mortality of pancreatic cancer: an analysis of the Surveillance, Epidemiology, and End Results (SEER) database. J Clin Oncol. 2025;43(4 Suppl):786. doi:10.1200/jco.2025.43.4_suppl.786
Banigallapati S. Current treatment methods in pancreatic cancer and the need for improvement. 2024. doi:10.20944/preprints202410.1569.v1
Jai M, Mozdziak P. Genetics and biology of pancreatic ductal adenocarcinoma. Med J Cell Biol. 2024;12(2):42-47. doi:10.2478/acb-2024-0006
Mukund A, Afridi MA, Karolak A, Park MA, Permuth JB, Rasool G. Pancreatic ductal adenocarcinoma (PDAC): a review of recent advancements enabled by artificial intelligence. Cancers. 2024;16(12):2240. doi:10.3390/cancers16122240
Colombo A, Porretto CM. Systemic therapy in metastatic pancreatic cancer: a review. Deleted J. 2024;4(6):1296-1303. doi:10.62225/2583049x.2024.4.6.3602
Nita G, Rebegea L, Grigorean VT, Coman IS, Coman VE, Pleşea IE, et al. Long-term survival in metastatic pancreatic adenocarcinoma of intestinal type. Stomatology. 2024;13(17):5034. doi:10.3390/jcm13175034
Yamaguchi H, Kato T, Narita Y, Honda M, Hamada K, Ishikawa Y, et al. Preliminary investigation of the efficacy and indications of proton beam therapy for stage IV pancreatic adenocarcinoma. Cureus. 2024. doi:10.7759/cureus.57771
Gupta K, Giurini EF, Ralph O, Pappas SG. Looking beyond checkpoint inhibitor monotherapy: uncovering new frontiers for pancreatic cancer immunotherapy. Mol Cancer Ther. 2024. doi:10.1158/1535-7163.mct-24-0311
Patel A, Laursen AA, Cockrum P, Liu Y, Surinach A, Rhodes W, et al. Effect of dose adjustments on overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX: a post hoc analysis of NAPOLI 3. J Clin Oncol. 2025;43(4 Suppl):716. doi:10.1200/jco.2025.43.4_suppl.716
Cockrum P, Chang R, Liu Y, Xu C, Duh MS, Kim GP. Overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line (1L) FOLFIRINOX (FFX): bridging the gap between the NAPOLI 3 trial and real-world practice. J Clin Oncol. 2025;43(4 Suppl):690. doi:10.1200/jco.2025.43.4_suppl.690
Tan CJ, Liu H, Farrokhi P, Garrido-Laguna I, Stenehjem DD. Cost-effectiveness of NALIRIFOX compared to other first-line treatments for metastatic pancreatic cancer. J Clin Oncol. 2025;43(4 Suppl):733. doi:10.1200/jco.2025.43.4_suppl.733
Winer A, Ioffe D, Ruth K, Ross EA, Bynum K, Mikkelsen E, et al. Redefining the use of a first-line FOLFIRINOX-like regimen in older patients with metastatic pancreatic cancer. J Clin Oncol. 2025;43(4 Suppl):681. doi:10.1200/jco.2025.43.4_suppl.681
George TJ, Rogers SC, Nassour I, Sahin I, Ramnaraign BH, Fabregas JC, et al. Results of a phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI study). J Clin Oncol. 2024. doi:10.1200/jco.2024.42.3_suppl.655
Gao J, Wang J, Guan C, Shi W, Dong Q, Sheng J, et al. Advances in drug therapy for metastatic pancreatic ductal adenocarcinoma. J Cancer. 2024;15:2214-2228. doi:10.7150/jca.89788
Huffman BM, Ellis H, Jordan AC, Freed-Pastor WA, Perez K, Rubinson DA, et al. Emerging role of targeted therapy in metastatic pancreatic adenocarcinoma. Cancers. 2022;14(24):6223. doi:10.3390/cancers14246223
Zhang DS, Liu F, Lu YX, Bai B, Zhang Y, Wang Z, et al. Preliminary results of a phase II study of surufatinib plus sintilimab, nab-paclitaxel, and gemcitabine (AG) as first-line therapy in patients (pts) with locally advanced or metastatic pancreatic adenocarcinoma (mPDAC). J Clin Oncol. 2024. doi:10.1200/jco.2024.42.3_suppl.659
Trieu V, Qazi S, Fein S, Maida AE, Joh T, Chang W. Abstract A012: meta-analysis comparing the incidence of serious adverse events, overall survival, and progression-free survival in pancreatic adenocarcinoma patients harboring unresectable tumors treated with modified FOLFIRINOX or FOLFIRINOX regimen. Cancer Res. 2024;84(17 Suppl 2):A012. doi:10.1158/1538-7445.pancreatic24-a012
Miller P, Romero-Hernández F, Calthorpe L, Wang J, Kim SS, Corvera CU, et al. Long-duration neoadjuvant therapy with FOLFIRINOX yields favorable outcomes for patients who undergo surgery for pancreatic cancer. Ann Surg Oncol. 2024. doi:10.1245/s10434-024-15579-0
Cecchini M, Salem RR, Robert ME, Czerniak SM, Bláha O, Zelterman D, et al. Perioperative modified FOLFIRINOX for resectable pancreatic cancer. JAMA Oncol. 2024. doi:10.1001/jamaoncol.2024.1575
Nichetti F, Rota S, Ambrosini P, Pircher C, Gusmaroli E, Droz dit Busset M, et al. NALIRIFOX, FOLFIRINOX, and gemcitabine with nab-paclitaxel as first-line chemotherapy for metastatic pancreatic cancer. JAMA Netw Open. 2024;7. https://doi.org/10.1001/jamanetworkopen.2023.50756
Cui J, Qin S, Zhou Y, Zhang Q, Sun X, Zhang M, et al. Irinotecan hydrochloride liposome HR070803 in combination with 5-fluorouracil and leucovorin in locally advanced or metastatic pancreatic ductal adenocarcinoma following prior gemcitabine-based therapy (PAN-HEROIC-1): A phase 3 trial. Signal Transduct Target Ther. 2024;9(1). https://doi.org/10.1038/s41392-024-01948-4
Jiao X, Barzi A. Comparative effectiveness of NALIRIFOX vs. FOLFIRINOX in pancreatic cancer. J Clin Oncol. 2024;42(16_suppl):4160. https://doi.org/10.1200/jco.2024.42.16_suppl.4160
Yuan M, Chen T, Jin L, Zhang P, Xie L, Zhou S, et al. A carrier-free supramolecular nano-twin-drug for overcoming irinotecan resistance and enhancing efficacy against colorectal cancer. 2023. https://doi.org/10.21203/rs.3.rs-3255371/v1
A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI study). J Clin Oncol. 2023;41(4_suppl):TPS778. https://doi.org/10.1200/jco.2023.41.4_suppl.tps778
Masane ND, Rathod AS, Akhand VG, Katekar VA, Deshmukh SP. Nanoparticles-based drug delivery system for cancer therapy. GSC Adv Res Rev. 2025;22(1):223–37. https://doi.org/10.30574/gscarr.2025.22.1.0014
Zhu J, Lee HH, Huang R, Zhou J, Zhang J, Yang X, et al. Harnessing nanotechnology for cancer treatment. Front Bioeng Biotechnol. 2025;12. https://doi.org/10.3389/fbioe.2024.1514890
Sayyad A. Nanotechnology in cancer therapy: A paradigm shift in oncology. Int J Sci Technol Eng. 2025;13(1):978–82. https://doi.org/10.22214/ijraset.2025.66446
Riaz A, Mansoor M, Rehman FU, Arif K, Fatima Z. Targeted drug delivery via nanoparticles for cancer treatment. Int J Sci Res Arch. 2024;13(2):1777–96. https://doi.org/10.30574/ijsra.2024.13.2.2266
Nankya W. Nanotechnology in cancer treatment: Targeted drug delivery. 2024;4(2):38–42. https://doi.org/10.59298/rojphm/2024/423842
Nair S, Selvo NS, Stolarski A, Nitz B, Federico SM, Stewart CF. Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability. J Chromatogr B. 2024;1245:124273. https://doi.org/10.1016/j.jchromb.2024.124273
Ji D, Shen W, Li J, Wang H, Bai J, Cao J, et al. Liposomal irinotecan (HR070803) in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors: A phase 1b dose-escalation and expansion study. Investig New Drugs. 2024. https://doi.org/10.1007/s10637-024-01442-2
Chen BS, Chan S-Y, Bteich F, Kuang C, Meyerhardt JA, Ma K. Safety and efficacy of liposomal irinotecan as the second-line treatment for advanced pancreatic cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2024;104386. https://doi.org/10.1016/j.critrevonc.2024.104386
Dutta A, Chakraborty A, Ghosh T, Kumar A. 5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage. Dent Sci Rep. 2024;14(1). https://doi.org/10.1038/s41598-024-73143-y
Frimpong E, Bulusu R, Okoro J, Inkoom A, Ndemazie NB, Rogers SC, et al. Abstract 1825: Synthesis and biological evaluation of novel 5-FU analogs against pancreatic cancer. Cancer Res. 2024. https://doi.org/10.1158/1538-7445.am2024-1825
Dasari M, Pelly SC, Geng J, Gold HB, Pribut N, Sharma S, et al. Discovery of 5’-substituted 5-fluoro-2’-deoxyuridine monophosphate analogs: A novel class of thymidylate synthase inhibitors. ACS Pharmacol Transl Sci. 2023;6(5):702–9. https://doi.org/10.1021/acsptsci.2c00252
Tahiya EC, Islam AA, Hatta M, Lusikooy RE, Prihantono P, Rudiman R, et al. 5-Fluorouracil for colorectal cancer: Mechanism of action and metabolism. Gazz Med Ital Arch Sci Med. 2024;183(4). https://doi.org/10.23736/s0393-3660.23.05249-x
Chao CJ, Gardner I, Lin CJ, Yeh KH, Lu WC, Abduljalil K, et al. Administration mode matters for 5-fluorouracil therapy: Physiologically based pharmacokinetic evidence for avoidance of myelotoxicity by continuous infusion but not intravenous bolus. Br J Clin Pharmacol. 2024. doi:10.1111/bcp.16061.
Yang Y, Zhang M, Zhang Y, Liu KX, Lu CH. 5-Fluorouracil suppresses colon tumor through activating the p53-Fas pathway to sensitize myeloid-derived suppressor cells to FasL+ cytotoxic T lymphocyte cytotoxicity. Cancers (Basel). 2023;15(5):1563. doi:10.3390/cancers15051563.
Boldig K, Ganguly AK, Kadakia M, Rohatgi A. Managing life-threatening 5-fluorouracil cardiotoxicity. Case Rep. 2022;15(10):e251016. doi:10.1136/bcr-2022-251016.
Udofot O, Affram K, Israel B, Agyare E. Cytotoxicity of 5-fluorouracil-loaded pH-sensitive liposomal nanoparticles in colorectal cancer cell lines. Integr Cancer Sci Ther. 2015;2(5):245–52. doi:10.15761/ICST.1000150.
VanderVeen BN, Cardaci TD, Madero SS, McDonald S, Bullard BM, Price RL, et al. 5-Fluorouracil disrupts skeletal muscle immune cells and impairs skeletal muscle repair and remodeling. J Appl Physiol. 2022;133(4):834–49. doi:10.1152/japplphysiol.00325.2022.
Meng X. Therapeutic efficacy of platinum-based medicines combined with various nanoparticles in the treatment of colorectal cancer: A comprehensive review. J Cancer Biother. 2025;2(1):57–72. doi:10.62382/jcbt.v2i1.32.
Ma Z, Ding XJ, Zhu ZZ, Chen Q, Wang DB, Qiao X, et al. Pt(IV) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116. RSC Med Chem. 2024. doi:10.1039/d4md00327f.
Sun Z, Han J, Xu J, Song W, Cui Y, Liu Y, et al. Discovery of the next-generation platinum-based anticancer agents for combating oxaliplatin-induced drug resistance. J Med Chem. 2024. doi:10.1021/acs.jmedchem.4c00366.
Modekurty S, Iglesia MD, Pedersen K, Salvador C, Haroutounian S, Lim K, et al. Molecular insights into oxaliplatin-induced peripheral neuropathy in colorectal cancer: Unraveling a potential signature. J Clin Oncol. 2024;42(16 Suppl):e15506. doi:10.1200/jco.2024.42.16_suppl.e15506.
O’Dowd PD, Sutcliffe DF, Griffith DM. Oxaliplatin and its derivatives – An overview. Coord Chem Rev. 2023. doi:10.1016/j.ccr.2023.215439.
Mahaki H, Mansourian M, Meshkat Z, Avan A, Gosseinshafiee M, Mahmoudian RA, et al. Nanoparticles containing oxaliplatin and the treatment of colorectal cancer. Curr Pharm Des. 2023. doi:10.2174/0113816128274742231103063738.
Cheng F, Zhang R, Sun C, Ran Q, Zhang CL, Shen C, et al. Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: Mechanisms, pharmacokinetics and strategies. Front Pharmacol. 2023;14. doi:10.3389/fphar.2023.1231401.
Hussein M, Khan G, Chandana SR, Pazo-Cid R, Kišš I, Gállego J, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Updated overall survival analysis with 29-month follow-up of NAPOLI 3. J Clin Oncol. 2024;42(16 Suppl):4136. doi:10.1200/jco.2024.42.16_suppl.4136.
Akbarali HI, Muchhala KH, Jessup DK, Cheatham SM. Chemotherapy-induced gastrointestinal toxicities. 2022;155:131–66. doi:10.1016/bs.acr.2022.02.007.
Matos RA, Mendonça ET, Salgado PO, Souza CC. Profile of patients with hematological toxicity grades 3 and 4 and gastrointestinal toxicity of patients undergoing chemotherapy. 2021;43:17–43673. doi:10.5902/2179460X43673.
Singaraju M, Palaian S, Shankar P, Shrestha S. Safety profile and toxicity amelioration strategies of common adverse effects associated with anticancer medications. J Pharm Res. 2020:18–30. doi:10.9734/JPRI/2020/V32I1130499.
Byju BC, Kurian SJ, R HK, R RJ, Rudraraju L, S MM. Assesment of safety profile of immunotherapeutic agents other than immune checkpoint inhibitors in cancer patients. Saudi J Med Pharm Sci. 2024;10(06):386–90. doi:10.36348/sjmps.2024.v10i06.009.
Levinson B, Goldberg JD. Toxicity (Adverse Events) [Internet]. 2014 [cited YYYY MMM DD]. Available from: https://doi.org/10.1002/9781118445112.STAT03697
Gu Y, Yang R, Zhang Y, Guo M, Takehiro K, Zhan M, et al. Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer. Mol Biomed. 2025;6(1). doi:10.1186/s43556-024-00239-2.
Nagampalli RSK, Vadla GP, EswarKumar N. Emerging strategies to overcome chemoresistance: Structural insights and therapeutic targeting of multidrug resistance-linked ATP-binding cassette transporters. Int J Transl Med. 2025;5(1):6. doi:10.3390/ijtm5010006.
Wang Y, He J, Lian S, Zeng Y, He S, Xu J, et al. Targeting metabolic–redox nexus to regulate drug resistance: From mechanism to tumor therapy. Antioxidants. 2024;13(7):828. doi:10.3390/antiox13070828.
Khatri M, Dhar S, Van de Ven P, Singh R. Understanding the pharmacological mechanisms of anticancer resistance: A multifaceted challenge in cancer treatment. Asian J Pharm Res. 2024;183–7. doi:10.52711/2231-5691.2024.00030.
Khan SU, Fatima K, Aisha S, Malik F. Unveiling the mechanisms and challenges of cancer drug resistance. 2024;22. doi:10.1186/s12964-023-01302-1.
Tian Y, Lei Y, Wang Y, Lai J, Wang J, Xia F. Mechanism of multidrug resistance to chemotherapy mediated by P glycoprotein (Review). Int J Oncol. 2023;63(5). doi:10.3892/ijo.2023.5567.
Xiao H, Zheng Y, Ma L, Tian L, Sun Q. Clinically-relevant ABC transporter for anti-cancer drug resistance. Front Pharmacol. 2021;12:648407. doi:10.3389/FPHAR.2021.648407.
Singhal R, Rogers SC, Lee JH, Ramnaraign BH, Sahin I, Fabregas JC, et al. A phase II study of neoadjuvant liposomal irinotecan with 5-FU and oxaliplatin (NALIRIFOX) in pancreatic adenocarcinoma. Future Oncol. 2023;19:1843–53. doi:10.2217/fon-2023-0256.
Wainberg O, Melisi D, Macarulla T, Pazo Cid R, Chandana SR, De La Fouchardiere C, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023. doi:10.1016/s0140-6736(23)01366-1.
Melisi D, Macarulla T, de la Fouchardiere C, Pazo Cid RA, Chandana S, Dean A, et al. 1619P Health-related quality of life with nalirifox versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): EORTC QLQ-C30 results from the NAPOLI 3 trial. Ann Oncol. 2023. doi:10.1016/j.annonc.2023.09.2568.
Melisi D, Merz V, Fazzini F, Pietrobono S, Zecchetto C, Malleo G, et al. 1620P A phase II study of perioperative nalirifox in patients with resectable pancreatic ductal adenocarcinoma (rPDAC): Survival update and biomarkers analysis of the NITRO trial. Ann Oncol. 2023. doi:10.1016/j.annonc.2023.09.2569.
Melisi D, Zecchetto C, Merz V, Malleo G, Landoni L, Quinzii A, et al. Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial. Eur J Cancer. 2023;196:113430. doi:10.1016/j.ejca.2023.113430.
Shinohara Y, Shirakawa T, Shimokawa M, Otsuka T, Shimokawa H, Nakazawa J, et al. Real-world evidence of nanoliposomal irinotecan and fluorouracil with folinic acid in patients with unresectable or recurrent pancreatic cancer: Final results of a multicenter observational study. J Clin Oncol. 2025;43(4_suppl):721. doi:10.1200/jco.2025.43.4_suppl.721.
Shao H, Fang H, Li Y, Jiang Y, Zhao M, Tang W. Economic evaluation of NALIRIFOX vs. nab-paclitaxel and gemcitabine regimens for first-line treatment of metastatic pancreatic ductal adenocarcinoma from U.S. perspective. Cost Eff Resour Alloc. 2024;22(1). doi:10.1186/s12962-024-00578-5.
Kim GP, Holland TA, Patrick C, Lewis M, Cockrum P, Eddy AC. Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin as a first line treatment for the management of metastatic pancreatic adenocarcinoma: A budget impact analysis from a U.S. payer perspective. J Clin Oncol. 2024;42(16_suppl):e16339. doi:10.1200/jco.2024.42.16_suppl.e16339.
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