Patient Factors Drive Chemotherapy Decision-Making in Metastatic Pancreatic Cancer

With multiple chemotherapy regimens approved for the frontline treatment of patients with metastatic pancreatic cancer, patient factors such as performance status and the presence of certain comorbidities can influence the selection of an appropriate regimen for specific patients, according to Shubham Pant, MD, MBBS.

Current frontline options include FOLFIRINOX (fluorouracil, oxaliplatin, and irinotecan), gemcitabine plus nab-paclitaxel (Abraxane), and NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-fluorouracil, and leucovorin). NALIRIFOX was the regimen most recently added to the frontline armamentarium following its FDA approval in February 20-24, based on data from the phase 3 NAPOLI 3 study.¹

Findings from the NAPOLI 3 showed that patients treated with NALIRIFOX (n = 383) experienced a median overall survival (OS) of 11.1 months (95% CI, 10.0-12.1) compared with 9.2 months (95% CI, 8.3-10.6) for those given gemcitabine plus nab-paclitaxel (n = 387; HR, 0.83; 95% CI, 0.70-0.99; P = .036).²

At the 2025 ASCO Annual Meeting, findings from a post hoc analysis of NAPOLI 3 showed that 12.5% of North American patients treated with NALIRIFOX during the study (n = 120) experienced an OS of at least 18 months.³ In this analysis of long-term survivors, investigators showed that most patients needed dose reductions of liposomal irinotecan (66.7%) and dose delays of liposomal irinotecan (86.7%), along with dose delays (80%) and dose reductions (80%) of oxaliplatin. Investigators concluded that these reductions and/or delays allowed for prolonged exposure to treatment and helped this long-term survivor group achieve a median OS of 19.5 months.

In an interview with OncLive^®, Pant outlined the key factors he examines when selecting a frontline chemotherapy regimen for a patient with metastatic pancreatic cancer, explained how NALIRIFOX fits into the current treatment paradigm, and detailed the possibility of incorporating targeted therapy into the frontline treatment setting.

Pant is a professor in Department of Gastrointestinal (GI) Medical Oncology of the Division of Cancer Medicine, director of Clinical Research, and a professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What are some factors driving first-line chemotherapy selection in metastatic pancreatic cancer?

Pant: The biggest thing is the performance status of the patient [and] if they have any comorbidities. [For example, treatment decisions can be affected] if they have a neuropathy from diabetes, or, overall, if they have any other core issues, like nausea, vomiting, or other comorbidities leading into [treatment]. Those are the two big [factors]. I [consider] the ECG, the performance status, and any comorbidities at the same time in a patient.

How has NALIRIFOX been integrated into the frontline treatment setting for metastatic pancreatic cancer since its FDA approval in February 2024? Has there any been any challenges adopting that regimen alongside FOLFIRINOX and gemcitabine plus nab-paclitaxel?

NALIRIFOX was compared [with] gemcitabine and nab-paclitaxel [in the NAPOLI 3 trial] and was found to be a superior regimen [in terms of OS (HR, 0.84; 95% CI, 0.71-0.99; P = .0403) and progression-free survival (HR, 0.70; 95% CI, 0.59-0.85; P = .0001)]. And interestingly, NALIRIFOX has a lower chance of [inducing] neuropathy because of a lower dose of oxaliplatin that was used in [NAPOLI 3].

However, we do have to watch out for diarrhea in our patients [treated with NALIRIFOX], which can be slightly increased. If a patient is already having diarrhea issues with gut intolerance, then we would tend to use another alternative regimen. Otherwise, I think [NALIRIFOX] a very appropriate regimen for patients in the frontline setting.

As the research continues to progress, how do you see targeted therapies or other agents impacting the first-line treatment paradigm in metastatic pancreatic cancer?

That is a great question because we have a lot of targeted agents that are coming into the field. The ones that are furthest along are the pan-RAS inhibitors, [including] a drug called daraxonrasib [RMC-6236], which is [being evaluated] in the phase 3 [RASolute 302] clinical trial [NCT06625320] in the second-line setting [for patients with metastatic pancreatic ductal adenocarcinoma].

Then we have a number of KRAS G12D inhibitors; approximately 40% of [patients with] pancreatic cancer [harbor KRAS G12D mutations], and we are testing [KRAS G12D inhibitors] as single agents and in combinations of chemotherapy. All that means that there is a lot of excitement in the pancreatic cancer space, and hopefully we should get more options for our patients in the near future.

With November being Pancreatic Cancer Awareness Month, what would be your message for your colleagues regarding the push to integrate new treatment approaches in the space?

[Clinicians] should, when appropriate, conduct next-generation sequence testing. And if a patient is appropriate for clinical trials, we should try to find a clinical trial for them. That’s important. Hope is on the horizon for this disease, and hopefully, we should be able to get some newer therapeutics for our patients.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed November 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
2. Wainberg ZA, Melisi D, Macarulla T, 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;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1
3. NAPOLI 3 phase 3 study of NALIRIFOX in metastatic pancreatic ductal adenocarcinoma: characteristics of the long-term survivors. J Clin Oncol. 2025;43(suppl 17):LBA4175. doi:10.1200/JCO.2025.43.17_suppl.LBA4175