Patient Preferences, Expected Toxicity Serve As Guiding Factors for Frontline Chemo Selection in Pancreatic Cancer

With seemingly similar efficacy outcomes and an absence of head-to-head data for all regimens, selecting between approved frontline chemotherapy options for patients with metastatic pancreatic cancer requires careful consideration of potential toxicities, drug delivery, comorbidities, and patient goals, according to Deirdre J. Cohen, MD, MS.

Prior to February 2024, the frontline armamentarium in metastatic pancreatic cancer comprised 2 standard chemotherapy options: modified FOLFIRINOX (leucovorin, fluorouracil [5-FU], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel (Abraxane).¹ However, the FDA approval of NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-fluorouracil, and leucovorin), which was supported by data from the phase 3 NAPOLI 3 study (NCT04083235), expanded available options in this setting.^1,2

“The interesting thing with NALIRIFOX is that there is certainly level 1 evidence that it has superior efficacy compared with gemcitabine plus nab-paclitaxel. That is something important to bring up with our patients,” Cohen shared in an interview with OncLive^®. “However, given that there is no level 1 evidence of how it performs compared with FOLFIRINOX, I am not entirely sure that one is necessarily better than the other.”

In the interview, Cohen discussed the current state of chemotherapy selection for metastatic pancreatic cancer, emphasizing the lack of effective biomarkers for frontline treatment selection; discussed her thought process when choosing between these 3 approved frontline regimens; and highlighted ongoing research with RAS inhibitors and immunotherapies that is expected to reshape the frontline pancreatic cancer paradigm.

Cohen serves as the director of the Gastrointestinal (GI) Oncology Program for the Mount Sinai Health System, is an associate professor of medicine (Hematology and Medical Oncology), and is the medical director of the Cancer Clinical Trials Office at The Tisch Cancer Institute in New York.

OncLive: What are some of the key factors considered when selecting between first-line chemotherapy options in pancreatic cancer?

Cohen: In 2026, we still do not have the perfect answer or biomarker for selecting a frontline [treatment] regimen, outside of homologous recombination deficiency or DNA damage response alterations in a tumor—such as BRCA or PALB2—where we know that patients derive more benefit from a platinum-containing regimen. When choosing between FOLFIRINOX or NALIRIFOX, it is really about discussing the data and patient preferences regarding logistics, such as how their drugs are delivered and the schedule, as well as the [potential] toxicities, the patient's performance status, and their comorbidities. In general, for a patient with good performance status, I tend to give FOLFIRINOX. I tend to look at NALIRIFOX if I am more concerned about pre-existing peripheral neuropathy, which is [an example of a] case where I use it.

In the absence of head-to-head data, what other safety consideration or drug delivery logistics help you select between these 3 regimens?

There is certainly more GI toxicity [associated] with NALIRIFOX, which is something I keep in mind because many patients already present with significant GI toxicity. However, as GI medical oncologists, we are very adept at managing those toxicities. The lower dose of oxaliplatin in NALIRIFOX might lend itself more [for use in patients with pre-exisiting neuropathy]. Both regimens are myelosuppressive and generally require growth factor support, so that factor does not sway me one way or another.

Are there situations where gemcitabine plus nab-paclitaxel is still considered an appropriate frontline regimen?

Based on a patient's performance status and shared decision-making, if a patient is not interested in an infusional 2-day pump, then gemcitabine plus nab-paclitaxel is a very important option. I also consider it if we are discussing a clinical trial involving gemcitabine/nab-paclitaxel plus an investigational agent.

Given that chemotherapy is the standard backbone for frontline therapies in pancreatic cancer, how do you decide whether to guide patients toward an investigational regimen via a clinical trial vs administer a standard-of-care option?

Right now, every one of my patients is offered a clinical trial if we have one for which they are eligible. I always say to my patients that if we cannot cure them 100% of the time with no toxicity, then we need to do better, and that is where clinical trials come in. That is my offer for every patient, provided that we have the right study.

How do you expect the first-line pancreatic cancer landscape to evolve as research with targeted therapies continues?

It is such an exciting time in pancreatic cancer where we are finally seeing remarkable early data from RAS inhibition, which we previously did not think we could achieve. The next 5 to 10 years are going to be about how to best combine RAS inhibitors [with other agents], and I see them moving into the frontline very quickly.

In addition to combinations, the next step is going to be understanding resistance mechanisms and how we can circumvent them to allow for more durable responses. Ultimately, we want to move [RAS inhibition] move not just into the first line, but also into the neoadjuvant and adjuvant space to see more cures.

How gratifying has it been for you and your colleagues see this research and these advances taking shape across the pancreatic cancer space?

It is very rewarding, although we certainly have not done enough and there is a lot more work to be done. I do think that the tip of the iceberg is finally emerging, and an understanding of RAS inhibition is going to open up a lot of exciting treatments for our patients. I also think a better understanding of the immune perspective and seeing the potential for immunology, vaccines, and other cellular-based therapies in this disease is really exciting.

References

1. Nichetti F, Rota S, Ambrosini P, et al. NALIRIFOX, FOLFIRINOX, and gemcitabine with nab-paclitaxel as first-line chemotherapy for metastatic pancreatic cancer: a systematic review and meta-analysis. JAMA Netw Open. 2024;7(1):e2350756. Published 2024 Jan 2. doi:10.1001/jamanetworkopen.2023.50756
2. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed February 18, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma