Aligning Patient Goals and Toxicity Burden Are Key in First-Line Chemo Selection in Pancreatic Cancer

First-line treatment selection for metastatic pancreatic adenocarcinoma increasingly hinges on aligning regimen choice with patient goals, anticipated symptom control, and tolerability, according to Kristen Spencer, DO, an associate professor in the Department of Medicine at NYU Grossman School of Medicine and director of the Phase I Developmental Therapeutics Program at Perlmutter Cancer Center in New York.

Spencer also noted that the approval of NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-fluorouracil [5-FU], and leucovorin) has expanded available first-line options beyond traditional FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) and gemcitabine-based regimens, offering added flexibility to tailor therapy based on toxicity profiles, performance status, and presenting symptoms.^1,2

“I think [NALIRIFOX] really offers us a little bit more flexibility in how we tailor our therapy, specifically based on the toxicity profile as well as the patient’s sort of presenting performance status and symptoms, rather than just making recommendations on efficacy,” Spencer explained in the interview.

In a discussion with OncLive®, Spencer explained that early visits often focus on balancing realistic expectations for survival extension with quality-of-life priorities in an incurable setting, particularly given the high symptom burden many patients present with. She emphasized the importance of achieving early disease control, integrating supportive oncology/palliative care into the treatment course, and obtaining up-front biomarker testing—including germline status and tumor-based somatic alterations—to identify actionable targets that may inform treatment decision-making.

OncLive: When a patient first presents with metastatic pancreatic cancer, what treatment goals guide the initial therapy discussion?

Spencer: Particularly in the first visit or first several visits, we’re spending a lot of time focusing on trying to align the treatment options with the patient’s goals, while also trying to set realistic expectations of what those treatments might achieve. There’s an important balance we try to set about how we’re realistically able to extend survival, while also recognizing that this is incurable, metastatic disease and [we need to acknowledge] what the next year [or] couple of years of that patient’s life will look like from a quality-of-life standpoint.

We want to make recommendations that will minimize any treatment-related toxicity as much as possible. At the same time, many times we’re seeing patients who have a very high symptom burden due to the extent of their disease. We do want to try to get some disease control very early on. Sometimes we can feel a little bit like we’re racing the clock. From that standpoint, we obviously want to engage supportive oncology—effectively palliative care—very early on in the patient journey. We’re often talking about those types of things very early with the patient.

One of the other really important things is to make sure that we’re working to identify any biomarkers that are potentially actionable. That’s becoming more and more important, even in the first-line setting. We want to know early on what the patient’s germline status is, as well as any somatic mutations or alterations they might have in their tumor that we might be able to use to make treatment recommendations, even in the first-line setting.

Since NALIRIFOX was FDA approved, how has it affected first-line treatment selection for metastatic pancreatic cancer?

NALIRIFOX is the most recent regimen we have approved in the first-line setting for pancreatic adenocarcinoma. For us, it expanded the first-line options that we have available to us beyond the traditional FOLFIRINOX or gemcitabine-based regimens. It’s a new multi-agent systemic chemotherapy option, similar to the ones we had available to us before, that perhaps may be better tolerated in select patients. What it really offers us is perhaps a little bit more flexibility in how we tailor our therapy, specifically based on the toxicity profile as well as the patient’s [baseline] performance status and symptoms, rather than just making recommendations on efficacy.

How does NALIRIFOX help meet first-line treatment goals, and what factors guide selection among NALIRIFOX, FOLFIRINOX, and gemcitabine plus nab-paclitaxel (Abraxane)?

Similar to FOLFIRINOX, NALIRIFOX does give us a certain degree of disease control, potentially even some management or shrinkage of disease, which is often critical for symptom relief, so we want to maintain that benefit. Potentially, there’s the benefit of reducing certain toxicities related to the oxaliplatin component of both of those regimens, as that was given at a lower dose with the NALIRIFOX regimen. For instance, neuropathy is a very classic [adverse effect (AE)] we hear about from our patients. It’s often dose-limiting when it starts to build up in patients, and that can be unpredictable to some degree. Sometimes it [occurs] early on, before you’ve been able to give much therapy to a patient. Therefore, [we may see] less oxaliplatin-related neuropathy up-front [with NALIRIFOX] compared with FOLFIRINOX, [which] could benefit patients with a longer treatment duration, if they’re able to tolerate the therapy a little bit better.

Beyond safety, what patient- or disease-specific factors and AE risks influence choosing between FOLFIRINOX and nalirifox, or another first-line option?

We’re taking a look at the whole patient when we meet them. Their baseline performance status or how functional they are, particularly at home, and a measure of maybe how frail they might be [are all things] that we’re considering when determining an initial treatment approach. I always like to ask about social support and their ability to manage the AEs at home, get back and forth from appointments. [It is important to determine if] they are able to get out and get the supportive care medications that they need. Are they able to dose themselves? Are they able to remember to take those medications when they’re having symptoms?

In addition, we’re really thinking about the individual risks of developing or perhaps compounding problems that are already there. Again, I’ll bring up neuropathy as an example. There are many patients with pancreatic adenocarcinoma who have baseline diabetes; they carry a certain amount of baseline neuropathy. That risk might be something that we weigh in when selecting a regimen that might potentially worsen baseline neuropathy. The same applies to things like their baseline liver function, which can be impacted if they have liver metastases. If they’re older, if they have an underlying bone marrow disorder; they may be at a higher risk of certain myelosuppressive issues, diarrhea, and fatigue—all these things we factor in when we’re making a treatment plan in the first-line setting.

When targeted agents and trials are available, how is the decision made between standard first-line chemotherapy and clinical trial enrollment?

I’m a clinical trialist at heart. Perhaps I’m a little bit biased here, but, I would really make the argument that unless we’re curing all our patients with our currently available standard-of-care therapies, we should be considering a clinical trial, and we should be discussing those early and routinely with all of our patients. Particularly, [I consider] if I have a clinical trial available that has a strong scientific basis to it, it has a strong track record, and we think that it’s going to offer some meaningful therapeutic benefit—as well as whether the patient is fit and motivated to participate in a trial. I’m having those conversations with all of them right off the bat.

That doesn’t mean that everybody can or wants to participate in a clinical trial, but I do certainly discuss it. The other thing in the first-line setting that’s particularly important is that we want to be quick and flexible in getting a patient on a clinical trial. We don’t want to compromise the timely disease control that we really need in pancreatic adenocarcinoma. It’s really important to identify these trials early, to get the biomarkers and the clinical information that we need early on, and to engage the study teams as early as possible as well.

What key unmet needs remain in first-line metastatic pancreatic cancer, and where should next-generation strategies build on current chemotherapy options?

We should be immensely proud of the work that’s been done to date in that we have management options for these patients, but there’s still a lot of work to be done. Obviously, we’re not curing any of these patients in the metastatic setting, and we’re really not prolonging meaningful survival much beyond a year with any of the standard-of-care therapies we have available. There’s a dire need for more effective systemic therapies that have a durable benefit, perhaps with less toxicity. The key is likely to be biomarker-driven strategies—so particularly things like KRAS and MET [alterations]—this is where the field is going, and I think it has tremendous potential to improve both quality of life and efficacy for patients in the first-line setting.

There’s still a lot of room for work to be done in improving toxicity management with all of these regimens, as well as expanding how we’re thinking about treatment in terms of immunotherapy, targeted approaches, and combination strategies. These are going to be really important, particularly as we need to address patients who suffer from early resistance, or who frankly have primary resistance and progress rapidly through some of the novel compounds that are coming into the clinic now.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. Updated February 16, 2024. Accessed January 29, 2026. 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. NAPOLI 3: a randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2023;41(suppl 4):LBA661. doi:10.1200/JCO.2023.41.3_suppl.LBA661