Next-generation sequencing (NGS) results, treatment flexibility, and patient age must be carefully weighed to determine whether irinotecan liposome (Onivyde) plus oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (NALIRIFOX) is an appropriate first-line treatment for patients with metastatic pancreatic cancer, according to Dong Kim, MD. The regimen received FDA approval for this population in 

“One of the themes you often hear is how much things have changed with NGS, molecular testing, and all of the targeted therapies,” Kim said in an interview with 

®. “There’s still a lot of basic research, in addition to clinical trials, that needs to be done to better understand what other therapies could be effective. Now that we know more about the genetic predisposition for pancreatic cancer, it’s important that everyone is aware of this and knows to ask about genetic testing.”

Kim is an oncologist and hematologist at Maryland Oncology Hematology in Silver Spring and Hyattsville.

In the interview, which took place during Pancreatic Cancer Awareness Month in November, Kim discussed his decision-making process when selecting a frontline chemotherapy regimen, the real-world uptake of NALIRIFOX, and other notable research areas in pancreatic cancer.

What factors do you weigh when selecting a frontline chemotherapy regimen for patients with metastatic disease and how do you tie patient treatment goals into this decision?

: There used to be a more traditional paradigm, and now there’s a more modern one. Traditionally, we focused on [factors including] the patient’s age, performance status, and how aggressive they wanted to be, with the general idea that gemcitabine/nab-paclitaxel [Abraxane] might be more tolerable. Those [factors] are still relevant, but I believe we’ve learned that age is a wide spectrum and doesn’t always tell us how fit a patient is. Sometimes we’re surprised by what patients can tolerate.

The more modern way of thinking is: what’s the probability that this patient may have some platinum sensitivity? How long do we need to wait for the NGS results to figure that out? Some patients seem more sensitive to gemcitabine/nab-paclitaxel. Do we really know how to determine that? Probably not.

It’s interesting timing for this discussion because [data from] the [phase 2] PASS-01 trial [NCT04469556] just came out. I think even community oncologists would say we’ve noticed that some patients are more sensitive to gemcitabine/nab-paclitaxel. The test they ran isn’t ready for clinical use yet, but it’s something we’re learning from.

Overall, I think the more modern view is that you don’t necessarily want to exclude someone from a platinum-based regimen like FOLFIRINOX [leucovorin, 5-FU, irinotecan, and oxaliplatin] or NALIRIFOX just because of age.

[Another] thing to consider is how long you can afford to wait for the NGS results. Typically, we can wait, but pancreatic cancer is such a time-sensitive disease and for many patients, we only get 1 line of therapy if we can’t get them into a clinical trial.

I [consider] the pretest probability that a patient may have a homologous recombination repair deficiency. You can’t tell for sure, but if there’s a family history, you might suspect a germline mutation that could influence the approach.

I also like to have an upfront conversation with the patient. [A certain therapy] might be better for a patient if they are platinum sensitive. We’re not always sure, but it’s worth considering.

Another important point is flexibility [because] you can pivot quickly if toxicity becomes an issue. Although gemcitabine/nab-paclitaxel is often seen as the less aggressive option, I don’t believe that’s the only way to view it. A lot depends on how aggressive the patient wants to be and their potential for platinum sensitivity. Finally, although the toxicities with modified FOLFIRINOX or NALIRIFOX are real, they’re not prohibitive.

How have you seen NALIRIFOX adopted in practice and what do you think it will take for its use to increase in the real-world setting?

One justified point is the cost. Switching to something that may not offer a dramatic benefit over modified FOLFIRINOX can be hard to justify. That said, people are slowly adopting it, and I’ve certainly used it.

Another way to think about it is that we don’t have a lot of options in pancreatic cancer. Even if the difference is small, for a patient, those extra months can matter. I also think NALIRIFOX has a slightly better toxicity profile. The data suggest that’s the case, and my experience supports it.

The slow adoption is partly because it’s not a huge or exciting change, but I’d encourage more oncologists to consider it. Since many patients with metastatic pancreatic cancer only receive 1 line of therapy, a regimen with a slight efficacy or toxicity advantage could meaningfully improve quality of life.

How do the safety profiles of the various regimens contribute to your frontline decision-making?

One factor I’ve been thinking about more is pharmacogenomics, specifically irinotecan metabolism. Theoretically, that could influence how patients tolerate these regimens, although we don’t yet have clear dosing guidance from that.

The gemcitabine/nab-paclitaxel every-other-week regimen is generally well tolerated and a good option for patients you’re concerned about. But with proper dose adjustments, the gastrointestinal [GI] toxicities from modified FOLFIRINOX or NALIRIFOX can also be manageable.

Upfront supportive care is critical [and that means] addressing pancreatic enzyme insufficiency, nutrition, and weight loss early. Just because a patient is cachectic or has GI issues doesn’t necessarily mean you should avoid those regimens.

 showed that a dose reduction with the liposomal irinotecan component in NALIRIFOX didn’t affect long-term outcomes, so starting at a reduced dose is very reasonable.

 That’s my personal practice. Being flexible early with dosing is key.

What’s the potential of RAS-targeted therapies in the frontline setting, either as monotherapy or in combination with chemotherapy regimens?

Over 90% of pancreatic cancers have some form of 

 mutation. Right now, the trials with KRAS-targeted therapies, or agents targeting that broader pathway, are what we’re most excited about. There are some preliminary, encouraging data showing responses, and I’ve personally enrolled patients on those studies. It’s early but promising.

Historically, therapies that have worked in other malignancies haven’t translated well to pancreatic cancer, so we have to be more creative, whether that’s CAR T approaches for solid tumors, KRAS inhibitors, or targeting 

 deletions. We need to cast a wide net and see what sticks.

What would you tell colleagues about the current state of frontline treatment in pancreatic cancer and where the paradigm is headed?

Even though our treatment options are limited right now, that doesn’t mean there aren’t important steps we can take. Beyond trying to get patients on clinical trials, it’s critical to address the genetic component. Sending NGS as early as possible and talking with families about germline testing [is critical].

I’m comfortable ordering [NGS] right away. It not only helps with family counseling and screening but also ensures we’re selecting the right therapy. If you start with gemcitabine/nab-paclitaxel and later find a homologous recombination pathway mutation, you may have missed an opportunity to use a more responsive regimen.

Part of the reason gemcitabine/nab-paclitaxel performed better in the PASS trial wasn’t just because of the new molecular subtype identified—it’s because they excluded patients with certain mutations, which earlier studies didn’t do. That likely made a difference.

I’d encourage all of us to raise awareness that there are still meaningful things we can do, even within standard frontline treatment, to make a difference for patients.

FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. Updated February 16, 2024. Accessed November 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma

Chung V, Kochenderfer MD, Natarajan N, et al. NAPOLI 3, a phase 3 study of NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): final overall survival (OS) analysis and characteristics of the long-term survivors. 

. 2025;43(suppl 17):LBA4175. doi:10.1200/JCO.2025.43.17_suppl.LBA4175

Articles

Dong Kim, MD, discusses the role of NALIRIFOX and other frontline chemotherapy regimens in the pancreatic cancer treatment landscape.

NALIRIFOX Expands Frontline Options in Metastatic Pancreatic Cancer 

The management of metastatic pancreatic cancer continues to evolve with an increasing focus on personalization—both biologically and holistically, according to Efrat Dotan, MD, who emphasized that when patients first present with metastatic disease, treatment discussions must extend beyond tumor biology to encompass comorbidities, performance status, nutrition, and patient goals to guide individualized care decisions.

“[We have to consider that] treatment for metastatic pancreatic cancer is very tough,” Dotan said. “It is not just about the chemotherapy and the treatment, but [rather something] broader than that.”

, Dotan discussed patient- and disease-related factors that help drive frontline treatment decision-making for patients with metastatic pancreatic cancer, underscoring the need to address patient goals when mapping out therapy.

She also spoke about the integration of NALIRIFOX (irinotecan liposome [Onivyde] with oxaliplatin, 5-fluorouracil [5-FU], and leucovorin) into the frontline treatment paradigm following 

the February 2024 FDA approval of the regimen

, based on data from the phase 3 NAPOLI 3 trial (NCT04083235).

 Additionally, Dotan outlined findings from the phase 2 GIANT trial (NCT04233866), which evaluated dose-reduced chemotherapy in older, frail patients with metastatic pancreatic cancer. Although this population experienced a median overall survival (OS) of 4.7 months (95% CI, 4.1-7.4) with modified gemcitabine plus nab-paclitaxel (Abraxane) vs 4.4 months (95% CI, 3.1-8.9) with dose-reduced 5-FU and liposomal irinotecan, patients between both arms who received at least 2 doses of treatment achieved a median OS of 8.0 months (95% CI, 5.9-10.0).

Dotan is executive medical director of the Ann B. Barshinger Cancer Institute, Cancer Services, and Cancer Research, as well as the chairperson of the Cancer Committee at Penn Medicine Lancaster General Health.

: When a patient is newly diagnosed with metastatic pancreatic cancer, what key goals guide your initial discussions regarding treatment planning?

: [When] these patients present, it’s a shocking diagnosis. People know how challenging pancreatic cancer is, how aggressive the disease is, and there’s a lot of fear and concern. The first meeting is a time to get a sense of the patient’s overall health, the patient’s goals, values, [and] support system. [We] assess how are they coming into this disease and try to get a sense of what the best approach would be for that patient.

We talk a lot about personalizing therapy and precision oncology, but in pancreatic cancer, it is critical that we think of the patient holistically and try to understand how to personalize therapy, not just to the biomarkers and the molecular changes, but also to the patient who is sitting in front of us—thinking about their goals, values, preferences, support system, and ability to go through therapy.

What are some of the key factors you typically discuss with patients that can ultimately influence the treatment decisions made in the metastatic setting?

Understanding the patient’s other comorbidities, functional status, and fitness [is critical]. Many patients with pancreatic cancer, regardless of age, can present with a lot of nutritional deficits [that affect] their performance status. [For example], if they have extensive liver involvement or significant biliary blockage, all those things can affect their ability to tolerate therapy.

Understanding holistically all these other factors that are related to the cancer—but not the cancer itself—is critical when deciding on treatment.

Then, more than that, we need to [consider] the patient’s overall function, how they’re functioning at home, and how active they are. There’s a big difference between somebody who shows up and is still active, [perhaps] not working but getting out and doing things, vs patients who are debilitated by pain or by difficulty [maintaining] their nutritional needs, and those [who] spend more than 50% of [their] time in bed. All those factors [help] clearly direct us toward the appropriate treatment recommendation.

How has the FDA approval of NALIRIFOX influenced the current treatment paradigm for patients with metastatic pancreatic cancer, particularly in terms of first-line therapy selection?

The adoption of NALIRIFOX has been slow in pancreatic cancer. Let me start by saying that [NAPOLI 3] was a very important trial. It’s important because it clearly demonstrated the superiority of a triple-drug regimen over gemcitabine and nab-paclitaxel. Before the study was published, we all thought, ‘Oh, there’s not a huge difference—maybe gemcitabine/nab-paclitaxel can be used for patients who don’t want a port or a pump.’ However, the trial actually showed that there was a benefit to giving triple-drug therapy up-front compared with gemcitabine/nab-paclitaxel. The data that came out of this study are very valuable.

The challenge, however, is that at the end of the day, the outcomes were very similar to those seen with FOLFIRINOX. Is it worth giving a patient NALIRIFOX instead of FOLFIRINOX, especially considering the cost of liposomal irinotecan and the comparable outcomes?

Physicians are already comfortable with FOLFIRINOX. They know how to use it, manage toxicities, and modify doses. So why change practice? There are two important pieces in the NALIRIFOX data. One is that the oxaliplatin dose was lower in the study, which is important, especially when treating patients who already have neuropathy or are older and at higher risk for developing neuropathy. That lower dose might allow patients to stay on treatment longer.

The other point is that [NAPOLI 3] enrolled more older patients compared with the original FOLFIRINOX trial, providing some proof of concept for treating older patients with this regimen. That said, many of us who treat pancreatic cancer and see older patients—since it’s a disease that affects older individuals—have already become accustomed to modifying and treating older adults with triple-drug therapy.

[NAPOLI 3] added important data, but I don’t believe NALIRIFOX has been widely incorporated into practice—at least not to the extent it would have been if the data had shown a significantly greater OS benefit.

How do you view clinical trial enrollment as a treatment option for patients with metastatic pancreatic cancer, and why is expanding

access to trials so critical for advancing therapy development in this population?

[Clinical trials] are the way to [expand] our treatment arsenal and move the needle forward. There’s a lot of excitement around new trials in pancreatic cancer—especially the new RAS inhibitors that are coming down the pipeline—and some other new targets that are quite exciting. [There are also] additional studies looking at drugs affecting cachexia, which is such a critical part of what patients with pancreatic cancer experience.

If I have a trial [available], I urge patients to join. If I have a patient who I think is very fit, interested in a trial, and willing to travel, I will do my best to find a study for them. The challenge with enrollment in clinical trials for patients with pancreatic cancer is that this is a really tough disease. To be able to travel to a distant site to participate in a trial when you have pancreatic cancer, a lot of things need to fall into place to make that happen—and many patients will struggle with that.

That’s a big challenge and why it’s important to open these trials as widely as possible—to try to get them opened in community sites where patients can get access. Then, I think enrollment will be better. If you bring the study to the patient, it becomes much easier to encourage participation.

What were the key takeaways and clinical implications from the preliminary analysis of the GIANT study?

We’re still waiting for the final analysis, but the preliminary results showed poor outcomes for patients who are very vulnerable and may not be able to tolerate chemotherapy. Identifying those patients and personalizing treatment to the individual sitting in front of you is critical in this disease.

The GIANT study was an important trial because it addressed a population that hasn’t been studied before. These were older, more frail patients [who were more representative of who] we see in clinic—and we all see them because pancreatic cancer is a disease of older adults. The study enrolled patients over the age of 70, and they had to have geriatric vulnerabilities to enroll. Patients were randomly assigned to receive dose-reduced therapy with gemcitabine and nab-paclitaxel given every other week, or 5-FU and liposomal irinotecan, also given every other week.

The study showed no difference in outcomes between both groups. Survival was quite poor [with a median OS of] less than 5 months for each arm. Toxicity was similar overall, although the regimens had different profiles: gemcitabine and nab-paclitaxel were associated with more neuropathy, while 5-FU and liposomal irinotecan caused more diarrhea. Overall, grade 3 toxicity rates were about the same.

What was really striking, in my opinion, was that patients who were able to tolerate more than two doses—the [72% of patients between both arms] who stayed on treatment for more than 1 month—had a median OS of 8.0 months. That’s comparable to what we would expect with standard-dose gemcitabine and nab-paclitaxel. Therefore, we could attenuate doses, give less treatment, and still achieve the same outcomes as with full-dose chemotherapy.

The big question is how to identify those patients. That’s the second significant finding from this trial: there were key baseline criteria related to nutrition, functional status, and quality of life that clearly predicted outcomes. Patients with better baseline quality of life and nutrition had significantly better outcomes when treated. Again, this brings me back to the point I mentioned earlier—personalization of therapy. Not everyone is a candidate for treatment or will benefit from it. We need to do a better job identifying those factors up-front and having those discussions with patients to ensure we are truly personalizing therapy and providing the best treatment for each individual.

What is your main takeaway message for colleagues when it comes to approaching treatment discussions and decision-making for patients presenting with metastatic pancreatic cancer?

It’s important to think about personalizing therapy in two ways. [The first] is biologically—every patient with metastatic pancreatic cancer should have molecular testing. That’s very critical, including 

 testing as recommended by all guidelines, but [we should conduct] next-generation sequencing. It’s rare that we find a target, but if we do, it can make a huge difference. With RAS inhibitors hopefully coming down the pipeline, we need to know the 

 mutation status. If they don’t have a 

 mutation, we need to dig deeper and find what other mutations or drivers are contributing to their cancer. Molecular and biologic personalization—or precision oncology—needs to happen for all of these patients.

On the other hand, personalization to the patient, their needs, core values, preferences, and goals is critical. Thinking about the holistic picture of the patient: What can they tolerate? What will benefit them? Is it worth it for them to go through therapy? For many patients, that may not be the right decision.

FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed February 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma

Dotan E, Catalano PJ, Lenchik L, et al. A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186. J Clin Oncol. 2024;42(suppl 16):4003. doi:10.1200/JCO.2024.42.16_suppl.4003

Efrat Dotan, MD, discusses patient factors to consider during treatment planning for metastatic pancreatic cancer. 

Personalized, Patient-Centered Strategies Shape the Evolving Management of Metastatic Pancreatic Cancer

Dr Dotan on Gemcitabine and Nab-Paclitaxel in Treatment-Naive, Older Pancreatic Cancer

“[These findings indicate that] we can attenuate doses; we can give less treatment and achieve the same outcome as we would with standard dosing.”

Efrat Dotan, MD, an innovation faculty member at the Penn Center for Cancer Care Innovation and the executive medical director of the Ann B. Barshinger Cancer Institute at Penn Medicine Lancaster General Health, discusses the phase 2 ECOG-ACRIN EA2186 (GIANT) trial (NCT04233866) evaluating gemcitabine and nab-paclitaxel (Abraxane) vs 5-fluorouracil (5-FU), leucovorin, and liposomal irinotecan in older patients with treatment-naive, metastatic pancreatic cancer. 

GIANT was an important trial because this older population of patients with metastatic pancreatic cancer had not been specifically studied before, Dotan began. The study enrolled patients who were at least 70 years of age with geriatric vulnerabilities, she continued. Patients were randomly assigned to receive modified gemcitabine and nab-paclitaxel or dose-reduced 5-FU plus leucovorin and liposomal irinotecan, she added.

Findings from the study showed that there were minimal differences in efficacy outcomes between the 2 arms, Dotan explained. The median overall survival values in the intention-to-treat population were comparable between the investigational (n = 76) and control (n = 78) arms, at 4.7 months (95% CI, 4.1-7.4) and 4.4 months (95% CI, 3.1-8.9), respectively (HR, 1.12; 95% CI, 0.76-1.66; 

In terms of safety, the toxicity rates were largely similar, with differences in the types of toxicities, Dotan said. For example, there were higher rates of neuropathy in the gemcitabine and nab-paclitaxel arm, whereas a greater incidence of diarrhea was observed in the 5-FU leucovorin and liposomal irinotecan arm, she said. Overall, the rates of grade 3 toxicities were approximately the same, she added.

Of note, patients who were able to remain on treatment for at least 4 weeks across arms (n = 127) achieved a median OS of 8.0 months (95% CI, 5.9-10.0), Dotan emphasized. This suggests that doses can be attenuated, leading to patients receiving less treatment while still achieving the same outcomes as standard dosing, she explained. How to best identify patients who would be candidates for this approach remains an open question, she said.

Patients with better baseline nutrition and quality of life measures were among those who achieved better outcomes, Dotan said. These findings underscore the importance of treatment personalization, she concluded.

Videos

Efrat Dotan, MD, discusses gemcitabine and nab-paclitaxel in treatment-naive, older patients with pancreatic cancer.

Dr Shameem on Selecting NALIRIFOX vs FOLFIRINOX in Advanced Pancreatic Cancer

“When I consider dose reduction, it gives me comfort to know that I know what I'm doing is what the [NAPOLI 3] trial did, [which demonstrated] efficacy [of a given agent in a given population].”

Raji Shameem, MD, a medical oncologist and hematologist at Orlando Health Cancer Institute, discussed clinical considerations for selecting NALIRIFOX (liposomal irinotecan [Onivyde], 5-fluorouracil, leucovorin, and oxaliplatin) vs FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) for the frontline treatment of patients with advanced pancreatic cancer. 

He emphasized the importance of aligning dosing strategies with those used in pivotal trials, noting that trial-based protocols for dose reductions provide a framework that ensures treatment efficacy is maintained and minimizes the risks associated with empiric, untested modifications. Findings from the phase 3 PRODIGE 24 trial (NCT01526135), which evaluated modified FOLFIRINOX (mFOLFIRINOX) in patients with resected pancreatic adenocarcinoma, demonstrated efficacy in a relatively younger patient population, as all patients in the mFOLFIRINOX arm of this trial were younger than 80 years of age, he said. 

In contrast, the phase 3 NAPOLI-3 trial (NCT04083235) of NALIRIFOX in patients with previously untreated metastatic pancreatic cancer enrolled a broader population without age restrictions, with the oldest enrolled patient being 85 years of age, and approximately 6% of participants 75 years of age or older, he explained. According to Shameem, this distinction between the trials is particularly relevant in practice settings with a high proportion of older patients, as it provides reassurance that efficacy and safety outcomes with NALIRIFOX were observed across a more inclusive age range.

Regarding patient selection, Shameem underscored performance status as a critical determinant. He noted that although both NALIRIFOX and FOLFIRINOX are reasonable for patients with good performance status, the use of regimens composed of multiple drugs in patients with an ECOG performance status of 2 or greater may lead to excess toxicity without proportional clinical benefit. He added that this consideration is particularly important in older patients, where the balance between tolerability and efficacy must be carefully assessed.

According to Shameem, the enrollment of older adults in the NAPOLI-3 trial supports the real-world applicability of NALIRIFOX, particularly in older populations often underrepresented in pancreatic cancer trials. He stressed that chronological age should not be the sole factor guiding treatment selection and that trial data demonstrating the safety and efficacy of NALIRIFOX in older patients provide additional confidence for oncologists considering intensive regimens in this group.

Raji Shameem, MD, discusses considerations for selecting between available chemotherapy regimens for patients with advanced pancreatic cancer.

 of irinotecan liposome (Onivyde) with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX), patients with metastatic pancreatic adenocarcinoma have gained a much-needed additional treatment option in the frontline setting; however, in the absence of head-to-head data, patient- and disease-related factors must drive treatment decisions when considering NALIRIFOX or FOLFIRINOX (fluorouracil, oxaliplatin, and irinotecan), according to Raji Shameem, MD, a medical oncologist and hematologist at the Orlando Health Cancer Institute in Florida.

At a median follow-up of 16.1 months (IQR, 13.4-19.1), findings from the phase 3 NAPOLI 3 trial (NCT04083235), which supported the 2024 regulatory decision, demonstrated that patients who received NALIRIFOX (n = 383) achieved a median overall survival of 11.1 months (95% CI, 10.0-12.1) vs 9.2 months (95% CI, 8.3-10.6) among patients who received nab-paclitaxel (Abraxane) and gemcitabine (n = 387; HR, 0.84; 95% CI, 0.71, 0.99; 

 The median progression-free survival was 7.4 months (95% CI: 6.0, 7.7) vs 5.6 months (95% CI, 5.3, 5.8), respectively (HR, 0.70; 95% CI, 0.59-0.85; 

®, Shameem discussed evolving frontline treatment options for metastatic pancreatic cancer, the effect that approval of NALIRIFOX has had on the frontline treatment paradigm in metastatic pancreatic cancer, and how he selects a frontline regimen for patients in this setting.

What is the current frontline treatment landscape for patients with metastatic pancreatic cancer?

: If you look at the National Comprehensive Cancer Network [NCCN] Guidelines, as many community oncologists do on a daily basis, it's sometimes hard to keep up to date with the new treatment options. For [patients with] pancreatic cancer, it had been more than a decade since we’ve gotten a new frontline therapy option.

NALIRIFOX is 1 of the new treatment options in the frontline setting. Prior to this, options included modified FOLFIRINOX and FOLFIRINOX, based on an important trial in 2011, the [phase 3] PRODIGE trial [NCT01526135], as well as gemcitabine plus nab-paclitaxel [Abraxane], based on the phase 3 IMPACT trial [NCT00844649].

When making [a frontline therapy] decision, I’d say every patient is different. Performance status is very important, and the NCCN guidelines highlight this. If a patient has a good performance status—ECOG 0 to 1—options would include a 3-drug regimen. For example, NALIRIFOX is a category 1 preferred option in this setting.

Since its FDA approval, how has NALIRIFOX been integrated into clinical practice?

[Clincians] are creatures of habit, and once we get used to something, we tend to stick with it. Our go-to regimen is FOLFIRINOX. [However], toxicity with conventional, run-of-the-mill FOLFIRINOX is tough, so we [often] use modified FOLFIRINOX.

It’s important to note that everyone’s modified FOLFIRINOX is different. You look at different institutions—even among the same providers—it's different. In my practice, we have our own modified FOLFIRINOX.

However, NALIRIFOX was a standardized regimen, [which was] evaluated NAPOLI 3, and the dosing was the same for every patient randomly assigned to that group. For NALIRIFOX, based on the trial’s dosing, efficacy, and safety, I’ve used it as an option for frontline therapy in my patients with metastatic pancreatic cancer.

What did it mean to have head-to-head data showing NALIRIFOX was superior to a long-standing standard of care in gemcitabine plus nab-paclitaxel?

That’s an important question. Prior to NALIRIFOX, we always assumed that 3 drugs were better than 2. However, in oncology—as in many fields—you shouldn’t make assumptions.

NAPOLI 3 compared infusional 5-fluorouracil, oxaliplatin at 60 mg/m², and liposomal irinotecan at 50 mg/m², vs gemcitabine plus nab-paclitaxel at standard dosing, just as it was administered in IMPACT.

Gemcitabine plus nab-paclitaxel was a standard frontline option, so this was truly a head-to-head trial between 2 frontline regimens for our [patients with] metastatic pancreatic cancer.

Since there hasn’t been a head-to-head comparison between NALIRIFOX and FOLFIRINOX, how do you choose between them in clinical practice?

One thing I do is look closely at the trial protocols, [including] how dose reductions were handled and when providers made those decisions. When I consider dose reductions, it gives me comfort to know I’m doing what the trial did rather than making it up as I go. That’s an important consideration.

I believe [NALIRIFOX and FOLFIRINOX] are reasonable for patients with good performance status. If a patient has an ECOG of 2 or more, a 3-drug regimen might lead to more toxicity than benefit.

It’s also important to note that when PRODIGE was conducted, there was an age limit—every patient was under 76 years old. In NAPOLI 3, there was no age limit. I believe the oldest patient was 85, and approximately 6% of patients were 75 years or older. That’s important because I practice in Florida and have an older population. I always say age is just a number, but it gives me comfort knowing that older patients were included in [NAPOLI 3].

Are there safety profile differences between NALIRIFOX and FOLFIRINOX that influence your treatment decisions?

It’s difficult to tease out differences in toxicity. There hasn’t been a head-to-head trial of NALIRIFOX vs modified FOLFIRINOX, and I see more similarities than differences.

I want to highlight that conventional irinotecan is different from liposomal irinotecan. Preclinical studies have shown that liposomal encapsulation may allow for better drug delivery of the active metabolite to tumor cells.

I’d say there are more similarities, [for example] diarrhea can occur with both [NALIRIFOX and FOLFIRINOX]. The key is knowing when to hold treatment and when to pursue dose reductions. [The findings from] NAPOLI 3 give us clear guidance on when to do that.

From a patient-centered perspective, how do those initial treatment conversations typically go?

That initial consultation with a patient who has been diagnosed with metastatic pancreatic cancer is overwhelming. Multiple family members are often in the room, and you’d be surprised how many patients ask me about NALIRIFOX. A lot of our patients are savvy—they’re looking up the most recent FDA-approved therapies, and I’ve been asked about NALIRIFOX specifically.

I review all available options, but I always make a point to mention the most recent FDA-approved treatment and talk about the NAPOLI 3 trial. A lot of patients want the newest option. I always counsel them on toxicity—no treatment is without toxicity—but a newer therapy can be very appealing.

What are the major unmet needs in first-line treatment, and where do you see the field heading?

Compared with other cancers, pancreatic cancer has far fewer targeted therapies. For all my patients with metastatic pancreatic cancer, I pursue next-generation sequencing [NGS] and germline genetic testing.

It’s important to know that patients [with disease] harboring somatic or germline homologous recombination–deficient alterations tend to respond well to platinum-based therapies. In those cases, I select a platinum regimen.

 mutations. Approximately 80% of patients with metastatic pancreatic cancer patients have disease with some type of 

 mutation. [For a long time], those mutations weren’t druggable; now, times have changed and we’re seeing the evolution of RAS inhibitors.

RAS inhibitors were evaluated initially in later-line settings and have shown impressive efficacy in pretreated patients. I foresee that these agents will move into the frontline setting—potentially in combination with chemotherapy. That’s an appealing option for patients who are [eligible to receive] all available therapies.

Many patients with pancreatic cancer don’t make it to second-line therapy—not because they don’t want it, but because the disease progresses so rapidly. When patients deteriorate, they deteriorate quickly. Therefore, combination therapy in the frontline makes a lot of sense.

How do you balance clinical trial participation vs starting an approved regimen?

Ever since I was in training, I always try to look for a clinical trial. Pancreatic cancer is estimated to be the second leading cause of cancer mortality by 2030, so we know that this is an aggressive disease. That’s part of the reason why I do NGS testing. The majority of our patients [cannot receive] targeted therapies, even on a clinical trial, but you never know which one of your patients might benefit from them. The idea of a clinical trial is always something I discuss with my patients, in addition to standard-of-care therapy,

FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 16, 2024. Accessed August 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma

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. 

. 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1

Raji Shameem, MD, discusses the significance of the FDA approval of NALIRIFOX and first-line treatment selection in metastatic pancreatic cancer.

NALIRIFOX Expands Options in First-Line Metastatic Pancreatic Cancer

Factors informing frontline treatment decisions in metastatic pancreatic cancer.

Navigating Frontline Treatment Decisions in Metastatic Pancreatic Cancer | Supplements and Featured Publications

NALIRIFOX Expands Frontline Options in Metastatic Pancreatic Cancer

Personalized, Patient-Centered Strategies Shape the Evolving Management of Metastatic Pancreatic Cancer

Dr Dotan on Gemcitabine and Nab-Paclitaxel in Treatment-Naive, Older Pancreatic Cancer

Dr Shameem on Selecting NALIRIFOX vs FOLFIRINOX in Advanced Pancreatic Cancer

NALIRIFOX Expands Options in First-Line Metastatic Pancreatic Cancer