Following the February 2024 FDA approval 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.1
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; P = .0403).2 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; P = .0001).
In an interview with OncLive®, 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.
OncLive: What is the current frontline treatment landscape for patients with metastatic pancreatic cancer?
Shameem: 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.
Typically, NGS results show TP53 and KRAS mutations. Approximately 80% of patients with metastatic pancreatic cancer patients have disease with some type of RAS 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,
References
- 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. Lancet. 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1