NALIRIFOX and FOLFIRINOX Facilitate Personalized Treatment in Metastatic Pancreatic Cancer

After NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-fluorouracil [5-FU], and leucovorin) joined FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) in the frontline setting of metastatic pancreatic cancer, oncologists are now able to use safety considerations, care goals, and reduction strategies to better personalize treatment for patients, according to Raji Shameem, MD.

In February 2024, the FDA approved NALIRIFOX for the frontline treatment of patients with metastatic pancreatic adenocarcinoma.¹ The regulatory decision was supported by data from the phase 3 NAPOLI 3 study (NCT04083235), which demonstrated that treatment with NALIRIFOX translated to a 16% reduction in the risk of death compared with gemcitabine and nab-paclitaxel (Abraxane; HR, 0.84; 95% CI, 0.71-0.99; P = .0403). A significant progression-free survival (PFS) benefit was also observed in the investigational arm (HR, 0.70; 95% CI, 0.59-0.85; P = .0001).

“Similar to other gastrointestinal malignancies, frontline regimen selection is critically important in pancreatic cancer. We have several treatment options available, but many patients unfortunately do not make it to second-line therapy because of how aggressive the disease can be,” Shameem said in an interview with OncLive®.

In the interview, Shameem, a hematologist and oncologist at Orlando Health Cancer Institute in Lake Mary, Florida, discussed frontline treatment selection considerations in pancreatic cancer, the potential of NALIRIFOX and FOLFIRINOX as combination backbones, and factors that make patients good fits for a clinical trial in the frontline space.

OncLive: How has frontline chemotherapy decision-making evolved to offer more personalized care in pancreatic cancer?

Shameem:One of the most important emerging treatment strategies for pancreatic cancer is KRAS inhibition. Approximately 80% of patients have a KRAS mutation, which was historically considered an undruggable target.² However, we now have multiple agents in clinical development, and the early results have been very impressive in terms of both efficacy and safety.

At the 2026 Gastrointestinal Cancers Symposium, one of the oral presentations focused on INCB161734, which is a KRAS G12D inhibitor. Although the data are early, coming from a phase 1 study [NCT06179160] with early phase 2 follow-up, investigators observed encouraging response rates and disease control.³ Importantly, the study included heavily pretreated patients, with a median of 2 or more prior lines of therapy, but also provided insight into patients who received the agent in combination with chemotherapy.

That raises an important question: can we improve frontline chemotherapy efficacy by adding a KRAS inhibitor? [Although] these data are still preliminary, the combination appeared tolerable, with manageable safety, and patients were able to remain on treatment as long as they were deriving benefit. Confirmatory testing and randomized trials are clearly needed, but this approach is certainly intriguing.

How do FOLFIRINOX and NALIRIFOX lend themselves to being effective combination components given their safety profiles?

One of the most important considerations is tolerability. Unfortunately, most patients with pancreatic cancer are not going to be cured, so maintaining quality of life is critical. For regimens such as NALIRIFOX in the frontline setting, we have strong guidance from the NAPOLI-3 trial regarding appropriate dose reductions and timing.

For example, if a patient develops diarrhea or other gastrointestinal toxicities, there are clear protocol-driven recommendations on when to hold treatment and when to dose reduce. Many patients worry that dose reductions may compromise efficacy, but in NAPOLI-3, more than 50% of patients required dose interruptions or modifications and still derived benefit, including an overall survival advantage. That provides reassurance for both us and patients when making these decisions.

As more real-world data emerge with FOLFIRINOX and NALIRIFOX, what factors influence frontline chemotherapy decision-making?

Every patient is different. They have different comorbidities, different goals of care, and different tolerances for treatment. Disease burden is a major consideration. In patients with high-volume disease or visceral metastases—which is very common in metastatic pancreatic cancer—I want a regimen that can produce a rapid response.

When reviewing trial data, I look closely at overall response rates. [Although] we should never make direct cross-trial comparisons, the response rates seen in NAPOLI-3 were impressive and clinically meaningful, particularly given that many patients may not receive second-line therapy.

Performance status is also a key factor. Age alone should not be a contraindication to more intensive chemotherapy, although dose reductions or interruptions may be necessary to maintain tolerability. Notably, the NAPOLI-3 trial did not have an upper age limit, unlike the original [phase 3] UNICANCER-PRODIGE23 trial [NCT01804790] evaluating FOLFIRINOX. That inclusion of older patients gives me confidence that this regimen can be used safely in a broader, real-world population, including geriatric patients.

How do you decide between standard chemotherapy and enrolling a patient in a clinical trial?

In the frontline setting, I always discuss clinical trial options with my patients. At my institution, we do have trials available, but KRAS inhibitor trials in particular are not always easy to access. Some patients are willing to travel for a clinical trial, and others prefer to remain close to home and pursue standard-of-care therapy.

Clinical trials become even more important in the second-line setting. Patients who progress after NALIRIFOX or modified FOLFIRINOX have limited options outside of gemcitabine-based regimens. If a patient has an adequate performance status and a relevant trial is available, that is something I strongly consider.

Although approximately 80% of patients have KRAS mutations, it is important to remember that some do not and therefore require standard treatment approaches. For patients who progress on a frontline gemcitabine-based regimen, a liposomal irinotecan–based regimen remains an evidence-based second-line option supported by phase 3 data.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. Updated February 16, 2024. Accessed January 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
2. Luo J. KRAS mutation in pancreatic cancer. Semin Oncol. 2021;48(1):10-18. doi:10.1053/j.seminoncol.2021.02.003
3. Wainberg ZA, Henry JT, Park H, et al. Preliminary phase 1 results of INCB161734, a novel oral Kirsten rat sarcoma (KRAS) G12D inhibitor, as monotherapy or in combination with chemotherapy for advanced/metastatic pancreatic duct adenocarcinoma (PDAC). J Clin Oncol. 2026;44(suppl 2):654. doi:10.1200/JCO.2026.44.2_suppl.654