Weighing Real-World Data Vs Clinical Trials for NALIRIFOX in PDAC

Clinical trial data provide the foundation for regulatory approval, but oncologists often look to real-world experience and exploratory subgroup analyses to refine how a regimen is actually used in practice. NALIRIFOX (liposomal irinotecan [Onivyde], oxaliplatin, and fluorouracil, leucovorin)) was evaluated in the phase 3 NAPOLI-3 trial (NCT04083235), which reported a response rate of close to 50% in patients with metastatic pancreatic cancer.¹ Questions have since emerged about how that trial-reported efficacy translates to everyday clinical settings, as well as what post hoc analyses of the trial itself can tell oncologists about how to manage the regimen over time.

Following a Frontline Forums program, Timmy Nguyen, MD, and Raji Shameem, MD, discussed how real-world outcomes with NALIRIFOX compare with what was reported in NAPOLI-3, and how exploratory trial data have informed their approach to dose reductions. Nguyen described a pattern in his own practice consistent with the trial's reported response rate, noting that symptomatic patients receiving NALIRIFOX tend to see meaningful improvement in pain and appetite within the first few cycles. Shameem then turned to a post hoc exploratory analysis of NAPOLI-3 presented at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium, which examined outcomes among patients who required dose reductions of liposomal irinotecan or oxaliplatin.²

Shameem is a hematologist and medical oncologist at Orlando Health Cancer Institute, and Nguyen is a hematologist and medical oncologist at Cleveland Clinic Florida.

Transcript:

CancerNetwork: How do current real-world data on these PDAC therapies compare with reports from clinical trials? How might these real-world findings influence your clinical decision-making?

Nguyen: The overall use of NALIRIFOX [was found] to have a relatively pretty good response…. For patients who are somewhat symptomatic and getting NALIRIFOX, their symptoms improve in terms of the pain, and they're eating better. As patients respond well, they tend to feel better overall. It coincides with the response rate of close to 50% on the clinical trial, so I see at least half the patient population responded pretty quickly within the first few cycles.

Shameem: At ASCO GI, there was a lot of data presented, a lot of great data. But one thing specific to NAPOLI-3 is the exploratory post hoc analysis. We looked at dose reductions—this is exploratory, and this is not powered for significance—but what they did see is that for patients who did undergo dose reduction for liposomal irinotecan and for oxaliplatin, the ones who had dose reduction tended to have better outcomes [when] looking at survival. But we also know that the patients who are able to undergo dose reduction tend to be doing better from the get-go. But it gives me confidence that dose reductions don't seem to worsen outcomes. By no means does dose reduction improve survival, but that's just encouraging. I do quote the data when I talk to patients about dose reductions in my practice.

References

1. Hussein MA, Khan G, Chandana SR, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): updated overall survival analysis with 29-month follow-up of NAPOLI 3. J Clin Oncol. 2024;42(suppl 16):4136. doi:10.1200/JCO.2024.42.16_suppl.4136
2. Patel AJ, Laursen AA, Cockrum P, et al. Effect of dose adjustments on overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX: A post hoc analysis of NAPOLI 3. J Clin Oncol. 2025;43(suppl 4):716. doi:10.1200/JCO.2025.43.4_suppl.716