NALIRIFOX Prolongs Survival With a Tolerable Safety Profile in mPDAC

NALIRIFOX (irinotecan liposome injection [Onivyde] plus 5-fluorouracil, leucovorin, and oxaliplatin) represents a potential new first-line standard of care (SOC) for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), according to Davide Melisi, MD, PhD, who noted that pending FDA approval, this effective and tolerable regimen could also inform future clinical trials designs for patients with pancreatic cancer.

In June 2023, the FDA accepted an supplemental new drug application seeking the approval of frontline NALIRIFOX for patients with mPDAC. The application was backed by findings from the phase 3 NAPOLI 3 trial (NCT04083235), which investigated NALIRIFOX vs nab-paclitaxel (Abraxane) and gemcitabine. In NAPOLI 3, treatment with NALIRIFOX led to statistically significant overall survival (OS) and progression-free survival (PFS) improvements compared with nab-paclitaxel plus gemcitabine, with respective HRs of 0.83 (95% CI, 0.70-0.99; P = .04) and 0.69 (95% CI, 0.58-0.83; P = .0001).

“These results are crucial because they establish for the first time that starting the treatment of a newly diagnosed patient [with mPDAC] with a 3-drug combination provides an advantage over starting with only a 2-drug regimen, marking a positive step forward in addressing the unmet needs for patients with pancreatic cancer,” Melisi said.

In an interview with OncLive®, Melisi discussed the treatment needs of patients with metastatic pancreatic cancer, key findings from the NAPOLI 3 trial, and the potential implications of an FDA approval of this regimen in this population.

Melisi is an assistant professor of medical oncology in the Department of Medicine at the University of Verona in Italy.

OncLive: What unmet needs exist for patients with metastatic PDAC that NALIRIFOX may address?

Melisi: Patients diagnosed with metastatic pancreatic cancer face significant challenges. There is a huge need for better treatments. Every year, approximately half a million patients are diagnosed with pancreatic cancer worldwide. The survival rate, especially for patients diagnosed with the disease in an advanced stage, is quite low.

Despite the advances in cancer research, there hasn’t been much progress in either detecting or managing pancreatic cancer in the past years. If this trend continues, pancreatic cancer is suspected to become the second leading cause of cancer-related deaths in Western countries by 2040. For almost a decade, there hasn’t been any significant improvement in the initial treatment options for patients with metastatic pancreatic cancer.

The NAPOLI-3 trial, which explored NALIRIFOX, brought a breakthrough. It showed that this new treatment, which [adds] liposomal irinotecan to a 3-drug combination strategy, is more effective than 1 of the most commonly used standard chemotherapeutic regimen for newly diagnosed patients, the combination of nab-paclitaxel plus gemcitabine. That was the control arm of the NAPOLI-3 trial.

What enrollment criteria did the NAPOLI 3 trial have, and how accurately did the trial population reflect the real-world mPDAC population?

The NAPOLI 3 trial enrolled patients who were recently diagnosed with metastatic pancreatic cancer. Patients needed to be in good general health, [with an] ECOG performance status of 0 or 1. There were no age restrictions. Patients as old as 85 years were part of the trial. The population of the trial recapitulates what we are used to seeing in our daily practice.

What were the key efficacy outcomes of NAPOLI 3?

The primary end point was OS. The NAPOLI 3 trial demonstrated that the NALIRIFOX regimen improved OS duration compared with standard nab-paclitaxel plus gemcitabine. [We also observed a] prolongation of PFS [with NALIRIFOX vs SOC]. It’s important to note that the benefits in these 2 clinical outcomes were consistent across different groups of patients based on different clinical characteristics, [such as] age, number of metastatic sites, and ethnicity, because the trial was conducted globally. These advantages were consistent in favor of the NALIRIFOX regimen.

What safety considerations with NALIRIFOX are important to remember?

The topic of safety has been a crucial aspect of this study because before this trial, the decision that oncologists had [to make] between using a 3-drug combination or a 2-drug regimen often depended on the different adverse effect [AE] profiles [of each regimen], with the general belief that the 2-drug combination was safer than the 3-drug regimen. Now, the NAPOLI 3 trial, [in which investigators] conducted a head-to-head comparison between these 2 different kinds of combination regimens, provides a clear answer to this long-debated question.

Patients receiving NALIRIFOX stayed on treatment significantly longer, more than 1 cycle longer, than those receiving gemcitabine/nab-paclitaxel. Also, notably, AEs were the main reason for stopping treatment in approximately one-quarter of patients receiving nab-paclitaxel plus gemcitabine, but only approximately 14% of those receiving NALIRIFOX stopped the treatment for this same reason. These 2 regimens had different AE profiles. NALIRIFOX [was associated with] a higher rate of gastrointestinal issues, especially diarrhea. On the other end, serious blood-related AEs, and peripheral neuropathy, which is a concern with other regimens containing oxaliplatin, were more common with gemcitabine plus nab-paclitaxel.

If NALIRIFOX gains approval from the FDA and other regulatory agencies for patients with mPDAC, what would be the significance of those decisions?

Getting NALIRIFOX approved by different regulatory agencies will be important, first, for our patients, who could take advantage of a novel regimen that has clearly [produced] improved efficacy. [The regulatory approval of this regimen] is also important for clinical research because it could open the path for novel clinical investigations, [such as] exploring a better second-line treatment after NALIRIFOX. We don’t know the best regimen [to utilize] after NALIRIFOX [and we need] to establish a clear, sequential therapeutic strategy. Most importantly, the approval of NALIRIFOX could allow for the use of this regimen as a novel chemotherapeutic backbone for future clinical trials in combination with novel, experimental therapeutics, which could be targeted agents or immune checkpoint inhibitors. This [approval would] open opportunities for more advanced and effective strategies in this disease.

Beyond potential regulatory approval, what does the future look like for NALIRIFOX in pancreatic cancer?

In the NAPOLI 3 trial, NALIRIFOX generated a significant increase in response rate. In light of this finding, we recently conducted another trial, [the phase 2] nITRo trial [NCT03528785]. In this trial, we explored the activity of NALIRIFOX in patients with resectable pancreatic cancer, not metastatic [disease. This trial included patients who] could be considered for surgery, and treatment was given for 3 [cycles] before and 3 [cycles] after surgery [with NALIRIFOX]. The goal was to shrink the pancreatic mass, making a complete removal of the mass more likely, and to prevent future metastasis by providing systemic treatment earlier.

[This trial] enrolled 100 patients and [generated] a higher rate of complete resections compared with our previous experiences. The patients who underwent surgery after receiving NALIRIFOX also had promising survival [outcomes,] with a median [OS of 44.3 months]. We are hopeful that future randomized trials can confirm these results because this [research] could establish NALIRIFOX as a new standard treatment for patients with pancreatic cancers across all stages, from early disease to advanced disease.

Reference

Ipsen announces US FDA submission acceptance of its supplemental new drug application for Onivyde regimen in first-line metastatic pancreatic ductal adenocarcinoma. News release. Ipsen Biopharmaceuticals. June 14, 2023. Accessed January 10, 2024. https://www.ipsen.com/us/press-releases/ipsen-announces-u-s-fda-submission-acceptance-of-its-supplemental-new-drug-application-for-onivyde-regimen-in-first-line-metastatic-pancreatic-ductal-adenocarcinoma/