December 16, 2022 • 4 Min

NAPOLI-3 Trial Meets Primary Endpoint in Metastatic Disease

Dr. Tanios Bekaii-Saab

With a disease as aggressive as pancreatic cancer, finding new regimens to control its spread and increase longer-term survival is a major focus of ongoing research.

In mid-2020, the results of a phase I/II study of a new regimen called NALIRIFOX was presented in a late-breaking abstract at the ESMO World Congress on Gastrointestinal Cancer. The data brought some promising news to a disease in desperate need of a win.

In that study, researchers including physician–scientist Tanios Bekaii-Saab, M.D., leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center (Rochester, Minnesota) and a consultant at the Mayo Clinic Hospital in Phoenix, Arizona, looked at the use of liposomal irinotecan (ONIVYDE) in combination with fluorouracil (5-FU), leucovorin, and oxaliplatin, a combination called NALIRIFOX, as a first-line treatment for patients with unresectable locally advanced or metastatic disease. That trial showed promising results with NALIRIFOX, leading to a study called NAPOLI-3. The preliminary results of that trial, which were just recently released, showed even more promise.

The NAPOLI-3 trial met its primary endpoint with the NALIRIFOX treatment regimen showing statistically significant improvement in overall survival compared to the standard-of-care gemcitabine plus nab-paclitaxel (Abraxane) regimen. It also met a key secondary endpoint of progression-free survival with a safety profile consistent with the previous study.

“But it’s important to remember the devil is always in the details,” says Bekaii-Saab, adding that further and full results from the NAPOLI-3 study will be presented at an upcoming medical conference.

“There will be more work to do, and you know I don’t make predictions,” he adds. “But I do think the data we have is moving us in the right direction. And hopefully this will provide us with another option for first-line treatment for our patients with metastatic disease. Our patients need that.”

That’s because metastatic pancreatic cancer has limited treatment options. And finding effective therapies and moving those therapies into earlier lines of treatment is an area of significant interest, explains Bekaii-Saab.

Fast-Tracking a Drug

In 2020, the U.S. Food and Drug Administration (FDA) granted Ipsen, the developer of ONIVYDE, Fast Track designation for the investigational use of ONIVYDE in combination with 5-fluorouracil/leucovorin and oxaliplatin together, known as NALIRIFOX, for patients with previously untreated, unresectable, locally advanced and metastatic pancreatic ductal adenocarcinoma. The FDA’s Fast Track program facilitates the development and expedites the review of drugs that treat serious conditions and have the potential to address an unmet medical need.

“Right now, what we have in first-line treatment for metastatic disease is gemcitabine/nab-paclitaxel and FOLFIRINOX as well as a few clinical trials,” says Bekaii-Saab. “It’s not enough, and we need options that improve on overall survival and progression-free survival.”

Overall survival with gemcitabine/nab-paclitaxel is about 8-12 months, and similar with FOLFIRINOX, at about 11-14 months. “It’s clear we need to do better than that,” Bekaii-Saab adds. “NAPOLI-3 was designed to see whether liposomal irinotecan plus 5-FU and oxaliplatin is associated with better outcomes versus gemcitabine/nab-paclitaxel.”

He also emphasizes that NALIRIFOX “isn’t just another FOLFIRINOX.” Indeed, there is a meaningful theoretical difference between irinotecan and liposomal irinotecan, he adds. Liposomal irinotecan is encapsulated by a nanoliposomal particle to prevent rapid metabolism in the peripheral blood and to potentially increase the concentration of the active drug into the tumor microenvironment.

Bekaii-Saab also believes it’s very important that NAPOLI-3 is the first study to compare a triplet regimen with the doublet regimen of gemcitabine/nab-paclitaxel. “We have never had data comparing this head-to-head, and that’s vital,” he says. “Gemcitabine/nab-paclitaxel when given weekly can be torturous for patients, and my preference is for bi-weekly administration. Since in NAPOLI-3 gemcitabine/nab-paclitaxel was given weekly, it will be interesting to see the toxicity differences between the two regimens.”

About the NAPOLI-3 Clinical Trial

In the phase III NAPOLI-3 trial, patients with previously untreated metastatic pancreatic cancer were randomized to treatment with the NALIRIFOX combination versus the standard-of-care combination of gemcitabine and nab-paclitaxel (Abraxane).

The trial met its primary endpoint, demonstrating clinically meaningful and statistically significant improvement in overall survival compared to gemcitabine plus nab-paclitaxel in 770 previously untreated patients with metastatic pancreatic ductal adenocarcinoma, and the key secondary efficacy outcome of progression-free survival also showed significant improvement over the active comparator arm.

The safety profile of ONIVYDE in the NAPOLI-3 trial was consistent with those observed in the previous phase I/II metastatic pancreatic cancer study.

The randomized, open-label study treated patients with the NALIRIFOX combination twice a month on days 1 and 15 of every 28-day cycle and compared it with injected gemcitabine and nab-paclitaxel 3 times a month on days 1, 8, and 15 of every 28-day cycle.

Other secondary outcomes for the study included objective response rate, quality of life, treatment-emergent adverse effects (AEs), serious AEs, and laboratory abnormalities.

To be included in the study, patients were required to have histologically or cytologically confirmed adenocarcinoma of the pancreas without prior treatment for metastatic disease, among other eligibility requirements.

Ipsen intends to file a supplemental New Drug Application with the FDA for ONIVYDE in combination with oxaliplatin plus 5-fluorouracil/leucovorin for the treatment of patients with previously untreated metastatic pancreatic cancer following the Fast Track designation granted in 2020.

Let’s Win will update this article when full results are presented in early 2023.