NALIRIFOX Shows Promise in Early Studies

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.

The results of a phase I/II study of a new regimen called NALIRIFOX recently presented in a late-breaking abstract at the ESMO World Congress on Gastrointestinal Cancer brought some promising news.

The study 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. No new safety signals were observed in the 32 patients evaluated from the recommended NALIRIFOX 50/60 mg/m2 dose (primary endpoint). And study participants achieved median progression-free survival of 9.2 months and median overall survival of 12.6 months (secondary endpoints.)

“A lot of oncologists use liposomal irinotecan because it’s approved with 5‑FU for second-line treatment after patients progress on a gemcitabine‑based regimen,” explains lead investigator Zev Wainberg, M.D., Assistant Professor of Medicine at UCLA and co-director of the UCLA GI Oncology Program in Los Angeles. “What this study was really designed to do was move it to front-line treatment in combination with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) to try to develop a newer regimen. The next goal now that we have results showing anti-tumor activity and safety is to recruit into our randomized phase III study.”

That study is the international phase III investigation called NAPOLI-3. Researchers will be looking at the safety and efficacy of NALIRIFOX versus gemcitabine plus nab-paclitaxel in the first-line setting. The trials are sponsored by the pharmaceutical company Ipsen.

“The phase I/II trial was a small study that gave us reassurance that we could move forward,” says Wainberg. “Now we’re moving on to a randomized study, NAPOLI-3. It’s going to be about 750 patients who will be randomized one-to-one. One group will get the NALIRIFOX regimen and the other group will be randomized to the standard therapy of gemcitabine plus nab-paclitaxel.”

The study’s primary endpoint will be overall survival. “What’s clear is that we need other first-line treatments,” Wainberg adds. “One of the big questions in metastatic pancreatic cancer is can another combination approach provide patients with improved outcomes. Hopefully, we’ll see if NALIRIFOX is it.”

Treating advanced disease can be frustrating. “We have cases all of the time of people who out of the blue wind up with diagnoses of metastatic pancreatic cancer,” he says. “We all look at the data and try to determine how to best manage people with advanced disease. Unlike other cancers, pancreatic cancer has simply not responded well to immunotherapy, for example, and that’s frustrating for patients, all of whom know about immunotherapy and want it. It’s also frustrating for those of us who want better options to help our patients.”

The phase I/II trial began as a dose escalation study, and then an expansion study for patients with metastatic disease. There were four different cohorts to determine the right dose. In general, side effects were similar to a standard FOLFIRINOX regimen, although there was significantly less GI toxicity and less neuropathy, Wainberg says, adding there was comparable neutropenia.

“So I’m cautiously optimistic about this approach. I find the regimen a little more tolerable than classical FOLFIRINOX, which will hopefully lend itself to longer durability for patients,” Wainberg explains. “But anyone who treats pancreatic cancer should obviously be a little bit cautious as to how they approach any study. That’s why we need to do the randomized studies.”

About the Phase I/II Study and Results

The phase I/II, open-label trial was designed to assess the safety, tolerability, and dose-limiting toxicities of NALIRIFOX for the first-line dosing of study participants with locally advanced and metastatic pancreatic cancer. Secondary objectives were to assess clinical efficacy, defined by median progression-free survival and median overall survival, best overall response rate, overall response rate, disease control rate at 16 weeks, and duration of response.

The final analysis as of the data cut-off on February 26, 2020 included all study participants from the pooled population. The total was 32 participants, seven of whom were from the dose exploration phase and 25 of whom were part of the dose expansion phase.

Phase I/II Safety Results and Efficacy Results

There was no reported grade 3 or higher issues of fatigue or peripheral neuropathy. Some treatment emergent adverse events included neutropenia, febrile neutropenia, hypokalemia, and anemia, among others. Study patients saw a median progression-free survival of 9.2 months and median overall survival of 12.6 months. The best overall response included one complete response, 10 partial responses, and 15 stable diseases. Disease control was achieved by 71.9% of study patients at 16 weeks. Trial sponsor Ipsen has provided a more complete look at safety and efficacy results.

Details About NAPOLI-3

In June 2020, the FDA granted a fast track designation to the NALIRIFOX regimen for the first-line treatment of patients with unresectable, advanced pancreatic cancer The combination of liposomal irinotecan and 5-FU/leucovorin is also FDA approved for the treatment of patients with pancreatic cancer after disease progression following gemcitabine-based treatment.

NAPOLI-3 is a phase III, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Enrollment is ongoing. Visit the NAPOLI-3 trial page to learn more about the study and eligibility requirements.