Zev Wainberg, MD, ULCA Medical Center-Santa Monica, CA, shares results from the NAPOLI-3 study first presented at the 2023 ASCO Gastrointestinal Cancers Symposium, which found that first-line NALIRIFOX (liposomal irinotecan, 5-fluorouracil, leucovorin, oxaliplatin) demonstrated clinically meaningful and statistically significant improvement of both overall survival and progression-free survival compared with nab-paclitaxel plus gemcitabine for patients with metastatic pancreatic ductal adenocarcinoma.

Dr Wainberg pointed out the importance of this study’s results as “no study has shown an overall survival advantage in pancreatic cancer since 2010.”

Transcript:

Hi, my name is Zev Wainberg. I'm a medical oncologist at UCLA and I'm pleased to be talking to you today about a recent study that we presented. The study was called NAPOLI-3, and it's one of the largest randomized, phase 3 clinical trials done in metastatic pancreatic cancer.

Fundamentally, we wanted to answer the question: what is an optimal frontline therapy for patients with metastatic pancreatic cancer? We all know that unfortunately despite many, many trials, the only drugs that have shown improvements in overall survival have been chemotherapies. We really want to ask: what is the optimal chemotherapy? Because for about a decade now, we've landed in a situation where for adequate performance status patients, they're either getting gemcitabine plus nab-paclitaxel, or they're getting FOLFIRINOX, and there haven't been any head-to-head studies. The principle behind our study was to ask that question, albeit with a derivative of FOLFIRINOX called NALIRIFOX, which in place of parental irinotecan uses liposomal irinotecan.

Now, liposomal irinotecan has already been approved for second-line metastatic pancreatic cancer in people who progress on gemcitabine. We first [did] a phase 1 study looking at the combinations of 5-FU, leucovorin, oxaliplatin, and liposomal irinotecan. We got to a safe and tolerable dose, which actually is slightly different than FOLFIRINOX because we used less doses of oxaliplatin, and less doses of liposomal irinotecan. When we got to that safe and tolerable dose, we launched the phase 3 study, which randomized patients globally. It was a true global study, [including] over 20 countries [and] over 250 sites around the world. The study was launched and randomized patients 1-to-1 to either arm A, which is NALIRIFOX or arm B, which is gemcitabine plus nab-paclitaxel. The study really took patients who were newly diagnosed, untreated with metastatic disease and who had to have adequate liver and kidney function and ECOG performance status of 0 or 1. There was a total of 770 patients who were randomized. The primary end point of the study was overall survival.

The study was well-balanced for all the typical demographic criteria: age, gender, ethnicity. Region of the world was well-balanced. The majority of the study, about 65%, was enrolled in Europe, Australia, South America, with about 35% in North America. The study was well-balanced for all the demographic characteristics.

The primary end point of the study was met. We did improve overall survival from 9.2 months with the control arm to 11.1 months with NALIRIFOX. It met its statistical significance. The curve separated at about 3 months and stayed slightly separated through the duration. The hazard ratio was 0.83 and the P-value was 0.04. The secondary end point, which was progression-free survival, was also met, with a hazard ratio of 0.67 and roughly an improvement of about 2 months also, from 5.4 or so to 7.3 with NALIRIFOX.

The other end point of response rate numerically favored NALIRIFOX about 42% to 35% or so with gemcitabine plus nab-paclitaxel, but it did not meet statistical significance. No statistical correlation can be made in that regard.

These regimens had a very different toxicity profile. The NALIRIFOX arm had more gastrointestinal toxicities including diarrhea and nausea, which is not a surprise given the active agents in that regimen, of irinotecan-based therapies, versus gemcitabine plus nab-paclitaxel, which had a lot more cytopenia: more neutropenia, thrombocytopenia, and anemia relative to the NALIRIFOX arm. It really is a trade-off of toxicities when we talk to our patients.

In conclusion, we presented this data for the first time at the 2023 ASCO Gastrointestinal Cancers Symposium, and certainly there are still a lot of questions related to some biomarker work that will be ongoing, related to other secondary endpoints, which will be reported later, and which include quality of life assessments. We'll be presenting some updated data sets in the next 6 months or so at some other congresses.

Obviously, the comparison of this relative to FOLFIRINOX has been made. The cross-trial comparisons have been made. There are some nuanced differences with respect to toxicity here and dosing here that make it slightly different from FOLFIRINOX. But fundamentally, the study did meet its primary end point and, in that respect, we're pleased because no study has shown an overall survival advantage in pancreatic cancer since 2010. Hopefully, this regimen will be ultimately approved by the FDA once the submission is made. Thank you very much for your attention today.

Source:

Wainberg ZA, Melisi D, Macarulla T, et al. NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Presented at ASCO Gastrointestinal Cancers Symposium; January 19-21; San Francisco, CA. Abstract LBA661