Frontline Liposomal Irinotecan/NALIRIFOX Improves Survival in mPDAC

Zev A. Wainberg, MD

In the pivotal phase 3 NAPOLI 3 trial (NCT04083235), the combination of irinotecan liposome injection (Onivyde), 5-fluorouracil (5-FU), oxaliplatin, and leucovorin (NALIRIFOX) improved overall survival (OS) and progression-free survival (PFS) compared with nab-paclitaxel plus gemcitabine in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

At a median follow-up of 16.1 months (95% CI, 15.3-16.8), 383 patients in the intent-to-treat (ITT) population who were given liposomal irinotecan plus NALIRIFOX elicited a median OS of 11.1 months (95% CI, 10.0-12.1) vs 9.2 months (95% CI, 8.3-10.6) for the 387 patients administered nab-paclitaxel plus gemcitabine (HR, 0.83; 95% CI, 0.70-0.99; P = .04).

The randomized, open-label NAPOLI 3 study enrolled patients with metastatic disease diagnosed 6 or less weeks prior to screening who had at least 1 metastatic lesion measurable by MRI or CT scan per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.

Patients in the trial were randomly assigned in a 1:1 ratio to receive 50 mg/m2 of liposomal irinotecan plus 2400 mg/m2 of 5-FU, 400 mg/m2 of leucovorin, and 60 mg/m2 of oxaliplatin on days 1 and 15 of each 28-day cycle, or 1000 mg/m2 of gemcitabine plus 125 mg/m2 of nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle. Investigators assessed OS as the primary end point of the study and the secondary end points of investigator-assessed PFS, overall response rate (ORR), and safety.

Additional data from the NAPOLI 3 trial presented at the 2023 Gastrointestinal Cancers Symposium showed that patients given the experimental arm of liposomal irinotecan and NALIRIFOX had a median PFS of 7.4 months (95% CI, 6.0-7.7) vs 5.6 months (95% CI, 5.3-5.8) with the control combination of nab-paclitaxel and gemcitabine (HR, 0.69; 95% CI, 0.58-0.83; P < .0001). The ORR for the experimental arm was 41.8% (95% CI, 36.8%-46.9%) vs 36.2% (95% CI, 31.4%-41.2%) for nab-paclitaxel/gemcitabine, and the complete response rate in both arms was 0.3%.

“I think that this adds value for the pancreatic cancer community, and I think it helps us springboard into the future, because now we have a new reference regimen that we can use to add drugs and to look at other strategies to improve outcomes,” said Zev A. Wainberg, MD, in an interview with Targeted Oncology^TM.

In the interview, Wainberg, a professor of medicine at University of California, Los Angeles, and co-director of the UCLA GI Oncology Program, discussed the rationale behind NAPOLI 3 and how findings from the study will influence the mPDAC space moving forward.

Targeted Oncology: What can you tell me about the NAPOLI 3 trial you presented at this year's ASCO GI meeting?

Wainberg: We presented the final results of the NAPOLI 3 trial which was a large, global, randomized, phase 3 trial in newly diagnosed patients with metastatic pancreatic cancer. The patients were randomized 1:1 to receive 1 of 2 chemotherapy regimens. Arm A was a regimen called NALIRIFOX, which was the combination of 5-FU, oxaliplatin, leucovorin, and liposomal irinotecan, and arm B was another regimen of nab-paclitaxel plus gemcitabine was another regimen.

The rationale behind this study, which has been the question for some time in pancreatic cancer is, is there an optimal chemotherapy regimen for newly diagnosed patients? We haven't had head-to-head data in this field ever for this question. So, this study attempted to answer that question to some extent.

What were the methods and design of the trial?

The study was a global study enrolling in 20 countries around the world with hundreds of sites. It was an intent to treat analysis with a randomized design in which patients were randomized 1:1 to 1 of those 2 arms. The primary end point of the study was overall survival. The secondary endpoints were progression-free survival, response rate, and safety.

Can you discuss the recent findings from NAPOLI 3?

We presented the top-line results, which included the overall survival, which was statistically significantly improved in the group of patients who've got NALIRIFOX over nab-paclitaxel plus gemcitabine by about 2 months. The median improvement was about 2 months, the hazard ratio is .83, and the P value is .04. The statistics also showed that this progression-free survival was superior with NALIRIFOX over nab-paclitaxel plus gemcitabine. There was no statistically significant difference in response rate, although the response rate was numerically higher with NALIRIFOX, but it did not make statistical significance.

The safety of the regimens essentially is a tradeoff, in my opinion, of toxicity between 1 regimen that causes more of the GI toxicity that have been influenced at higher rates of diarrhea and nausea, as opposed to higher rates of cytopenias, which are neutropenia, anemia and thrombocytopenia. Those were seen more commonly in the nab-paclitaxel plus gemcitabine arm. It is a tradeoff of toxicity profiles when one talks to their patients.

How can you hopefully use these data to and build off of them in the future?

We haven't had head-to-head data [before], so it's good to have that in this field. In my opinion, it's good to ask the questions for the community about what the optimal frontline regimen is? I think to some extent, we have answered that question here as best as we can. I think that this adds value for the pancreatic cancer community, and I think it helps us springboard into the future, because now we have a new reference regimen that we can use to add drugs and to look at other strategies to improve outcomes. Certainly, nobody's satisfied with the state of affairs, so we have an obligation to build off this to improve outcomes with new additions.

What unmet needs still exist in the space?

We have many unmet needs, and they include which patients might benefit more than others. I think that's always an ongoing question, pancreatic cancer to look at biomarker subsets. That's something we haven't yet looked at in the study, but we intend to. We also

can improve, and hopefully make an impact in the second-line of therapy by using gemcitabine and nab-paclitaxel as a standard second-line regimen and add agents to that context, that might be 1 of the new avenues we can explore. There are several different opportunities to use this as a leverage point in which to design future trials and go from there.

For the community oncology audience, what do you think are some important takeaways from this study?

The community oncology audience is the primary audience we hoped to help by doing this study. I think we can now safely answer the question that a 4-drug regimen, in this case NALIRIFOX, is superior to nab-paclitaxel plus gemcitabine in an average ECOG 0-1 patient. That's my main conclusion. I think that there's obviously some nuance differences between FOLFIRINOX and NALIRIFOX that will be the subject of much discussion. But in terms of answering a question for the community, I think we can feel good that in an average ECOG 0-1 patient, we now have an answer to the question.

REFERENCE

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. J Clin Oncol. 2023;41(suppl 4):LBA661. doi:10.1200/JCO.2023.41.3_suppl.LBA661