NAPOLI-3: Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma


A review of recent data from NAPOLI-3 comparing the NALIRIFOX chemotherapy regimen versus nab-paclitaxel plus gemcitabine for patients with metastatic pancreatic ductal adenocarcinoma.

Rohit Gosain, MD: Certainly, as you're talking about pancreatic cancer, and this being devastating disease, our next study focuses on this, particularly in metastatic settings, NAPOLI 3. Previously, we had covered this study post-GI ASCO 2023, but now we have updated overall survival data. Dr Beg, if you can please dig a little deeper into the study design and its findings following that.

Muhammad Shaalan Beg, MD: Yeah, the NAPOLI 3 trial looked at nanoliposomal irinotecan based FOLFIRINOX and compare that with gemcitabine nab-paclitaxel. And it's the first time that these two regimens have been compared head-to-head for a newly diagnosed group of pancreatic cancer patients. They took people who had confirmed pancreatic cancer, newly diagnosed metastatic disease with good performance status and randomized them to this- to one of these two regiments. For those who are not familiar this is the modified FOLFIRINOX regimen where the irinotecan has been replaced with nanoliposomal irinotecan at 50 milligrams per milliliter squared, and the 5-fluorouracil leucovorin oxaliplatin is fairly similar to what we're used to seeing the oxaliplatin being 60 milli per meter squared given every two weeks and the Gem nab-paclitaxel is the way we've been giving it for years, day one end with 15. And they randomized patients head-to-head and when you look at the Kaplan-Meier curves, the orange Kaplan-Meier curve, which was the NALIRIFOX had a higher median overall survival compared to Gem nab-paclitaxel at 11.1 months, compared to 9.2 months. We had seen early results and GI ASCO and made a plenary presentation at GI ASCO and it's good to see that this survival benefit has maintained itself at the 18-month mark where the difference in overall survival at 18 months is 19 months versus 29 months. So, I think we have a winner in terms of selecting 5-fluorouracil versus gemcitabine-based regimens for pancreatic cancer. And for people who are about to start their treatment with who have been diagnosed with metastatic pancreas cancer, I think the discussion is much simpler now that we have the results of the studies, previously we- I would at least present both options and make the decisions largely based on whether someone is able to carry a pump, and whether they can come in on day eight, and what their risk of neutropenia is, but now we have clear oncologic data that one is oncologically superior to the other.

Rahul Gosain, MD: Dr Beg in this particular study, I think a fair criticism is was Gem Abraxane a fair comparator arm because ideally, we would have liked to see modified FOLFIRINOX because now we're stuck with this cross-trial comparisons saying, now NALIRIFOX is very similar to modified FOLFIRINOX, and if this is approved, which one do you use?

Muhammad Shaalan Beg, MD: Yes, this study didn't try to answer that question. We had the same question when Gem nab-paclitaxel clinical trials came up is that nobody compared it with regular Rituxan, and why are we jumping straight to nab-paclitaxel. So, I think we can only interpret these results based on the question that they set out to answer which was to compare it with standard of care FDA approved, Gem nab-paclitaxel which before this study started, everybody would have- most people would have said that these regimens are equivalent. So, it was a very fair comparator to be evaluated with but if the question was going to be whether nanoliposomal irinotecan is better than regular irinotecan, that's not what the study was trying to address for better or for worse.

Rahul Gosain, MD: Absolutely.

Muhammad Shaalan Beg, MD: And we're kind of stuck with those results.

Rohit Gosain, MD: Now we do know that nanoliposomal irinotecan does perform at later lines. Now when in comparison to the first line if we utilize that, would you keep the Gem Nab-paclitaxel or gemcitabine approach single agent in the later lines then?

Muhammad Shaalan Beg, MD: Yes, you're right. That's a very important point. Nanoliposomal irinotecan now has activity both in the first line as part of NALIRIFOX and in the second line in combination with 5-FU. We don't have good second line data of Gem Nab-paclitaxel, after progression of 5-FU based regimen. That is what folks are doing in clinic, it is very hard to give gemcitabine Nab-paclitaxel three weeks in a row in general, let alone as a second line in pancreatic cancer. So, folks are frequently modifying that both in the first- and second-line regimen. But given there aren't many other comparator treatment options, and we know that this regimen has activity in pancreatic cancer. I think it's a very reasonable second line options for people after they've progressed on by FU based chemotherapy.

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