The NAPOLI-1 Trial in Pancreatic Cancer

Transcript:Philip A. Philip, MD: We have been using gemcitabine plus nab-paclitaxel in the frontline treatment because of the benefit we’ve seen over gemcitabine alone, based on the MPACT trial. There is no trial that prospectively randomized patients to gemcitabine/nab-paclitaxel versus gemcitabine alone or nab-paclitaxel alone. So, we don’t have that sort of information, and to my knowledge, such a study is not being done. The use of gemcitabine and nab-paclitaxel in the second-line setting is simply something we’ve been doing because we don’t have other options to give patients most of the time, or in patients, especially, who have received fluoropyrimidine-based treatment in the frontline, such as the FOLFIRINOX regimen. In the absence of prospective control data, I can tell you that from my own experience and what is out there, based on other people’s experiences, we cannot give them full doses of the gemcitabine/nab-paclitaxel the majority of the time. If someone has received frontline treatment, and in this case it will be a FOLFIRINOX-type therapy, and they go for second-line treatment, you’ll be giving them gemcitabine/nab-paclitaxel. As a clinician, I cannot see that I can give them the full dose because oftentimes I end up with myelosuppression being one of the problems for which I have to give the reduced dose. And, in fact, people at Yale looked at their experience and they found that they had to stop therapy with lower doses. Not only that, they had to do further dose reductions. The question is, what is the efficacy of gemcitabine/nab-paclitaxel in the second-line setting? We don’t have a good handle on it. We know that some patients will respond to the treatment; we know that the treatment may delay the progression. But, I can’t make a statement about how good that would be.

So, one thing we also don’t know is the use of nab-paclitaxel as a single agent in the second-line or even in a third-line setting. I have experience with it and I’ve seen some patients who can benefit, and mainly I see a transient drop in the CA19-9 levels. But, I would say that I have not seen a patient who had a major response or benefit to a single-agent nab-paclitaxel treatment in the second-line or third-line setting. Certainly, the use of nab-paclitaxel in the second- or third-line setting also can be limited by patients who had developed neuropathy on the frontline treatment, like with oxaliplatin. That may be a reason why you can’t even give it in the second-line setting in some patients who are still trying to recover from the neuropathy. But, I can tell you that’s not really a common problem.

NAPOLI-1 was a randomized study that prospectively looked into the benefits of combining nanoliposomal irinotecan, also known as MM-398, combined with 5-fluourouracil and leucovorin versus 5-FU/leucovorin alone. There was also a third arm of the study which included single-agent MM-398. Patients who were included were those who failed gemcitabine-based therapy. That could be gemcitabine alone, or gemcitabine combined with other agents such as nab-paclitaxel. Or, in fact, there were also a few patients who had other combinations like with 5-fluourouracil or capecitabine. So, it was a study that was based on patients failing frontline treatment. And failing frontline treatment not only means that the disease was progressing on the frontline treatment, but it could be that patients were not able to tolerate the frontline therapy. Patients had good performance status, 0 or 1, so they were not the typical patients we see in some practices. A lot of the patients who come to us with failure on the frontline therapy might not be in a category of favorable performance status.

There was a selection of good patients, if you will, and, in those patients, there was definitely a benefit of the combination of the MM-398 plus 5-FU versus 5-FU alone. And there was a 2-month improvement in survival. And, usually, in a disease like pancreatic cancer, where survival is really short, a 2-month benefit is certainly worthwhile. Obviously, the question would be, are these a good 2 months or are they a bad 2 months? And that comes down to, did they have a lot of side effects or did they have manageable toxicity? And I can tell you up front that the toxicity or the side effects of the treatment were as to be expected from this combination, and that it was certainly manageable. It wasn’t like people were seeing severe toxicities requiring lots of hospitalizations or even death from treatment. It was a manageable toxicity profile as we would have expected from this combination treatment based on our knowledge of irinotecan, but also based on our knowledge of the outcome of the initial studies that led to this study.

Transcript Edited for Clarity