The Evolution of Sequencing Strategies in Pancreatic Cancer - Episode 5

Liposomal Irinotecan in Advanced Pancreatic Cancer

Transcript:Johanna Bendell, MD: So, everybody’s been alluding to all of the second-line data. Caio, tell us a little bit more about MM-398, or nanoliposomal irinotecan, and the data that we saw emerge for the second-line setting.

Caio Max S. Rocha Lima, MD: They are actually interesting and exciting data because it changed the landmark. We now have a randomized phase III trial in patients previously treated with gemcitabine-based therapy. They were randomized either to 5-FU (fluorouracil) and leucovorin, to the combination of 5-FU/leucovorin plus liposomal irinotecan, or just to the single agent with the liposomal irinotecan. And that trial actually tells 2 important endpoints: liposomal irinotecan, despite being an active agent, is not superior to 5-FU/leucovorin. The winner was the combination therapy. You had an immediate survival of 6.2 months as compared to 4.2 months. That is clinically meaningful. There was also an associated improvement in progression-free survival and response rate, as well as an improvement in the decrease of CA19-9.

Historically, there is a very close relationship between progression and quality of life in cancer. Going back to the FOLFIRINOX data, patients had very good performance status. Measurements of a drop in quality of life and progression were mimicked. There was a major improvement in the quality of life (by the lack of drop in quality of life) in the FOLFIRINOX group as compared to the gemcitabine group based upon the fact that the patients progressed much slower in the FOLFIRINOX arm—it actually was 2 times slower in the FOLFIRINOX arm over the gemcitabine arm.

Johanna Bendell, MD: So, you’re talking about the original, first-line setting?

Caio Max S. Rocha Lima, MD: The first-line, right. Mimicking that into the second-line setting (it was not, as you know, incorporated in that trial, but one could segue to that), the same phenomenon may have a place in this—not only in improving survival, but also in maintaining quality of life. But again, if you go there, it is directed toward a selected patient population. And when the patients progress with pancreatic cancer, their performance status may drop, their organ function may drop, and we do not have the opportunity to take them into the second-line setting.

Johanna Bendell, MD: And John, we know that in pancreatic cancer, the tumor itself is a hard nut to crack. So, what makes nanoliposomal irinotecan so special? This is the whole issue with a drug delivery type of development.

John Marshall, MD: I was thinking the same thing. We’ve been having this debate, internally, about whether liposomal encapsulation is important for the benefit in this patient. It’s more toxic than regular irinotecan. And we already know that irinotecan, in a frontline setting, has activity. It’s more expensive because it’s a new drug. So, is it worth it?

And the principle, of course, is that it changes the pharmacology. It may be delivery, but we know it changes the exposure in the pharmacology, and you see that then in the toxicity—it’s a longer exposure to these folks. So, I don’t think we know the answer to that yet (if we could swap them out). It’s certainly a very positive result. We’ve got to run with that and figure it out.

We certainly see it with frontline therapy and, you know, paclitaxel. So, it may be something about that drug delivery that gets it to the tumor better, hangs on to it, if you will, and delivers the drug. What we need to do is figure out if that delivery is important to the overall response.

Johanna Bendell, MD: Yes. You mentioned this increase in toxicity. Can you tell us a little bit more about what people should expect when they’re using that?

John Marshall, MD: Yes. You may just think that it’s “a little infusion of irinotecan” and you’re there. A little more diarrhea, a little more myelosuppression, a little more fatigue, and a little more nausea, I would say, are all on the list. But it’s a drug that can be given. It’s dosed and dose-modified accordingly. It’s not super spicy, but it’s one you’ve got to pay attention to. Remember, this is in a second-line pancreatic cancer patient who’s already been through a little bit by this point. They’re good patients, they’re trained, and they know how to report (which is good), but they’ve also been around the block a couple of times, so they can be worn out.

Transcript Edited for Clarity