Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Winson Y. Cheung, MD, MPH, University of Calgary and CancerControl Alberta; Manuel Hidalgo, MD, PhD, Harvard Medical School and Beth Israel Deaconess Medical Center; Ramesh K. Ramanathan, MD, Mayo Clinic; Tanios Bekaii-Saab, MD, FACP, Mayo Clinic; Thomas Seufferlein, MD, University of Ulm
Johanna C. Bendell, MD: We talked a little about sequencing. We’ve mentioned nanoliposomal irinotecan, or MM-398. Thomas, tell us about nanoliposomal irinotecan. What’s the rationale behind it, and what kind of data have we seen?
Thomas Seufferlein, MD: I found it fantastic that for the first time, a pharmaceutical company took the risk of doing a second-line clinical trial in pancreatic cancer.
Johanna C. Bendell, MD: Very true.
Thomas Seufferlein, MD: This was unique. Before, you would run against the wall when you would propose such a trial. This is good and it actually led to approval, which is also excellent. Now we have an approved drug that is efficacious, prolongs survival, and is tolerable. We have, of course, some heme-related toxicity. We have some diarrhea, which is irinotecan related, but it’s manageable. It’s actually well tolerated by the majority of patients.
In Germany, we have another protocol. This is an academic trial, the off-protocol 5-FU/oxaliplatin regimen in a modified version. It seems to work very well, as well, at least in our hands in Germany. So, we have several options. We now also have approved phase III evidence for a drug combination that works in the second-line setting. I’m very happy about that, to be honest.
Johanna C. Bendell, MD: And this is a very interesting drug where we talk about drug delivery to a pancreas tumor. Tony, can you tell us a little bit about how it was designed and why we think it’s good?
Tanios Bekaii-Saab, MD, FACP: It’s intriguing. It belongs to this whole world of formulating drugs, liposomal formulations, and in this instance, it’s a nanoliposomal formulation where the thought is you pack a big punch of irinotecan in a liposome and you let it circulate around the system. In fact, it does do this over about a 3-day period with a very low leakage rate into the circulation. And most of the effective agent, SN-38, ends up in the tumor. The goal is, essentially, to try to optimize efficacy without changing much of the toxicity profile of irinotecan, which ends up being true here. The toxicities are very similar to what you would expect with irinotecan. So, it’s a very interesting formulation.
I think its impact is clearly shown—again, this is a second-line study—when we think about sequencing. We’re starting with gemcitabine/nab-paclitaxel, where neuropathy is a concern and 17% of patients will get grade 3 neuropathy. A regimen like oxaliplatin would probably be contraindicated, and then a regimen with noncrossover toxicities, like nanoliposomal irinotecan plus 5-FU, would fit perfectly. So, again, it fits this whole purpose of moving from what I call the kitchen sink approach—with FOLFIRINOX, for most patients—to a more sequential approach. And I think that really fits nicely in that sequential approach.
Johanna C. Bendell, MD: Ramesh, can you tell us a little bit about the NAPOLI study that got the approval for us?
Ramesh K. Ramanathan, MD: This was a phase III study in patients who failed gemcitabine. And looking at the paper, it also included third-line patients. About one-third of patients had failed 2 prior regimens. So, it started off as a 3-arm study. The weekly high-dose 5-FU was used in Germany with MM-398, or Onivyde. The study was amended to increase the numbers to give adequate power, and the combination of 5-FU and MM-398, what we call nanoliposomal irinotecan, was superior to 5-FU alone. There was about a 2-month difference, statistically significant, and that led to FDA approval. There have been some questions as to whether you can you use this after nab-paclitaxel/gemcitabine, because some of the patients in the study had received nab-paclitaxel/gemcitabine treatment. But about half of the patients had gemcitabine combination therapy, so I think it’s reasonable to use it after nab-paclitaxel/gemcitabine.
Johanna C. Bendell, MD: Yes, and the nonoverlapping toxicity profile is very nice. Winson, do you use it in Canada?
Winson Y. Cheung, MD, MPH: That’s a really good question. We’re still waiting for approval and access, actually. As physicians, I think we all want access to all potential options. I think it’s forthcoming. We’re really looking forward to having access for our patients.
Johanna C. Bendell, MD: And the toxicity profile? Diarrhea and neutropenia?
Tanios Bekaii-Saab, MD, FACP: It’s very similar to irinotecan. The one thing you skip is alopecia. There’s very little or no alopecia. I think that’s one thing about irinotecan that you see, and sometimes it’s an issue. In this instance, you don’t see alopecia. An important point when thinking about second-line is that the data from Germany were positive, but the data from British Columbia were negative. And we just recently published a meta-analysis looking at oxaliplatin versus irinotecan. In fact, the irinotecan-based regimens do better in the second-line setting (versus oxaliplatin-based regimens). Progression-free survival seems to be improved to about the same in both, but overall survival seems to favor irinotecan-based regimens in the second-line setting (versus oxaliplatin). Again, this fits the whole picture, I think, a little bit better. We still have very limited options in this disease. Hopefully, more are coming.
Thomas Seufferlein, MD: And there is concern about toxicity because we’re using irinotecan for such a long time. In colorectal cancer, it isn’t a problem for physicians to really handle side effects. These are not out of the ordinary, even less, as you say, alopecia. So, I think this is a very manageable protocol.
Johanna C. Bendell, MD: Yes. Then you could argue that maybe your sequence should be nab-paclitaxel/gemcitabine, 5-FU, and nanoliposomal irinotecan. But if they progress, you could still do another regimen. Would you move to a 5-FU/oxaliplatin regimen after that?
Tanios Bekaii-Saab, MD, FACP: Yes.
Manuel Hidalgo, MD, PhD: I would agree with that.
Tanios Bekaii-Saab, MD, FACP: Yes, I would agree.
Manuel Hidalgo, MD, PhD: Nanoliposomal irinotecan avoids the neurotoxicity that the oxaliplatin causes, sometimes, if the patient has preexisting neurotoxicity. What is missing in the NAPOLI study is a FOLFIRI arm. That’s what makes the study a little bit incomplete. Sometimes we have patients who have no reimbursement for Onivyde. Then, your dilemma is, do you do FOLFOX with a positive and a negative study? Or do you do FOLFIRI? We are doing FOLFIRI more and more.