Meet The Professors: Pancreatic Cancer Edition, 2016 - Video 9Mechanism of action of nab paclitaxel and efficacy in combination with gemcitabine
4:32 minutes.
TRANSCRIPTION:
DR LOVE: So I was curious what you were saying about your thoughts about the mechanism of action of nal-IRI. In contrast, what’s your vision about mechanism — I mean, it sounds simple — mechanism of action of nab paclitaxel? DR BEKAII-SAAB: So again, another black hole of oncology is whether that albumin-bound piece is helping paclitaxel to get into the stroma at higher levels and higher concentration. And that’s the whole conundrum. And the thought that essentially in a very simple way attaching paclitaxel to an albumin-bound formulation that you will actually be able to achieve higher levels intratumorally. So with pancreas cancer more specifically, the original thought was that SPARC is like that hook that gets — DR LOVE: Can you explain that again, because it’s been a while since I’ve heard that talked about, SPARC? DR BEKAII-SAAB: It turns out that SPARC doesn’t matter, but — DR LOVE: Okay. Maybe that’s why they’re not talking about it. DR TEMPERO: It was a good story at the time. DR BEKAII-SAAB: But the original thought was, you have this protein called SPARC just sitting there in the stroma of pancreas cancer. And essentially, it hooks on that albumin and just pulls the paclitaxel into, and you get a higher concentration in the tumor. And you change a little bit the toxicity profile, because you have, again, less of it inducing the typical toxicities of paclitaxel. But it turns that SPARC doesn’t really matter for the activity of nab paclitaxel. And we don’t really know what, if anything, leads to that improvement when nab paclitaxel is added to gemcitabine. And the same question that brought about irinotecan and nanoliposomal irinotecan applies also to paclitaxel and nab paclitaxel. In pancreas cancer it’s never been done. It’s been done in other tumors. DR LOVE: Yes. I was just going to ask that question. Margaret, any sense, any guesses — we don’t have the data — how nab compares to just pac — we know there’s a difference in terms of allergic reaction, lack of corticosteroids, shorter infusion, but what about efficacy? DR TEMPERO: I think we have a sense, because there were previous trials with gemcitabine and a taxane. And we did not see the level of activity that we certainly see with gemcitabine and nab paclitaxel. So I think we kind of do have a sense that it is more active. DR BEKAII-SAAB: Yes, in some ways, although those studies never made it to the Phase III. But the other thing is, we did recently publish a study with, actually, carboplatin and paclitaxel in pancreas cancer. This was because we were working with a certain virus and the control arm had to be carboplatin plus paclitaxel, a Phase II randomized study. And it was very interesting. It got published in Molecular Therapy. It was very interesting, because the combination of carboplatin and paclitaxel historically performed equally well — and this was in first line — equally well as what you would expect with gemcitabine and nab paclitaxel. The survival was about 9 months, a little bit less than 9 months. And the PFS was 5.2 months. If you put the two together, they look eerily the same. Here’s the other thing: A lot of the critique was, “This is a clinical trial.” But think about it. We had 4 institutions along with us. And you see the next patient you want to put on a trial, first of all, you select off those patients who would go on FOLFIRINOX. And then the second is, because carboplatin and paclitaxel is nonstandard, then again you choose probably the less — and we had patients who were less well than what you would expect for gemcitabine/nab paclitaxel. And yet the results were eerily similar to gemcitabine and nab paclitaxel. So it raises that question, I think. DR TEMPERO: Right. But then you were adding a DNA-damaging agent. I mean, that was the key, don’t you think? DR BEKAII-SAAB: The platinum could have helped, certainly. The platinum could have helped with paclitaxel. But the experience with breast and lung doesn’t suggest that there is much of a difference. So the question mark remains with all these new formulations whether it’s nab or whether it’s nal. In pancreas cancer you feel compelled to use them, because options are few and you don’t have data with others that is as strong as with those two. But the question remains. |