DR GROTHEY: Aflibercept will go head to head, more or less, with bev beyond progression. That’s where the data are. The data are very similar. Toxicity profile is different.
Whenever a novel agent comes about, you like to get your hands on it and you like to use it. I’d like to use aflibercept just to see how it is and how patients feel on it. But I could see that after this initial take-up is kind of a stable down — that a lot of people will probably go for bev beyond progression, something that we’ve been using for quite some time in first-line therapy and in second-line therapy now. Because the data are very, very similar because of the better toxicity profile.
DR LOVE: So Charlie, how would you think you might approach it? And would you approach it different if you needed a response?
DR FUCHS: It’s a great question. The relative benefit appears to be similar between TML and VELOUR. I think I’d like to try to use it. I haven't ever used the drug yet. But my guess is, initially my practice may be a preponderance of using bevacizumab.
DR KULKE: I think I might actually go the other way. It seems like the relative benefits are similar. We don’t have firm data one way or the other. We do know that aflibercept, perhaps, has a slightly different mechanism of action, maybe there's a little better benefit there. So I might be tempted to switch.
DR O'NEIL: I think aflibercept has a tough hill to climb because, frankly, the TML study is more relevant to our practice than the VELOUR study because all of the patients got up-front bevacizumab. For VELOUR, we have to take it on faith that it really is just as good in patients who already got bevacizumab as it is in patients who didn’t because it’s just a subset analysis.
So that, to me, is a problem. I think we really need to see a head-to-head trial before I’d be convinced that I should use aflibercept instead of just using bevacizumab.
DR BERGSLAND: I agree that the path of least resistance will be to continue bevacizumab in a patient who’s tolerating it well. I actually do think the aflibercept data are intriguing, again, because of the potentially different mechanism of action and the fact that it binds all of the ligands for the VEGF receptor as opposed to just VEGF. But I would guess what will happen is that patients may end up getting all of these agents and that they may try one. They may continue bevacizumab with FOLFIRI in the second-line setting, and if that doesn’t work they may ultimately get aflibercept, which I think is a really interesting question. But the issue is, it isn’t. We haven’t answered it yet. But I think certainly, what we see clinically when we see patients that are referred in, often heavily pretreated, they’ve often gotten multiple regimens in various combinations, often things that aren’t necessarily proven and established, but there are certainly anecdotally patients who seem to have benefitted from these various combinations, sometimes given again with capecitabine instead of 5-FU, et cetera.
So the bottom line is, I think that’s what’s going to happen — people may end up seeing both drugs.
DR BEKAII-SAAB: You’ve mentioned the response rate, and FOLFIRI/aflibercept does seem to have an intriguing response rate of 20%. I must remind everyone that ECOG-3200 with FOLFOX/bevacizumab in the second line had a response rate of 20, 21% as well, very similar. And the group with FOLFIRI/aflibercept that was exposed to bevacizumab actually had even a lower response rate, close to 12%.
So if you’re exposed to the VEGF inhibitor bevacizumab, you actually lose some of that response rate in the subset analysis. So I’m not as intrigued by the differences in response and I do agree that given the familiarity with bevacizumab and given the TML data that’s very similar to all others, and given the fact that the toxicities are more invisible, it's going to continue to be bevacizumab in the second line.
DR LOVE: Do you see yourself, Alan, using aflibercept? And if so, where?
DR VENOOK: I feel like a dolt. If we're leaders — around the table here we’re leaders, and none of us have prescribed a dose, that’s problematic. So I would probably look for a place to use it just to get familiar with it because I think that’s one of our expectations and responsibilities. We’ve talked about doing a study, a dosing study, for example, but is that interesting enough to build in biomarkers? So I think I would use it, but probably just expecting it to be more toxic but equivalent to bevacizumab, looking to see if that, indeed, is the case.
DR FUCHS: One interesting comparison is the approval of panitumumab after cetuximab. And when we looked, we found that of the patients to get panitumumab, 40% had previously gotten cetuximab.
DR VENOOK: That’s right.
DR FUCHS: So, akin to Emily’s point, that may be what happens with aflibercept.
DR GOLDBERG: So I was just going to say that we are opening a study next week of FOLFOX plus aflibercept in the first-line setting. It’s a Phase II, but at least we’ll get our hands on the drug and have some experience with it.
DR GROTHEY: So I could see a role for aflibercept in a patient population that was not colored by the TML study, which is the early progressor — I mean, kind of the patients who were excluded from TML. And where I said “I would not expose patients to bev beyond progression” when they had rapid progressive disease but a drug that has a little bit broader spectrum of mechanism of action, et cetera, I could see for K-ras-mutant tumors, early progressors on FOLFOX/bev, to look at FOLFIRI/aflibercept along the lines of VELOUR.
So I think I’d find patients to get my hands on aflibercept. Because I agree with Alan, we need to get our experience because we will talk about it. Nothing beats really hands-on experience.
DR VENOOK: I totally agree.