RTP On Demand — Head & Neck/Thyroid | Research To PracticeOverview of VEGF tyrosine kinase inhibitors (TKIs) in thyroid cancer
4:34 minutes.
TRANSCRIPTION:
DR LOVE: Let’s talk about some of the VEGF TKIs that have been studied in thyroid cancer. Here’s a list of them. But maybe we can kind of go through each one very briefly in terms of what we know. In a way, axitinib, I was thinking about renal cell, that vascularity and the responses that you see. Does that strike you as a similarity also? DR COHEN: There are a lot of similarities between thyroid cancer and renal cell carcinoma in terms of the activity of the TKIs and the natural history of the disease with patients being treated on the TKI, but with one exception. We know that clear cell carcinoma often harbor mutations, especially in VHL, that make them susceptible to anti-angiogenic approaches. That is not true of thyroid cancer. We don’t see those mutations in thyroid cancer. So they’re both angiogenic tumors that respond to these drugs, renal cell with a mutation. Thyroid cancer, we don’t see a mutation. DR LOVE: So what about axitinib? DR COHEN: This was from a study we did now several years ago, looking at patients with all histologies in thyroid cancer. And clearly we can see activity. The response rate was 30%. We actually just published a follow-up of a second trial, exclusively in differentiated thyroid cancer patients, and saw the exact same 30% response rate. So clearly axitinib is an active agent. And what’s worth pointing out is that if we look at the waterfall plots, if we look at the response rates from all of these studies, we can clearly see that there’s a consistency here. The VEGF receptor TKIs are active in differentiated thyroid cancer. DR LOVE: Other than lenvatinib, does there seem to be any differentiating factor in terms of efficacy? I mean, does sorafenib seem to be indirectly more effective? DR COHEN: We can talk about a couple of things with respect to efficacy. And what we have to keep in mind is that it’s difficult to compare directly between the Phase II studies and, in fact, between the Phase III studies, because the patient populations weren’t exactly the same and there’s never been a head-to-head trial. With that in mind, we can probably make some general statements, that in terms of response rate, lenvatinib appears to be quite high. Pazopanib is probably up there, 50% response rate reported in the Phase II study. Sunitinib, probably also, a high response rate. Axitinib is somewhere around 30%. And then sorafenib is a little bit lower than that in terms of response rate, anywhere from 10% to 20%. In the Phase III trial, it was a 12% response rate. But, of course, just like renal cell — so again, the parallels with renal cell carcinoma — response rate isn’t the whole story, that we can get efficacy, as defined by, for instance, progression-free survival benefit, without necessarily seeing RECIST-defined responses. And that’s clearly true for sorafenib. DR LOVE: Any comments about pazopanib? DR COHEN: So the pazopanib, as you can see from this study and, in fact, even a follow-up study done in Europe, clearly an effective agent. Here they reported a 50% partial response rate across all histologies of differentiated thyroid cancer. It’s also a fairly well-tolerated drug and it’s one that’s commonly used for differentiated thyroid cancer, because of those 2 aspects. DR LOVE: What about vandetanib? We think about it in terms of medullary cancer, but it’s also been looked at in terms of differentiated thyroid cancer. DR COHEN: Exactly. It was looked at in a randomized Phase II study, which is fairly unique for these agents, especially when this trial was reported. So this was a study versus placebo looking at progression-free survival as the primary endpoint and a clear benefit. In fact, the benefit parallels what we saw in the Phase III study with sorafenib. So it does look like vandetanib is an efficacious drug. It has a response rate, although the response rate tends to be lower than, say, in lenvatinib or pazopanib, at least from what we’ve seen, but clearly there’s efficacy there. DR LOVE: What do you see in terms of tolerability with vandetanib? DR COHEN: Vandetanib has a little bit of a different side-effect profile, primarily for 2 reasons. First, it inhibits EGFR quite robustly, and so most of the other drugs that we talked about don’t target EGFR. So we see the EGFR-related skin rash that you wouldn’t see with many of these other TKIs. The other thing is that it has an idiosyncratic toxicity of QT prolongation. And, of course, that’s something that we have to be aware of. That’s something we have to monitor. As long as you know about it, you can manage it, usually by dose reduction. But you definitely have to be aware of it, because it’s something that can cause a lot of trouble. |