The Future of RET Inhibitors in Non-Small Cell Lung and Thyroid Cancer - Episode 3
Transcript: Jacob Sands, MD: Regarding the multikinase inhibitors like cabozantinib and vandetanib, these were attempts at targeting patients with RET fusions. Although they do that to some extent, they’re really much dirtier, so they hit multiple others and hence multikinase inhibitors. And in doing so, it really increased the toxicity profile. These are mentioned in NCCN [National Comprehensive Cancer Network] Guidelines, and they do in fact target that. At this point, we have a couple of other drugs that have been brought forward, which now are much more selective in their targeted therapies. Therefore, they have have much less in toxicity and really have demonstrated more effectiveness than what we saw with these prior multikinase inhibitor therapies.
The response rates we saw with these multikinase inhibitors were just not as significant. Many of the studies have, like, a 20%, 30% range of responses. On top of that, without the same durability that we’re seeing with some of the other drugs we’re going to talk about, with a worse toxicity profile. Although these really were important investigations prior, we fortunately seem to have passed what were advances in some ways when those drugs were developed.
Marcia Brose, MD, PhD: Vandetanib and cabozantinib were the first 2 FDA-approved agents for medullary thyroid cancer. These are both kinase inhibitors, and primarily they inhibit VEGF receptors, but they also inhibit RET to a lesser degree.
Both of these, in being approved, were shown to be effective in resulting in extended progression-free survival and some responses in medullary thyroid cancer. Until now, those are the only 2 only agents that are available. They can be used interchangeably. One can be used first, the other can be used second. They both have different safety profiles, but in general these are the first 2 agents that are usually used in patients with medullary thyroid cancer.
Both progression-free survival and response rates—overall response rates—are improved with vandetanib and with cabozantinib, but the trials were different. In vandetanib, they didn’t require progression at the time of that study. The progression-free survival in the placebo arm was about 16 months. Then in the patients who were treated, it wasn’t even reached because it was so far out there. But it was a significant difference, which is why it got FDA approved.
In cabozantinib, in contrast, they required progression at the time of entering into the study. Progression-free survival was only 4 months, and then that was improved to 11 months in the phase III study. In both of these cases, the patients had response rates usually between about 16% and, say, 25% to 30%. I’m not sure exactly what it was, but you could expect patients to have up to 30% shrinkage. Usually what happens with the response is they respond in the first few months and then kind of plateau off.
Specifically, vandetanib’s adverse-effect profile is very different from cabozantinib’s adverse-effect profile. In vandetanib, the main thing we look for are things like diarrhea and fatigue. Some patients don’t tolerate it based on that alone. Patients can also get a bad acne type of rash. Those are the most common. More rarely, patients sometimes have prolongation of the QT interval, which causes a slowing of part of the rhythm of the heart that can be a risk factor for something called torsades, or a fatal heart arrhythmia. For that reason, for physicians to prescribe to them, vandetanib patients have to go through a risk-strategy management training, and then they have to be sure to make sure to monitor electrolytes as well as regular EKGs [electrocardiograms].
Cabozantinib, on the other hand, while it shares the fact that it can cause diarrhea and fatigue, tends to cause more diarrhea and fatigue up front. It tends to not cause the rash, but it can cause something called mucocytes, and it can also cause something causing the hand-foot skin reaction. Those are some things that are slightly different. Patients can get into trouble in both TKIs that I just talked about. Many times what we do is we will hold the drug. Sometimes patients feel better, and if they don’t feel better, we sometimes are required to drop the dose. In the case of vandetanib from 300 mg to 200 mg or 100 mg. And in the case of with cabozantinib, from 140 mg, which some people don’t even start at, to 100 mg or 80 mg or a little lower.
Transcript Edited for Clarity