Major Advances in RET Inhibition for NSCLC and MTC - Episode 2

Multikinase TKIs for RET Fusion+ NSCLC


Jared Weiss, MD: Prior to these drugs, your options were chemotherapy or nonspecific TKIs [tyrosine kinase inhibitors]. By nonspecific TKI, I mostly mean cabozantinib and vandetanib. More recently, alectinib has been approved for ALK and does happen to have some RET activity as well. But most of the clinical experiences are with the first 2 of those agents. Scientifically, these are drugs not targeting RET but rather targeting other targets, particularly VEGF receptors and then what we sometimes colloquially referred to as dirty kinase inhibitors, meaning that they have broad activity in the kinome, and that’s why we’re able to bring them in here. Part of that dirtiness happens to include RET. But in terms of thinking about their adverse effects and their efficacy, it’s important to note that they’re not particularly potent against RET. They have lots of activity elsewhere that’s not helpful in these cancers but does lead to toxicity. In summary, these agents are not that great in lung cancer. Their response rates are low, their PFS [progression-free survival] is low, and their toxicity is quite real.

Only 1 of these agents has randomized data, and that is vandetanib. These data are not against another agent, and vandetanib is not even in lung cancer. It’s against placebo in medullary thyroid. The best experience I can cite for you is that response rate was better than placebo. Interestingly, placebo had a response rate. PFS was better than placebo, although medullary thyroid can be invalid, and you get a decent PFS with placebo alone. Overall survival wasn’t even budged despite being a large and well-powered trial. Efficacy was not what we’re looking for, and toxicity is pretty bad with these agents. Vandetanib, for example, has a black box warning for both torsades de pointes and death. We see a lot of GI [gastrointestinal] toxicity, hypertension, and LFT [liver function test] elevations. That nonspecific access is critically important from a human standpoint but not captured in toxicity tables. That spectrum of “Doc, I feel great” to “Doc, I feel awful.” Patients feel awful on cabozantinib and vandetanib. These are not patient-friendly drugs.

Benjamin P. Levy, MD: Have you used these drugs in your clinic? I don’t have a lot of experience with these drugs. I’ve used it maybe once or twice. I would agree with you that the toxicity can be prohibitive. They have a lot of off-target effects. They aren’t that selective. The responses, if they are there, are not that durable in lung cancer. What do you experience with vandetanib and cabozantinib in non–small cell lung cancer?

Jared Weiss, MD: My secret as a thoracic expert is that I also treat head and neck cancer. In that context, I do have a decent amount of experience using these agents for medullary thyroid. Medullary thyroid and lung are different diseases, though. The biology is different as you explained very nicely earlier, but clinically they look different. My most common and favorite treatment of medullary thyroid cancer is a chemotherapy with absolutely no adverse effects, known as no treatment at all. We watch medullary thyroid all the time. We’re watching the bulk of disease, its anatomic location and its growth rate. In summary, you asked if it is a threat to the patient, right? Is this disease going to risk to the patient’s life or quality of life? Imaging thyroid is very often no, and we have the privilege of observing.

In lung cancer we almost never choose that path. In fact, just about every time it’s been tried in a clinical trial, either in an unselected population or in a highly selected 1, active observation has gone disastrously. That’s because, unlike medullary thyroid, the toxicity of lung cancer itself is awful, perhaps even worse than some of our most awful cytotoxic chemotherapy agents. I have used these in medullary thyroid. You do see disease control. It’s better than the awful and completely inactive chemotherapy that people sometimes used historically. But even in medullary thyroid, where it looks better than in lung, one can’t have great enthusiasm. Because we’re in a lung program, I’ll shift quickly back to that and just leave a summary statement that these drugs are absolutely and completely replaced by the new specific TKIs in RET-mutated medullary thyroid or RET-fusion papillary thyroid.

Benjamin P. Levy, MD: I agree with you. In my experience with the dirty TKIs, as you called them, it is the cabozantinib and vandetanib not eliciting meaningful activity and toxicities. The times I’ve used them I’ve struggled a tremendous amount with rash and diarrhea. These are not easy drugs to give, and this is a welcome change to have selpercatinib and pralsetinib, which we’ll talk about next or at least further down the line. They certainly have altered the way we perceive these types of tumors and the way we treat them.

Transcript Edited for Clarity