Using RET Inhibitors in Clinical Practice

Transcript: Jacob Sands, MD: We’ve seen a timeline of other targeted therapies, and ultimately these drugs really, I think, have their best benefit in the frontline setting. And we’ve seen in these studies with both BLU-667 and selpercatinib, in both of them we see responses in patients who have undergone prior therapies as well as in the treatment-naïve setting. As we get more of these data and really push approvals, these are ultimately really going to be important to use in the frontline setting. We find that, well, in both cases effective and well-tolerated drugs. When you’re comparing that with alternatives such as chemotherapy, it makes it even more appealing. And so I fully expect these to be frontline treatments.

I think the big thing is going to be, and we’re seeing this across other different targets as well, making sure that every patient is actually getting tested for this. And so we see people with EGFR mutations or ALK translocations where they’re not ending up on those targeted therapies or in some patients where this isn’t really being looked for. Now, in this setting, we’re talking about something more on the level of ROS1 as far as the number we see. So 1% to 2% of patients have RET, and this is something that people are going to have to really think about and make sure that they’re waiting until they get that result before starting therapy.

And that’s starting to get into the paradigm of what we’re seeing with some of these other known oncogenic drivers where we have very good targeted therapy. I do expect these to be frontline treatment, and I think what we’re ultimately going to be pushing to make sure the testing is done for these people, so they can get started on what we know to be very effective therapy with a very manageable toxicity profile, so people can continue on with their lives—they take a pill of therapy and carry on.

Benjamin Besse, MD, PhD: I think that with the new selective RET inhibitors, the multikinase inhibitor use will disappear. Any of these drugs, at least in lung cancer, was approved. So it was off-label prescription. The efficacy of the elective RET inhibitor outperformed the efficacy of multikinase inhibitors. So I think they will not be used any more in these patients.

We yet don’t know very well what is the exact resistance mechanism to RET inhibitors because these drugs are so new. We know that some tumors may acquire resistance mutation in the kinase and then become resistant to these inhibitors. If we do a parallel with ALK inhibitors, for example, this resistance mutation has led to the development of second- and third-generation inhibitors that are able to overcome this resistance mutation. But for RET, this is the beginning of the story.

Jacob Sands, MD: The question is when to consider the multikinase inhibitors or 1 of the specific RET inhibitors. I’d say that for

anyone who has a RET fusion with lung adenocarcinomas, where we’re typically seeing RET fusions as the alteration, I can’t imagine a scenario where I’d use a multikinase inhibitor over 1 of these highly selective RET inhibitors. The RET inhibitors really outperform the multikinase inhibitors in all aspects of efficacy and tolerability. As far as the situation, and which 1 I would choose, I would always choose the highly selective RET inhibitor.

Benjamin Besse, MD, PhD: Today if you want to choose 1 drug over another, you look at 2 things. First is efficacy, and it’s very clear that the selective inhibitor is much more potent than the multikinase inhibitors. So my first choice would be selective inhibitors.

The second is safety. Again, the safety profile of the selective RET inhibitors is, look much better than the safety profile of the multikinase inhibitors.

Alexander Drilon, MD: The data that we’ve seen with the selective RET inhibitor shows us that these agents really beat older multikinase drugs in terms of activity and adverse-event profile. As a clinician, if I had access to both clinical trials, I would naturally reach for a selective RET inhibitor before even considering an older drug like cabozantinib or vandetanib.

Marcia Brose, MD, PhD: Most people would choose a RET inhibitor over a multitargeted tyrosine inhibitor, mostly because of toxicity. It’s great to have response rates. Many of these patients, however, will be asymptomatic. How much they respond, in a way, is sort of a moot point. Of course it’s always great that responses are high in patients who are symptomatic. In patients who say, “Came to us late, already had shortness of breath, or had invasive disease,” then a response rate is going to matter. I would actually say that in clinical practice, that’s a minority of patients. Most patients will need these drugs, and we’ll be giving these drugs when they’re still asymptomatic.

But what’s really going to make a difference is the fact that these are so well tolerated. These patients have metastatic disease. They’re going to be on these agents a long time. The more we can preserve people’s quality of life by giving them minimally toxic agents, it’s really going to be a game changer. It doesn’t mean that we can’t use the other agents; those will be in second line. And we’ll have to learn more about how well they work after the other kinase agents and there will have to be additional studies to let us know that. But I think that’s when patients are going to be getting treated. This is a chronic illness now, and we’re going to try to move into that space. Now toxicity will probably move to the forefront in our decision making.

Transcript Edited for Clarity