The Next Steps in RET Inhibitor Research



Jacob Sands, MD: The discovery of RET and the demonstration of drugs that work in this setting, I don’t know that that’s necessarily a new frontier as much as a continuation of a frontier that we’ve been going on. So we’ve been very much within a genomics era and a targeted-therapies era. Some people have thought that we really hit all the targets that we could, and it’s very encouraging to see that we’re still finding targets and we’re still finding drugs for those targets. To have something like RET with such effective therapies is an excellent step within that era of the ongoing genomics era that we’re seeing.

Benjamin Besse, MD, PhD: For the next step is understanding the best sequence between the available selective RET inhibitors. Should we use 1 of 2 inhibitors we have after the first 1? This is the first question. One of the key questions is that resistance mechanism and the development of new RET inhibitors.

Marcia Brose, MD, PhD: I think that there is a space for us to understand how RET inhibitors compare with the multitargeted inhibitors. A really good study would show us the difference. You have to remember when you’re doing clinical trials that you need to do the clinical trials in the same population. The numbers and the study designs that we had for both vandetanib and cabozantinib were in all-comers. We don’t really know how they perform in RET patients. It’s possible that they would improve their performance. So that would be good to know because these might be a little more comparable than what we already know. I think the toxicity profile won’t necessarily change, but I think some head-to-head comparisons between CABO [cabozantinib] and vandetanib and these RET inhibitors is really in order. I think that’s the last piece we really need to know to really understand what their role should be, and their placement in our clinical trial paradigm or in our clinical treatment paradigm.

At our center at the Perelman School of Medicine, which is a center for rare cancers and personalized therapy, this is really what we think is the future of medicine. If we can find in cancers the actual change that we can directly target with no toxicity—that in my opinion is the holy grail of what we do. And I think that as more inhibitors come out that are like RET, in the case of larotrectinib, which we didn’t talk about today, but another highly focused targeted agent with very few adverse effects.

These agents really can change for the patients who have those mutations, can really make a huge difference in their prognosis, how well they’re going to do on these drugs, and how long, I think that they’ll end up living. I mean, it’s early to say that, but I do believe that these agents are going to end up prolonging life. And so I think that these are important things we will be looking for in the future.

Unfortunately, not all patients will have mutations. It really is also going to change the landscape on how we test. Because historically you know testing was sort of like an add-on— you know, we’d do it if we could. Now it’s really going to be essential, because you would never want to miss 1 of these incredibly effective low-toxicity agents in a patient who would be eligible.

Alexander Drilon, MD: In terms of next steps for RET-dependent targeted-therapy research, it will be important to understand the profile of resistance to these first-generation selective RET inhibitors such as selpercatinib and pralsetinib. And that’s important because if these cancers retain some dependency on RET—if they develop, for example, on-target kinase domain mutations—then these may be amenable to next-generation agents that hopefully will hit the clinic and thereafter reestablish disease control, giving patients a second pill option after progression on a prior selective RET inhibitor.

This is definitely a major leap forward for precision oncology because this is adding to the group of matched-driver and targeted-therapy pairs that currently have regulatory approval, assuming that these drugs get approval by 1 or more regulatory agencies in the future. As mentioned, this would meet a huge need for patients who currently have no targeted-therapy options.

Transcript Edited for Clarity

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