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RET Treatment: Novel Compounds to Replace Current TKIs

Insights From: Jacob Sands, MD, Dana-Farber Cancer Institute; Benjamin Besse, MD, PhD, Institut d'Oncologie Thoracique; Alexander Drilon, MD, Memorial Sloan Kettering Center; Marcia Brose, MD, PhD, Perelman School of Medicine
Published: Wednesday, Nov 20, 2019



Transcript: 

Benjamin Besse, MD, PhD:
Multikinase RET inhibitors have very limited efficacy in non–small cell lung cancer [NSCLC] with a RET fusion. The PFS [progression-free survival] is usually less than 7 months. In lung cancer we are very used to these drivers—EGFR and ALK, for example—and we know that when the drug really works, we will see a response rate that is over 50% and PFS that is usually about 10 months. This is really the pattern of the addiction on lung cancer, and it’s very clear that with the multikinase inhibitor we have not reached this pattern. Because of this limited efficacy, we need more potent and more selective RET inhibitors to be more potent on the target and induce less toxicity, because this multikinase inhibitor will activate a lot of different kinases, and each of these kinases will have its own toxicity.

Marcia Brose, MD, PhD: In medullary thyroid cancer we have these 2 agents. As I just mentioned in the toxicity discussion, these clearly are not agents that are easy to take. And it can be relatively difficult. One thing I’ll say is that many times, a patient will tolerate 1 and not the other. Even though we have 2 agents, sometimes we really have only 1 line of therapy.

The second thing you need to know is that these patients will not last forever on any of these drugs, and for the most part, within a year or 2, it will eventually stop responding to them. They’ll have resistant lesions that will start to grow in spite of being on the drug. Sometimes the patient just doesn’t tolerate it and may have to stop for toxicity reasons.

Most of these patients actually are pretty healthy. And so there definitely is a need for other options. One that are less toxic, and 2, that might cause responses that last longer than just a year or 2.

Benjamin Besse, MD, PhD: For patients with lung cancer, in whom we find somatic driver mutation, we are used to whole drugs that are very selective, with few toxicities. This is linked to a very high quality of life because the patients are completely free in their life. They just take pills with limited toxicity. In RET-fusion positive and NSCLC, the only treatment we can give so far is either toxic chemotherapy or multikinase inhibitors that are not as potent. The third option, immunotherapy, is so far not very potent in this field. We need the emergence of a new class of drug, more important, and less toxic.


Transcript Edited for Clarity
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Transcript: 

Benjamin Besse, MD, PhD:
Multikinase RET inhibitors have very limited efficacy in non–small cell lung cancer [NSCLC] with a RET fusion. The PFS [progression-free survival] is usually less than 7 months. In lung cancer we are very used to these drivers—EGFR and ALK, for example—and we know that when the drug really works, we will see a response rate that is over 50% and PFS that is usually about 10 months. This is really the pattern of the addiction on lung cancer, and it’s very clear that with the multikinase inhibitor we have not reached this pattern. Because of this limited efficacy, we need more potent and more selective RET inhibitors to be more potent on the target and induce less toxicity, because this multikinase inhibitor will activate a lot of different kinases, and each of these kinases will have its own toxicity.

Marcia Brose, MD, PhD: In medullary thyroid cancer we have these 2 agents. As I just mentioned in the toxicity discussion, these clearly are not agents that are easy to take. And it can be relatively difficult. One thing I’ll say is that many times, a patient will tolerate 1 and not the other. Even though we have 2 agents, sometimes we really have only 1 line of therapy.

The second thing you need to know is that these patients will not last forever on any of these drugs, and for the most part, within a year or 2, it will eventually stop responding to them. They’ll have resistant lesions that will start to grow in spite of being on the drug. Sometimes the patient just doesn’t tolerate it and may have to stop for toxicity reasons.

Most of these patients actually are pretty healthy. And so there definitely is a need for other options. One that are less toxic, and 2, that might cause responses that last longer than just a year or 2.

Benjamin Besse, MD, PhD: For patients with lung cancer, in whom we find somatic driver mutation, we are used to whole drugs that are very selective, with few toxicities. This is linked to a very high quality of life because the patients are completely free in their life. They just take pills with limited toxicity. In RET-fusion positive and NSCLC, the only treatment we can give so far is either toxic chemotherapy or multikinase inhibitors that are not as potent. The third option, immunotherapy, is so far not very potent in this field. We need the emergence of a new class of drug, more important, and less toxic.


Transcript Edited for Clarity
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