Biology of RET Genetic Alterations

Jared Weiss, MD: Hello, I’m Jared Weiss. I’m a thoracic oncologist at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill. It’s a privilege to be joined by a good friend and colleague, Dr Benjamin Levy, also a thoracic oncologist at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

Benjamin P. Levy, MD: Thanks a lot for having me, Jared.

Jared Weiss, MD: Our topic today is RET. The basic science here: What is a RET genetic alteration, and why is it an attractive therapy for targeting?

Benjamin P. Levy, MD: The RET proto-oncogene like many oncogenes encodes the transmembrane receptor tyrosine kinase, and we were well aware that constitutive activation of tyrosine kinase can lead to uncontrolled growth. For RET, this constitutive activation can occur through 2 distinct mechanisms, and it’s important to talk about these 2 distinct alterations. RET can be altered in 2 distinct ways. No. 1, it can be a point mutation. These point mutations are found predominantly in medullary thyroid cancer, which comes in different shapes and varieties. There is obviously a familial form of medullary thyroid cancer, of which RET mutations make up about 90%, and then there is a sporadic medullary thyroid cancer, and RET mutations are about 60% of those. Mutations are important specifically for thyroid cancers, but perhaps more relevant and germane to our discussion are fusions.

Fusions, just like point mutations, can lead to an altered receptor tyrosine kinase that can be constitutively activated. Fusions, interestingly, are seen in papillary thyroid cancer, but they’re more relevant: 1% to 2% of all non–small cell lung cancer harbors a RET fusion. It’s important that this nomenclature distinguishes between RET mutations and RET fusions or arrangements because both can be relevant in solid tumor cancers. Both can lead to constitutive activation of an altered receptor tyrosine kinase. But perhaps more relevant here are the fusions that seem to predict efficacy to tyrosine kinase inhibitors [TKIs], which we will talk about. Mutations in lung cancer, RET mutations, don’t seem to do that, so it’s a little confusing. For the purpose of this conversation, RET fusions are what we’re trying to identify in non–small cell lung cancer.

Jared Weiss, MD: There are 2 new drugs, and so a natural segue may be to ask what the rationale is for actioning these targets with these drugs?

Benjamin P. Levy, MD: We have a track record in lung cancer of developing tyrosine kinase inhibitors. The whole goal of developing these drugs is that, 1), they’re selective for RET tyrosine kinase, so they have very few off target effects, and 2), they are potent, so they can elicit responses below the neck and across the blood-brain barrier. They’re highly selective for the RET, the protein product of either the RET fusion or the RET mutation. Given that 2% of all lung cancers have RET fusions, it makes a lot of sense, given our track record, to develop tyrosine kinase inhibitors that selectively target and shut the constitutive activation of the receptor tyrosine kinase off. It’s been nice to have a track record with this in EGFR and ALK.

I just want to mention that similar to the ALK fusion and RAS fusion, there are different partners. The most common partners for RET fusions are to the KIF5B. That’s probably 70% of all the fusion partners, but there are other fusion partners as well. CCDC6, NCOA4, these are also fusion partners that can exist. I mention these only because we’re still learning about whether fusion partners matter in terms of the efficacy these of these drugs that we’re talking about. It makes a lot of sense, and we’ll talk about this. Jared, we’ll flip the switch here, and I’ll start asking you some questions about the approved drugs prior to the approval of these TKIs. But I think you would agree that these new drugs, for which we will go in and deep-dive, have been a real game changer for patients with RET fusion, non–small cell lung cancer.

Transcript Edited for Clarity