Lori J. Wirth, MD: For medullary thyroid cancer, all patients need to have molecular testing done. Now we’re looking for 2 different things in molecular testing. It’s complicated, though not really. As I mentioned, medullary thyroid cancer [MTC] can be seen in hereditary syndromes, particularly MEN2A and MEN2B. Those patients all harbor germline RET mutations, and in any index case where there isn’t already a known family history of MEN2A [multiple endocrine neoplasia type 2A] or MEN2B [multiple endocrine neoplasia type 2B], we need to rule out familial syndrome in these patients because of the implications not only for patients diagnosed with MTC but also their family members, who are at risk for harboring germline mutations as well. When we find a patient with a germline MEN2A or MEN2B mutation, we need to make sure their family members do not harbor the mutation because of the implications of those patients needing treatment—for example, thyroidectomy, to remove the thyroid before a medullary thyroid cancer becomes established.

There are also somatic RET mutations that can occur. Twenty-five percent of medullary thyroid cancers will be familial, whereas 75% of medullary thyroid cancers will be sporadic. Of those 75% of sporadic cases, 60% of patients will harbor somatic RET mutations in their tumor. Now that we have RET-specific inhibitors available in our arsenal of therapies, any patient who needs systemic therapy should have somatic RET testing done, typically by NGS [next-generation sequencing] assays, to evaluate for a RET mutation. If a patient has medullary thyroid cancer that’s limited to the neck and they’re essentially cured with surgery, there’s not necessarily a role for RET somatic testing in those patients, but anyone with metastatic disease who we know doesn’t have familial syndrome should have RET testing done.

Most patients who are diagnosed with medullary thyroid cancer will have an actionable mutation found. As I mentioned, all patients who have a familial MTC will harbor germline RET mutations. Then, 60% of patients with sporadic MTC will have driver RET mutations in their tumors but not germline. The highest frequency of other mutations seen in MTC are seen in RAS, which aren’t necessarily entirely targetable at this moment. As I mentioned, most patients will harbor RET alterations that are potentially targetable. In patients with sporadic MTC, the most common mutation is RET M918T, which is the germline mutation seen in most patients with MEN2B. The most common MEN2A mutation is in the RET C634, and those mutations and other mutations can be found in sporadic MTC as well.

RET is a receptor tyrosine kinase. When the gene is mutated, the protein receptor tyrosine kinase is constitutively activated by homodimerization, when there’s an extracellular cysteine-rich mutation in RET such as at C634. When there is a RET M918T mutation, the protein is constitutively activated intracellularly, and homodimerization is not necessarily required for activation of the tyrosine kinase.

The idea of targeting RET specifically came about in part because of the known role that RET plays in MTC, but also RET fusions are seen in a small subset of patients with non–small cell lung cancer as well as in patients with RET fusion, other thyroid cancers such as differentiated thyroid cancer, poorly differentiated thyroid cancer, or even anaplastic thyroid cancer. With the awareness of the role of RET activation in these multiple tumor types and the fact that RET is a tyrosine kinase, that has certainly presented itself as a rationale target for drug development. Thus, the first generation of RET inhibitors has been studied. Selpercatinib is the first RET-specific inhibitor that was FDA approved and basically was designed to very specifically and potently inhibit the RET kinase and not inhibit other kinases, such as KDR, VEGFR2, and other kinases that are inhibited in the multikinase inhibitors that we have in our arsenal in oncology. The idea there is that you can really drive up RET inhibition but limit the adverse-effect profile that comes into play when there are multiple other kinases inhibited as well.

Transcript Edited for Clarity