Bullseye: Targeted Drug Hits Mutations in Thyroid Cancers as well as Lung Cancers

Medical oncologist Eric Sherman

Medical oncologist Eric Sherman is leading several trials evaluating new treatments for thyroid cancer.

When thyroid cancers are detected early, they often can be successfully treated with surgery, radioactive iodine therapy, or a combination of these treatments. But for cancers that are more advanced or that come back after treatment, better therapies are needed. In May 2020, the US Food and Drug Administration (FDA) approved a new drug for advanced thyroid cancer: the targeted therapy selpercatinib (RetevmoTM), which is effective in thyroid cancers with molecular changes involving a gene called RET. (The drug was also approved for lung cancer.)

Some thyroid cancers have what are called RET fusions. With these changes, part of the gene RET gets rearranged and attaches itself to another gene. That can drive cells to grow out of control and lead to cancer. RET fusions are found in about ten percent of thyroid tumors that originate in follicular cells. This includes anaplastic thyroid cancer, the most aggressive and difficult-to-treat form of the disease.

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Another type of thyroid tumor, called medullary cancer, has a different kind of RET alteration. Rather than a fusion, it has a mutation, or change in the gene’s sequence. RET mutations are found in more than half of all medullary thyroid cancers. Medullary thyroid cancer is rare, aggressive, and often runs in families. In these cases, the RET mutations are inherited and are passed down from parent to child. RET mutations are common in medullary thyroid cancer. They occur in all patients with the hereditary form and around 50 percent with the nonhereditary form.

Selpercatinib works on both types of RET mutations, says MSK medical oncologist Eric Sherman, who cared for patients in the clinical trials that led to selpercatinib’s FDA approval for thyroid cancer. “But at the same time, it’s very specific at blocking the RET protein, and only the RET protein.”

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Research Leads to New Drugs

Dr. Sherman contrasts the effectiveness of selpercatinib with earlier drugs shown to block RET, like cabozantinib (Cometriq®) and vandetanib (Caprelsa®). “Those were what we called ‘dirty’ kinase inhibitors, because they hit a lot of different protein targets,” he explains. “These drugs were sometimes effective, but they had a lot of side effects.”

“Because selpercatinib is a ‘cleaner’ drug, it works better,” he adds. “And we can give it at higher doses — and thereby have high inhibition of the target RET gene — because it typically doesn’t have serious side effects compared to the other drugs.”

Nonmedullary thyroid cancer (for example, papillary thyroid cancer) may have other gene alterations that can be targeted in a similar fashion. The most common gene that’s implicated in thyroid cancers is BRAF. Drugs that were originally developed to target BRAF in other types of cancer have shown promise in thyroid cancer and are currently being studied in thyroid cancer, both in combination with other drugs and in other novel ways (such as to restore the sensitivity of the thyroid cancer cells to radioactive iodine).

Thanks to MSK-IMPACTTM, the molecular test that looks for mutations in more than 500 cancer-related genes, patients can be matched with the best targeted therapies for their cancers. “We use MSK-IMPACT to sequence every advanced thyroid cancer as soon as possible when patients come to us,” Dr. Sherman says. “Because of this, we’ve learned a lot about the changes that drive these cancers, which will lead to more treatments in the future.”

Dr. Sherman has provided services to Bristol-Myers Squibb (uncompensated), COTA Inc., Eisai, Loxo Oncology, Novartis, and Regeneron Pharmaceuticals Inc. He has ownership and equity interests in Goldilocks Therapeutics Inc.

MSK News Winter 2020
Alexander Drilon is leading the development of new targeted drugs that can control lung cancer better than ever before. Read about his work in our Winter 2020 issue.