Treatment Options for NTRK and RET Alterations in Thyroid Cancer

EP: 1.Identifying NTRK and RET Alterations in Differentiated Thyroid Cancer

EP: 2.Challenges for Thyroid Cancer With RET and NTRK Alterations

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EP: 3.Treatment Options for NTRK and RET Alterations in Thyroid Cancer

EP: 4.Combating Resistance Mechanisms to Treatment in Thyroid Cancer

NTRK fusions are found in 2 to 4% of differentiated thyroid cancers. Two FDA-approved drugs, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), target these specifically and have high response rates with manageable adverse effects, mainly affecting the central nervous system.

RET alterations include both RET fusions (in papillary cancer) and RET mutations (in medullary cancer). Selpercatinib (Retevmo) is currently the only approved drug for RET alterations in thyroid cancer. It was recently shown to be superior to standard treatments for medullary cancer. Drugs targeting RET or NTRK are generally well-tolerated compared to older medications.

In an interview with Targeted Oncology^TM, Lova Sun, MD, MSCE, assistant professor of medicine at the Hospital of the University of Pennsylvania, discusses these targeted therapies.

Transcription:

0:05 | For NTRK fusions, which again are present in single digits, 2 to 4% of differentiated thyroid cancers, there are 2 FDA approved agents and these are sort of disease-agnostic approvals. So any NTRK fusion-positive solid tumor, we have entrectinib and larotrectinib, 2 specific inhibitors for NTRK fusions, both with very high response rates associated and generally pretty tolerable with mostly CNS, central nervous system, side effects, including mood changes.

0:42 | In terms of RET, we used to have 2 approved agents: selpercatinib and pralsetinib [Gavreto]. Unfortunately, pralsetinib was recently withdrawn. So at this point, we have selpercatinib for thyroid cancer as our only approved agent for RET fusions. And keep in mind, selpercatinib and the RET inhibitors work for either RET fusions that are seen in papillary thyroid cancer or RET mutations that characterize medullary thyroid cancers. And in fact, a recent phase 3 trial, LIBRETTO-531 [NCT04211337], actually just confirmed superiority of selpercatinib over frontline vandetanib [Caprelsa] or cabozantinib [Cabometyx, Cometriq]. This is for medullary thyroid cancer. Again, all of these agents whether we're talking about the NTRK or RET, agents have response rates upwards of 70%. So really effective drugs, relatively specific to the target they are inhibiting and well tolerated, especially compared to our otherwise frontline standard of care multitargeted tyrosine kinase inhibitors such as lenvatinib [Lenvima] and cabozantinib.

1:49 | In terms of selpercatinib, the side effects we watch out for are blood pressure elevation, sometimes liver function abnormalities, and some [gastrointestinal (GI)] side effects, and edema, but again, generally pretty well tolerated. So you know, the safety and efficacy profile of RET and NTRK inhibitors are certainly very favorable is especially compared to our generic mutation-agnostic kinase inhibitors.