Medullary Thyroid Carcinoma (MTC)

Retevmo™ (selpercatinib) is a selective receptor tyrosine kinase RET (rearranged during transfection) inhibitor that is indicated for the treatment of cancers harboring RET modifications.1,2 Retevmo is approved for the treatment of the following patients: adults with metastatic, RET fusion-positive non-small cell lung cancer (NSCLC); adults and children 12 years of age and older who have advanced or metastatic RET-mutant medullary thyroid cancer (MTC) requiring systemic therapy; and adults and children 12 years of age and older who have advanced or metastatic RET fusion-positive thyroid cancer requiring systemic therapy and whose disease is refractory to treatment with radioactive iodine. Retevmo was granted accelerated approval on the basis of the overall response rates and duration of the responses observed in clinical trials.1 Approval in the United States was first granted in May 2020.1,2

Credit: PubChem

Mechanism of Action and Use of Retevmo

MTC is a rare tumor of the thyroid gland, accounting for 2% to 3% of all thyroid tumors. This neuroendocrine tumor originates from parafollicular cells (C cells), which produce the hormone calcitonin. Calcitonin is involved in the regulation of calcium and sodium metabolism and may protect the human skeleton from calcium loss. MTC can be aggressive and metastasize via lymph nodes or the bloodstream.3

MTC can develop spontaneously, with no known underlying cause, but may also be hereditary in approximately 30% of patients. Abnormalities in specific oncogenes may support tumor development.3 Mutations of the RET proto-oncogene have been linked to MTC,4 with RET mutations occurring in about 70% of cases of MTC.5 The RET proto-oncogene encodes a tyrosine kinase transmembrane receptor, and mutations of RET can lead to the stimulation of signaling pathways involved in cellular proliferation and survival.6 

Get detailed prescribing information on the Retevmo monograph page at MPR.

Currently, several multiple-target kinase inhibitors are approved for the treatment of MTC, such as vandetanib and cabozantinib. However, their safety and the durability of the observed treatment responses are offset by the toxicity that develops because these drugs also inhibit other, non-RET kinases.5 Selpercatinib is the first therapy that is approved specifically for patients with RET gene modifications.3 Both in vitro and in vivo, the drug has demonstrated highly selective and potent inhibition of RET-mutant MTC cells and RET fusion-positive papillary thyroid carcinoma cells.1,7 The antitumor activity of selpercatinib was also observed in mice after the intracranial implantation of an RET fusion-positive tumor from a patient.7

The recommended dose of Retevmo is 120 mg for patients who weigh less than 50 kg and 160 mg for patients who weigh more than 50 kg. The drug is administered twice a day, with an interval of approximately 12 hours between doses, and is supplied as hard gelatin capsules that contain 40 or 80 mg of active drug.1 Retevmo can be associated with changes in liver enzyme levels (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]); with changes in glucose, sodium, and calcium levels; and with hypertension and fatigue.1 The AST and ALT levels should be evaluated before treatment, and the patient’s blood pressure should be also monitored and controlled. Cardiac effects have been observed in patients treated with Retevmo, with a concentration-dependent prolongation of the QTc interval. Patients being treated with Retevmo require close monitoring for other effects, such as tumor lysis syndrome and hemorrhagic events.1

Retevmo in Clinical Trials

The safety and efficacy of Retevmo were first evaluated in a multicenter, open-label, multicohort phase 1/2 clinical trial, LIBRETTO-001 (NTC03157128), which enrolled adolescent and adult participants who had solid tumors with an activating RET mutation.5 Participants were included who had advanced or metastatic RET-mutant MTC previously treated with cabozantinib, vandetanib, or both drugs. Also included were participants who had RET-mutant MTC not previously treated with cabozantinib or vandetanib, and participants who had RET fusion-positive thyroid cancer. The primary analysis of this study revealed an overall response rate of 69%, and the median duration of response was not reached after 14.8 months.2 In the patients with RET fusion-positive thyroid cancer, the overall response rate was 79%. The rates of toxicity associated with selpercatinib were low The most common adverse events described were hypertension, increase in liver enzymes, decrease in sodium levels, and diarrhea.5

Other ongoing clinical trials are evaluating the efficacy of selpercatinib. LIBRETTO-531 (NTC04211337) is a randomized phase 3 trial that is evaluating the efficacy of selpercatinib in patients with RET-mutant MTC. The study is designed to compare the drug with the standard of care in 400 patients having treatment-naïve advanced or metastatic RET-mutant MTC. Participants in the study receive selpercatinib or another drug, either cabozantinib or vandetanib.8 The efficacy of selpercatinib is also being examined in a phase 2 clinical trial in China, LIBRETTO-321 (NCT04280081). This trial is enrolling patients with advanced solid tumors, including RET fusion-positive solid tumors such as MTC.2 LIBRETTO-121 (NCT03899792) is an open-label, multicenter, dose escalation phase 1/2 study of pediatric patients with RET-altered and advanced solid tumors, as well as patients with primary CNS tumors; this trial is evaluating the safety of oral selpercatinib and the overall response rate.2


1. RETEVMOTM (selpercatinib) capsules. Highlights of prescribing information. Eli Lilly. Revised January 2021. Accessed August 18, 2021.

2. Markham A. Selpercatinib: first approval. Drugs. 2020;80(11):1119-1124. doi:10.1007/s40265-020-01343-7. Erratum in: Drugs. 2021;81(1):181

3. Thyroid cancer. National Organization for Rare Disorders (NORD). Published 2020. Accessed August 18, 2021.

4. Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F. State-of-the-art strategies for targeting RET-dependent cancers. J Clin Oncol. 2020;38(11):1209-1221. doi:10.1200/JCO.19.02551

5. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651

6. Ceolin L, Duval MA da S, Benini AF, Ferreira CV, Maia AL. Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives. Endocr Relat Cancer. 2019;26(9):R499-R518. doi:10.1530/ERC-18-0574

7. Subbiah V, Velcheti V, Tuch BB, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018;29(8):1869-1876. doi:10.1093/annonc/mdy137

8. Lilly opens phase 3 clinical trial in RET-mutant medullary thyroid cancer. News release. Eli Lilly. December 30, 2019. Accessed August 18, 2021.

Reviewed by Harshi Dhingra, MD, on 8/30/2021.