Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
Medullary thyroid cancer (MTC) is a rare type of cancer that arises from calcitonin-producing parafollicular C cells in the thyroid gland. MTC can either occur sporadically or be hereditary due to germline mutations in the RET proto-oncogene.1
The best treatment option for MTC is a total thyroidectomy and bilateral central neck dissection.2 There are also two drugs, vandetanib and cabozantinib, that are approved in the US and EU for the treatment of advanced, progressive medullary thyroid cancer. Both drugs are multi-kinase RET inhibitors.1
Additionally, there are a number of other experimental RET inhibitor therapies that are currently in clinical trials.
BOS172738 is a RET inhibitor that has demonstrated potent preclinical activity in RET-driven tumors.3
Being developed by Boston Pharmaceuticals, it is currently in Phase 1 clinical trial in patients with advanced RET gene-altered tumors including medullary thyroid cancer.
The aim of the trial is to evaluate the safety, efficacy, and tolerability of BOS172738 in 114 participants. Patient recruitment is open at sites in the US, Belgium, France, Spain, Hong Kong, the Republic of Korea, and Taiwan. The estimated completion date of the trial is December 31, 2021.4
Pralsetinib is a selective RET inhibitor being developed by Blueprint Medicines that targets oncogenic RET alterations.5
It is currently being tested in a Phase 1/2 clinical trial in patients with MTC among others. The trial is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic activity of Pralsetinib. It is currently recruiting up to 647 adult participants at 79 study locations and is estimated to be completed on February 29, 2024.6
Selpercatinib (LOXO-292, LY3527723)
Selpercatinib is a small-molecule inhibitor of RET by Loxo-oncology, which is potent against RET fusions, activating RET point mutations, and acquired resistance mutations. It is highly selective for RET and has limited activity against other tyrosine kinases.7
Two clinical trials are currently testing selpercatinib in patients with MTC.
The first is a Phase 1/2 trial of oral selpercatinib in patients with advanced solid tumors, including medullary thyroid cancer. The open-label, first-in-human study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of selpercatinib in 989 participants, ages 12 and older at 83 locations across the globe. According to the interim results in 226 participants, 43.5% of patients had clinically meaningful improvement in diarrhea. The trial is currently still open for recruitment at 83 locations across the world, and analyses will continue to be conducted as more data is created. The trial is estimated to be completed in November 2023.8
The second is a Phase 3 trial that aims to compare selpercatinib to cabozantinib or vandetanib. The primary outcome measure of this trial is treatment failure-free survival (TFFS). Secondary measures include progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), and overall survival (OS). The trial is currently recruiting 400 participants, ages 12 and older with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer at 160 locations across the globe. It is estimated to be completed in November 2026.9
TPX-0046 is a next-generation RET inhibitor by Turning Point Therapeutics, which is currently in Phase 1/2 clinical trial in adults with advanced solid tumors harboring RET fusions or mutations including medullary thyroid cancer.
TPX-0046 is a dual inhibitor that inhibits both RET and SRC. It is hoped that by also inhibiting SRC TPX-0046 could have increased therapeutic effects since SRC is involved in bypass resistance.10
The trial will evaluate the safety and tolerability of TPX-0046. It also aims to determine the maximum tolerated dose and the objective response rate of the treatment. It is currently recruiting up to 362 adult participants in the US and the Republic of Korea. It is estimated to be completed in March 2025.11
Ponatinib is an oral multi-tyrosine kinase inhibitor by ARIAD Pharmaceuticals. The treatment has already been approved in the US for the treatment of leukemia but is not yet approved for MTC.
The objective overall response rate of patients with advanced or metastatic medullary thyroid cancer who have tumors with and without RET mutations to ponatinib who have previously been treated with cabozantinib or vandetanib is being tested in a Phase 2 clinical trial. This small trial is currently recruiting 10 participants at Columbia University Medical Center in New York and is estimated to be completed in June 2022.12
HA121-28 is an experimental drug being developed by CSPC ZhongQi Pharmaceutical Technology that can inhibit RET among others.13
Its antineoplastic activity, safety, and tolerability are currently being tested in a single-arm, open-label, multi-center Phase 2 study in 30 adult patients with medullary thyroid carcinoma. The study is recruiting participants in China and is expected to be completed in March 2025.14
- Spitzweg C, Morris JC, Bible KC. New drugs for medullary thyroid cancer: new promises? Endocr Relat Cancer. 2016;23(6):R287-97. doi:10.1530/ERC-16-0104
- Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist. 2008;13(5):539-47. doi: 10.1634/theoncologist.2007-0239
- BOS172738. Boston Pharmaceuticals. Accessed June 9, 2021.
- Safety, efficacy, and tolerability of BOS172738 in patients with advanced rearranged during transfection (RET) gene-altered tumors. US National Library of Medicine. Last update posted: February 24, 2021. Accessed June 9, 2021.
- Subbiah V, I-Nan Hu M, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion–positive solid tumors. J Clin Oncol. 2021;39:3_suppl, 467-467. doi:10.1200/JCO.2021.39.3_suppl.467
- Phase 1/2 study of the highly-selective RET inhibitor, pralsetinib (BLU-667), in patients with thyroid cancer, non-small cell lung cancer, and other advanced solid tumors (ARROW). National Library of Medicine. Last update posted: July 1, 2021. Accessed June 9, 2021.
- Shah MH, Sherman EJ, Robinson B, et al. Selpercatinib (LOXO-292) in patients with RET-mutant medullary thyroid cancer. J Clin Oncol. 2020;38:15_suppl, 3594-3594. doi: 10.1200/JCO.2020.38.15_suppl.3594
- A study of LOXO-292 in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). National Library of Medicine. Last update posted: July 7, 2021. Accessed June 9, 2021.
- A study of selpercatinib (LY3527723) in participants with RET-mutant medullary thyroid cancer (LIBRETTO-531). National Library of Medicine. Last update posted: July 7, 2021.
- TPX-0046. Turning Point Therapeutics. Accessed June 9, 2021.
- Study of TPX-0046, A RET/SRC inhibitor in adult subjects with advanced solid tumors harboring RET fusions or mutations. National Library of Medicine. Last update posted: May 4, 2021. Accessed June 9, 2021.
- Ponatinib in Advanced or Metastatic Medullary Thyroid Cancer. National Library of Medicine. Last update posted: May 18, 2021. Accessed June 9, 2021.
- The group’s “HA121-28” and “alprostadil liposome injection” were granted clinical trial approvals. CSPC PHARMACEUTICAL GROUP LIMITED. November 6, 2017. Accessed June 9, 2021.
- A Study of HA121-28 tablets in patients with medullary thyroid carcinoma (MTC). National Library of Medicine. Last update posted: March 8, 2021. Accessed June 9, 2021.
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.