This site is intended for healthcare professionals. If you are a patient or caregiver, please contact your physician to discuss clinical trial eligibility.
Clinical Trials Exploring RET
An investigational, oral, and selective inhibitor in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase.
Phase 1 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET-Fusion Lung Cancer, and Medullary Thyroid Cancer
This is a phase 1, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of LOXO-292 administered orally to patients with advanced solid tumors, including RET-fusion non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other tumors with increased RET activity.See Trial Information and Study Locations
About RET Alterations
RET kinase is a transmembrane receptor tyrosine kinase.1 RET kinase plays an essential role during the development and maintenance of a broad range of tissues, including neural and genitourinary tissues.1-7 Normally, RET signaling activates cellular proliferation, survival, invasion, and migration pathways in a tightly regulated way.1
Oncogenic alterations to the RET proto-oncogene, which include RET rearrangements (leading to RET fusions) and activating point mutations, occur across multiple tumor types with varying prevalence.8-15
- RET fusions can occur with a variety of fusion partners, with the most common being KIF5B and CCDC6 in NSCLC and CCDC6 and NCOA4 in papillary thyroid carcinoma (PTC)1,14-16
- RET point mutations account for approximately 60% of sporadic MTC and nearly 100% of inherited familial MTC17-25
Each of these alterations result in overactive or constitutively active RET activity, which prompts uncontrolled cell growth and may also enhance a tumor’s invasiveness.1,20,26,27 Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.8,13,14,27-32
For additional information about the LOXO-292 clinical trial, please refer to clinicaltrials.gov.
Interested physicians and patients may contact the Loxo Oncology RET Physician and Patient Clinical Trial Hotline at +1-855-RET-4-292 or email email@example.com.
Policy for Access to Investigational Agents
Loxo Oncology is committed to helping patients who have not responded to available therapies and may benefit from its investigational therapies. Loxo Oncology's Policy for Access to Investigational Agents describes the principles and government regulations that the company will follow when considering a request.
- Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173-186.
- Schuchardt A, D’Agati V, Pachnis V, Costantini F. Renal agenesis and hypodysplasia in ret k mutant mice result from defects in ureteric bud development. Development. 1996;122(6):1919-1929.
- Chi X, Michos O, Shakya R, et al. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell. 2009;17(2):199-209.
- Davis TK, Hoshi M, Jain S. To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol. 2014;29(4):597-608.
- Meng X, Lindahl M, Hyvönen ME, et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science. 2000;287(5457):1489-1493.
- Naughton CK, Jain S, Strickland AM, Gupta A, Milbrandt J. Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Biol Reprod. 2006;74(2):314-321.
- Jijiwa M, Kawai K, Fukihara J, et al. GDNF-mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells. Genes Cells. 2008;13(4):365-374.
- Ballerini P, Struski S, Cresson C, et al. RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation. Leukemia. 2012;26(11):2384-2389.
- Ju YS, Lee WC, Shin JY, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22(3):436-445.
- Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18(3):375-377.
- Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18(3):382-384.
- Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378-381.
- Bossi D, Carlomagno F, Pallavicini I, et al. Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies. Mol Oncol. 2014;8(2):221-231.
- Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.
- Yoshihara K, Wang Q, Torres-Garcia W, et al. The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene. 2015;34(37):4845-4854.
- Kohno T, Nakaoku T, Tsuta K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res. 2015;4(2):156-164.
- Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851-856.
- Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458-460.
- Eng C, Smith DP, Mulligan LM, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3(2):237-241.
- Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375-376.
- Agrawal N, Jiao Y, Sausen M, et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab. 2013;98(2):E364-E369.
- Ji JH, Oh YL, Hong M, et al. Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer. PLoS Genet. 2015;11(8):e1005467.
- Taccaliti A, Silvetti F, Palmonella G, Boscaro M. Genetic alterations in medullary thyroid cancer: diagnostic and prognostic markers. Curr Genomics. 2011;12(8):618-625.
- Margraf RL, Crockett DK, Krautscheid PM, et al. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2 associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat. 2009;30(4):548-556.
- Wells Jr. SA, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149-3164.
- Grieco M, Santoro, M, Berlingieri, MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990;23(60):557-563.
- Díaz-Beyá M, Navarro A, Ferrer G, et al. Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene. Leukemia. 2013;27(3):595-603.
- Plaza-Menacho I, Morandi A, Robertson D, et al. Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. Oncogene. 2010;29(33):4648-4657.
- Esseghir S, Todd SK, Hunt T, et al. A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. Cancer Res. 2007;67(24):11732-11741.
- Boulay A, Breuleux M, Stephan C, et al. The Ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer. Cancer Res. 2008;68(10):3743-3751.
- Camós M, Esteve J, Jares P, et al. Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3 CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. Cancer Res. 2006;66(14):6947-6954.
- Luo Y, Tsuchiya KD, Il Park D, et al. RET is a potential tumor suppressor gene in colorectal cancer. Oncogene. 2013;32(16):2037-2047.
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