Reference Detail

Ref Type Journal Article
PMID (29912274)
Authors Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Cabanillas ME, Wirth LJ, Stock S, Smith S, Lauriault V, Corsi-Travali S, Henry D, Burkard M, Hamor R, Bouhana K, Winski S, Wallace RD, Hartley D, Rhodes S, Reddy M, Brandhuber BJ, Andrews S, Rothenberg SM, Drilon A
Title Selective RET Kinase Inhibition for Patients with RET-Altered Cancers.
Journal Annals of oncology : official journal of the European Society for Medical Oncology
Vol
Issue
Date 2018 Apr 18
URL
Abstract Text Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed inhibit diverse RET fusions, activating mutations and acquired resistance mutations.Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, multikinase inhibitor-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six multikinase inhibitor regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and calcitonin-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET M918T RET V804M thyroid medullary carcinoma sensitive LOXO-292 Case Reports/Case Series Actionable In a clinical case study, a patient with thyroid medullary cancer harboring RET M918T and RET V804M demonstrated an initial response to LOXO-292, which included a decrease in allelic fraction of RET M918T and RET V804M over 8 weeks and a radiographic response of nearly 54% post 6.9 months of treatment (PMID: 29912274; NCT03157128). 29912274
RET M918T thyroid medullary carcinoma sensitive LOXO-292 Preclinical - Cell culture Actionable In a preclinical study, thyroid medullary carcinoma cells harboring RET M918T were sensitive to treatment with LOXO-292 in culture, demonstrating decreased cell proliferation (PMID: 29912274). 29912274
RET M918T RET V804M lung adenocarcinoma resistant Alectinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma initially treated with chemotherapy and immunotherapy was found to harbor KIF5B-RET, and was then treated with Alecensa (alectinib), which resulted in an intracranial response, but eventually led to further progression (PMID: 29912274; NCT03157128). 29912274
RET C634W thyroid medullary carcinoma sensitive LOXO-292 Preclinical - Cell line xenograft Actionable In a preclinical study, thyroid medullary carcinoma cells harboring RET C634W were sensitive to treatment with LOXO-292, demonstrating decreased cell proliferation in culture and inhibition of tumor growth in cell line xenograft models (PMID: 29912274). 29912274
RET M918T RET V804M thyroid medullary carcinoma resistant Everolimus + Vandetanib Case Reports/Case Series Actionable In a clinical case study, a patient with thyroid medullary carcinoma harboring RET M918T progressed on multiple therapies, including Nexavar (sorafenib), Caprelsa (vandetanib), Cometriq (cabozantinib), MGCD-516 (sitravatinib), and RXDX-105 (CEP-32496), and upon progression with the combination therapy, Caprelsa (vandetanib) and Afinitor (everolimus), cell-free DNA testing revealed RET M918T and acquisition of a secondary drug resistant mutation, RET V804M (PMID: 29912274; NCT03157128). 29912274
RET M918T Advanced Solid Tumor sensitive LOXO-292 Preclinical - Cell culture Actionable In a preclinical study, cells expressing RET M918T were sensitive to treatment with LOXO-292 in culture, demonstrating decreased cell proliferation (PMID: 29912274). 29912274