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Ref Type Abstract
PMID
Authors Alexander E. Drilon, Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Jane Ung, Dong Lee, Laura Rodon, Armin Graber, Zachary Franklin Zimmerman, Brion W Murray, Vivek Subbiah
Title The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models.
Journal Vol Issue Date Pages Journal Short Title
Journal of Clinical Oncology 38 15_suppl May 20, 2020
URL https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.3616
Abstract Text RET fusions/mutations drive oncogenesis in lung and thyroid cancers, and several other malignancies. Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. On-target resistance includes the acquisition of solvent front mutations (SFMs i.e. RET G810 substitutions). TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations including SFMs. Methods: The rationally-designed, compact, macrocyclic RET/SRC inhibitor TPX-0046 was characterized in RET-driven in vitro and in vivo tumor models. Results: In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. It was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 < 10 nM) in tumor cell lines (LC2/ad, CCDC6-RET; TT, RET C634W) and Ba/F3 engineered RET models (WT, G810R). In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values ~1 nM. Ba/F3 RET engineered cells with SFMs (e.g. G810C/R/S) were potently inhibited by TPX-0046 (mean proliferation IC50 1–17 nM). TPX-0046 demonstrated marked in vivo anti-tumor efficacy in RET-driven cell-derived and patient-derived xenograft tumor models. In a Ba/F3 KIF5B-RET xenograft model, a single dose of 5 mg/kg TPX-0046 inhibited > 80% of RET phosphorylation (corresponding mean free plasma concentration: 51 nM). At 5 mg/kg BID, tumor regression was observed in RET-dependent xenograft models, including those that harbor RET SFMs: TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R. Conclusions: TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391).

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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
Gene 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 G810R Advanced Solid Tumor predicted - sensitive TPX-0046 Preclinical - Cell culture Actionable In a preclinical study, TPX-0046 treatment led to inhibition of cell proliferation in a transformed cell line expressing RET G810R in culture (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 3616-3616). detail...
RET G810S Advanced Solid Tumor predicted - sensitive TPX-0046 Preclinical - Cell culture Actionable In a preclinical study, TPX-0046 treatment led to inhibition of cell proliferation in a transformed cell line expressing RET G810S in culture (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 3616-3616). detail...
RET G810C Advanced Solid Tumor predicted - sensitive TPX-0046 Preclinical - Cell culture Actionable In a preclinical study, TPX-0046 treatment led to inhibition of cell proliferation in a transformed cell line expressing RET G810C in culture (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 3616-3616). detail...