Reference Detail

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 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...
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...