Fusions and mutations involving the RET gene have been identified as oncogenic drivers in lung and thyroid cancers, as well as several other malignancies. Selective RET inhibitors such as selpercatinib and pralsetinib are active in patients with these cancers. However, resistance may occur, including the acquisition of solvent front mutations (SFMs) such as RET G810 substitutions. Results of RET-driven in vitro and in vivo tumor models of TPX-0046, a novel RET inhibitor, were presented at the 2020 ASCO Annual Meeting.
TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations, including SFMs. In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. TPX-0046 was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 <10 nM) in tumor cell lines and Ba/F3 engineered RET models. In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values of approximately 1 nM.
In addition, TPX-0046 demonstrated marked in vivo antitumor 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 more than 80% of RET phosphorylation. With dosing of 5 mg/kg twice daily, tumor regression was observed in RET-dependent xenograft models. Tumor regression was also observed in models with RET SFMs, including TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR 1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R.
The investigators conclude that TPX-0046 is a unique next-generation RET inhibitor that demonstrates potent in vitro and in vivo activity against a range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial is currently under way to determine the safety and efficacy of TPX-0046 in patients with advanced or metastatic solid tumors harboring RET mutations or alterations.
Source: 2020 ASCO Annual Meeting. Abstract 3616.