Background: Somatic oncogenic fusions of NTRK with other genes, such as ETV6, LMNA, TPM3, PAN3, etc. occur in a wide range of adult and pediatric tumors. Clinical application of 1st generation TRK inhibitors, i.e., larotrectinib and entrectinib, for the treatment of NTRK fusion-positive cancer patients has achieved high response rates regardless of tumor types. However, prolonged treatment often leads to acquired drug resistance attributed to various mutations in TRK kinase domains. Here we report the development of a 2nd generation pan-TRK inhibitor, ICP-723, potently inhibits activities of wild-type and some mutant forms of TRK.

Results: ICP-723 effectively inhibits kinase activities of TRKA, TRKB, TRKC with IC50 values < 1 nM. In the KINOMEscan, at a concentration of 100 nM, ICP-723 competitively binds to TRKA/B/C with 100% of inhibition rate, indicating high selectivity for pan-TRK. To evaluate the anti-proliferative activity of ICP-723 in TRK-driven tumor cells, KM12 colorectal cancer cell line bearing TPM3-NTRK1 fusion, as well as a panel of 19 Ba/F3 pro-B murine cell lines over-expressing wild-type or mutant forms of NTRK fusions are tested. ICP-723 demonstrates robust in vitro efficacy in all wild-type TRK-driven tumors. It also overcomes solvent front mutations (e.g., TRKA G595R, TRKC G623R/E) often developed following 1st generation TRK inhibitor treatment. Amongst other TRK mutations, ICP-723 exerts reduced activity in gatekeeper mutations (e.g., TRKA F589L, TRKB F633L, TRKC F617L) and some xDFG mutations (e.g., TRKA G667C/S, TRKB G709C); but retains activity in other xDFG mutations (e.g., TRKA G667A, TRKC G696A/C) and unclassified mutations (e.g., TRKA V573M, TRKA A608D, TRKB V689M). In vivo efficacy studies further demonstrate its robust anti-tumor effects in xenograft models. Treatment with 1 mg/kg of ICP-723 results in 89.5% TGI of KM12 tumors, similar to the efficacies of larotrectinib or selitrectinib at 30 mg/kg dose levels. Treatment with 1 or 3 mg/kg of ICP-723 leads to 100% survival of mice bearing Ba/F3 LMNA-NTRK1 G595R tumors, confirms the effectiveness of ICP-723 against solvent front mutant TRKA. The in vivo efficacy of ICP-723 is also well accompanied by pharmacodynamic modulation of TRK phosphorylation, where ICP-723 exposure levels correlate with the inhibition of TRK phosphorylation. The pharmacokinetic parameters of ICP-723 are overall favorable, with high oral bioavailability. Preclinical safety evaluations also exhibit acceptable drug tolerance in SD rats and Beagle dogs.

Conclusions: ICP-723 is a novel, 2nd generation pan-TRK inhibitor with broad-spectrum anti-tumor activities against wild-type and various acquired drug-resistant mutations of NTRK gene fusions. ICP-723 is now in phase I clinical trial in China and United States.

Citation Format: Ruixia Liang, Chao Zhou, Yingrui Han, Prince Lu, Charles Ying Wang, Zuopeng Wang, Richard Liu, Norman Kong, Jason Bing Zhang, Jasmine Jisong Cui, Davy Xuesong Ouyang. ICP-723 is a potent pan-TRK Inhibitor with robust anti-tumor activities against wild-type and acquired drug-resistant mutations of NTRK fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6187.