Abstract CT056: Development of a novel next-generation RET inhibitor
Authors: Zhong Jun , Xiao Ruxue , Xie Wenya , Chen Minchun , Chen Xiaohu , Wang Hao , Liu Yongbo , Gao Qin , Wang Xiupeng , Wang Zongbao , Chen Qian , Yang Jing , Ji Yizhe , Wang Yuxun 
Published: April 2024

Abstract
Oncogenic RET alterations confer constitutive activation in multiple types of human cancers. Two first-generation selective RET inhibitors selpercatinib and pralsetinib have been approved for patients with RET-driven solid tumors including non-small cell lung cancer (NSCLC) and thyroid cancer. However, critical unmet medical needs remain due to drug resistance caused by RET mutations in patients treated with the first-generation RET inhibitors. To address this emerging clinical issue, we discovered a highly potent and selective RET inhibitor with novel chemical scaffold through structure-based drug design, APS03118. Preclinical studies showed APS03118 had stronger in vitro and in vivo biological activity than the first-generation RET inhibitors targeting a broad range of RET fusions and mutations. Importantly, APS03118 was highly potent against a series of resistant RET mutations including the solvent front mutations RET G810C/R/S (IC50 0.04-5.72 nM) and gatekeeper mutations RET V804E/L/M (IC50 0.04-1.36 nM). Off-target screen analysis using the 468-kinase panel demonstrated APS03118 was highly selective for RET. APS03118 was orally bioavailable with good ADME and PK properties and markedly suppressed tumor growth in various RET-driven mouse xenograft tumor models (tumor growth inhibition 87-108% at 10-30 mg/kg BID). In addition, APS03118 exhibited excellent brain penetrating properties with strong efficacy in the in vivo orthotopic brain tumor model. GLP toxicity studies showed acceptable safety profiles. APS03118 received IND approval from both US FDA and China NMPA, and was granted the fast-track designation by FDA. We recently achieved First-in-Human milestone for APS03118 and the Ph 1 clinical trial is ongoing. As of January 5, 2024, three dose levels have been tested. Plasma exposure of APS03118 increased proportionally following single and repeated administration of APS03118 at different doses. APS03118 was well tolerated in NSCLC and thyroid cancer patients harboring RET fusions or mutations relapsed on the chemotherapy, multi-kinase inhibitor and first-generation RET inhibitor therapy. In addition to the favorable safety profiles, we observed sign of efficacy in the RET altered cancer patients in response to APS03118 treatment even in the early clinical trial testing. Partial response and stable disease were observed in patients 2-4 months after administration of APS03118 and dose limiting toxicity (DLT) dose has not been reached. Dose escalation for APS03118 is continuing. Taken together, APS03118 is a novel highly potent and selective next-generation RET inhibitor overcoming resistance following treatment with the first-generation RET inhibitors. APS03118 warrants further clinical development.
Citation Format: Jun Zhong, Ruxue Xiao, Wenya Xie, Minchun Chen, Xiaohu Chen, Hao Wang, Yongbo Liu, Qin Gao, Xiupeng Wang, Zongbao Wang, Qian Chen, Jing Yang, Yizhe Ji, Yuxun Wang. Development of a novel next-generation RET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT056.