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A series of novel 4′-[(benzimidazol-1-yl)methyl]biphenyl-2-sulphonamides was designed, and their molecular model simulation fitting to a new HipHop 3D pharmacophore model was examined.

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Introduction: Cellular mesenchymal-epithelial transition (cMET) dysregulation has been described in non-small-cell lung cancer (NSCLC) and implicated as a negative prognostic factor. It can occur as amplification, overexpression or mutations leading to exon 14 skipping. Bozitinib (PLB-1001, CBT-101) is a potent highly selective cMET inhibitor, which has demonstrated superior activity in both in vitro and in vivo NSCLC models. Methods: This was a phase I, open-label multicenter study conducted in locally advanced or metastatic NSCLC patients that included a dose-escalation (19 patients) and a dose-expansion phase (18 patients) (NCT02896231). A traditional 3+3 design was adopted for dose escalation. The primary objective was to characterize the safety and tolerability of single agent Bozitinib. The secondary objectives included pharmacokinetics (PK) analysis and antitumor activity assessed by RECIST v1.1. cMET dysregulation was defined by: IHC 3+ expression in >50% of tumor cells or gain of copy numbers (GCN) ≥5 or cMET/centromere ≥2.2 by FISH or MET copy number ≥2.25 or with exon 14 skipping by next-generation sequencing (NGS). Only central laboratory testing was acceptable. Patients≥18 years with locally advanced or metastatic NSCLC with an ECOG performance status ≤2 were enrolled. Those previously treated with cMET inhibitor or HGF targeting therapy were excluded. Patients were orally administrated with Bozitinib capsules in a total of 6 dose cohorts: 5 BID dose cohorts (50 mg BID, 100 mg BID, 150 mg BID, 200 mg BID and 275 mg BID), and 1 QD dose cohort (300 mg QD). The enrollment had been completed by October 31 2019 with 37 enrolled patients. Results: Of the 37 enrolled patients, with a median age of 61: 8 had overexpression; 11 had exon 14 skipping; 8 had amplification and 10 patients had more than 1 type of MET alterations. Bozitinib was generally well-tolerated in all cohorts. Treatment-related AEs of any grade were observed in 35 patients and those of ≥ grade 3 were observed in 10 patients (in 200mg BID, 275mg BID and 300mg QD groups), including ALT increase, AST increase, bilirubin increase and peripheral edema. Common AEs occurring in more than 20% of patients included: ALT increase (40.5%), AST increase (40.5%), bilirubin increase (40.5%), peripheral edema (32.4%) and QTc interval prolongation (18.9%). Bozitinib showed good linear PK characteristics, with dose-dependent increases in exposure and a half-life around 13.8-44.6h. 36 were included in the BOR analysis. One patient was excluded due to the development of brain metastases after first dose. This cohort presented an ORR of 30.6% (11/36) and a DCR of 94.4% (34/36). Sub-analysis of ORR for patients with overexpression, amplification and exon 14 skipping were 35.7%, 41.2% and 66.7%, respectively. ORR for patients with overexpression and amplification (N=6) was 50%. ORR for patients harboring both exon 14 skipping and amplification (N=4) was 100%. Conclusions: Based on safety profiles, PK and efficacy analyses, 200mg BID was determined to be RP2D. Bozitinib was well-tolerated with manageable safety profiles when administered at RP2D. Preliminary antitumor activity was observed in patients with exon 14 skipping and/or amplification, particularly in those with NGS-identified exon 14 skipping. Citation Format: Jinji Yang, Qing Zhou, Huajun Chen, Lin Wu, Jun Zhao, Renhua Guo, Yun Fan, Hepeng Shi, Weizhe Xue, Peilong Zhang, Han-Zhang Han, Xuan Lin, Shuyin Chen, Lu Zhang, Hao Liu, Xinru Mao, Bin Gan, Yilong Wu. A phase I study of cMET inhibitor bozitinib in patients with advanced NSCLC harboring cMET alterations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT127.