Abstract 4131: Antitumor effects of ensartinib in non-small cell lung cancer harboring MET exon 14-skipping mutations

Abstract Background: Met proto-oncogene (MET) exon 14 skipping mutations are tumor drivers in approximately 3% of lung cancer patients. The antitumor efficacy of ensartinib, a novel multi-kinase inhibitor, against non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations was investigated in this study. Methods: The MET-mutant binding affinity and antitumor activity of ensartinib were assessed in vitro and in vivo. Preliminary therapeutic activity of ensartinib in patient-derived organoids was observed. To explore clinical activity, 17 NSCLC patients with MET exon 14 skipping mutations were treated with ensartinib at 225 mg qd. Results: Molecular dynamic simulations revealed that ensartinib exhibited favorable binding to c-MET. Ensartinib was highly effective in inhibiting the kinase activity of the MET exon 14 deletion protein (IC50 = 7.9 nM). Furthermore, ensartinib potently suppressed the MET pathway and the growth of Hs746T cells that were subcutaneously implanted into mice. Most importantly, of 17 patients with 14 different types of MET exon 14 skipping mutations undergoing ensartinib treatment, 1 (6%) showed a complete response, 11 (65%) achieved a partial response, and 4 (24%) exhibited stable disease. Thus, the objective response rate (ORR) was 71% and the disease control rate (DCR) was 94%, and the ORR in MET-TKI naive patients was even higher (12/15, 80%). In 2 patients with brain metastasis without prior brain radiation, we observed one partial response in the brain, while in the other patient the brain lesions were stable for 6 months. The most frequently reported adverse events were rash, peripheral edema, and nausea; however, no fatal adverse events occurred. Conclusions: These results provide the first evidence that ensartinib exhibits both preclinical and clinical antitumor activity against MET exon 14 skipping mutations with the potential of strong intracranial efficacy and warrant further evaluation in a planned phase II study thus providing more options to patients with MET exon 14 skipping mutations. Updated data including duration of response, PFS and and OS will be provided at the time of the presentation with additional few months of follow up. Citation Format: Yang Xia, Fen Lan, Jing Zhao, Hua-Hao Shen, Giovanni Selvaggi, Wen Li. Antitumor effects of ensartinib in non-small cell lung cancer harboring MET exon 14-skipping mutations [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 4131.