Abstract 3071: Repotrectinib demonstrates promising activities in ROS1 wild-type and solvent-front mutant lung cancer patients-derived preclinical models
Authors: Kim Dong Hwi , Kim Seok-Young , Joo Hyeong Seok , Lee You Won , Kang Han Na , Hong Min Hee , Kim Hye Ryun , Cho Byoung Chul , Yun Miran 
Published: August 2019

Abstract
The ROS1-rearranged non-small-cell lung cancer (NSCLC) is currently treated with ALK/ROS1 tyrosine kinase inhibitor (TKI) crizotinib as a first-line agent. However, resistance invariably develops and subsequent therapeutic option for overcoming them is limited. Therefore, we investigated the antitumor activity of several ROS1-TKIs in ROS1-positive patient-derived preclinical models.
In this study, we established 6 patient-derived cells (PDCs) from patients with different types of ROS1 fusion partners as follows: treatment-naïve (YU1078, YU1082 and YU1083), crizotinib-resistant G2032R (YU1079) and crizotinib- or entrectinib- primary resistant (YU1081 and YU1085). Sanger sequencing and whole-exome sequencing were then conducted to determine the characteristics. The in vitro and in vivo antitumor activities of ROS1-TKIs in these PDCs were evaluated by comparing the survival, expression assay, duration of tumor re-emergence and ability to penetrate the blood-brain barrier (BBB).
Repotrectinib potently inhibited cell proliferation and ROS1-downstream signaling pathways in YU1078 (CD74-ROS1). In YU1078-derived xenograft models, repotrectinib induced the marked tumor regression and delayed the duration of tumor re-emergence following drug withdrawal compared with crizotinib and entrectinib. Interestingly, both YU1081 (TPM3-ROS1) and YU1082 (SLC34A2-ROS1) with cross primary resistance to other clinically available ROS1-TKIs exhibited high sensitivity to repotrectinib in the concentration range of 100~200 nM. Immunoblot analysis demonstrated that repotrectinib completely suppressed the phosphorylation of ROS1 and STAT3. Notably, repotrectinib showed the selective and highly potency in vitro and in vivo against solvent-front mutant G2032R conferring crizotinib resistance. In G2032R-mutant xenograft models, the response of repotrectinib was still maintained until the end of the experiment (120 days) after drug withdrawal, but loratinib- or cabozantinib-treated tumors rapidly re-emerged. Moreover, repotrectinib induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. As clinical proof of concept, the potent systemic and intracranial activity of ropotrectinib has been observed in patients who had progressed on prior TKIs or TKI-naïve patients, who were enrolled on-going phase 1/2 clinical trial (NCT03093116).
Our finding indicated a superior antitumor activity of repotrectinib in both wild-type and mutant ROS1 fusion, providing a rationale that repotrectinib may be an effective subsequent or upfront treatment option for patients with ROS1-positive NSCLC who have relapsed on the available TKIs as well as TKI naïve, including patients with progressive CNS metastases.
Citation Format: Dong Hwi Kim, Seok-Young Kim, Hyeong Seok Joo, You Won Lee, Han Na Kang, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho, Miran Yun. Repotrectinib demonstrates promising activities in ROS1 wild-type and solvent-front mutant lung cancer patients-derived preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3071.