Zidesamtinib has differentiated preclinical brain penetrance and intracranial activity compared to other ROS1 inhibitors

Introduction. Tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, repotrectinib, and taletrectinib are FDA-approved for ROS1-positive non-small cell lung cancer. Clinical challenges with these TKIs may include disease progression due to emergent ROS1 resistance mutations, most commonly G2032R, and/or brain metastases, and treatment-limiting central nervous system (CNS) adverse events attributed to off-target TRK inhibition. ROS1-selective investigational TKI zidesamtinib and dual-TRK/ROS1 TKIs repotrectinib and taletrectinib have reported clinical activity against ROS1 G2032R and intracranial disease. In this study, we compared brain penetrance and intracranial ROS1 G2032R antitumor activity of ROS1 TKIs in preclinical settings. Methods. Brain penetrance of ROS1 TKIs was assessed by the CNS multiparameter optimization (MPO) score, P-glycoprotein (Pgp) efflux in MDCK-MDR1 cells, and unbound brain-to-plasma partitioning (Kp,uu) in Wistar-Han rats after a single 10 mg/kg oral dose. Balb/c nude mice intracranially harboring Ba/F3 CD74-ROS1 G2032R luciferase tumors were treated with zidesamtinib (3 mg/kg twice daily), taletrectinib (100 mg/kg once daily), or repotrectinib (75 mg/kg twice daily). Tumor growth was monitored by bioluminescence imaging. Plasma samples were collected for pharmacokinetics analysis; TKIs achieved plasma exposures near or above reported clinical plasma exposures. Results. In this preclinical study, zidesamtinib's CNS MPO score suggested potential for brain penetrance. Zidesamtinib showed lower efflux in cells expressing Pgp, the primary transporter involved in exclusion of small molecules from the brain, and higher Kp,uu than all approved ROS1 TKIs. Taletrectinib had a CNS MPO score, efflux ratios, and Kp,uu comparable with crizotinib, a TKI with insufficient brain exposure. In the intracranial CD74-ROS1 G2032R model, all vehicle-treated mice rapidly developed brain tumors and succumbed by Day 21 (median overall survival [mOS] = 12 days). Taletrectinib and repotrectinib provided brief tumor suppression, and all mice succumbed by Day 34 (mOS = 28 days) and Day 30 (mOS = 30 days), respectively. By contrast, zidesamtinib achieved sustained intracranial tumor suppression over the treatment duration, and all mice survived to the Day 42 study endpoint (mOS > 42 days). Switching from taletrectinib to zidesamtinib on Day 7 or 17 improved disease control, and all mice survived to the Day 42 endpoint (mOS > 42 days). Conclusion. Zidesamtinib demonstrated improved preclinical brain penetrance and intracranial activity against ROS1 G2032R compared with taletrectinib and repotrectinib. Zidesamtinib's increased ROS1 G2032R potency and brain penetrance potentially underlie its differentiated intracranial activity in this preclinical setting.