We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases. •PF-06463922 is a highly potent and selective ALK inhibitor•PF-06463922 inhibits ALK mutants resistant to current clinical ALK inhibitors•PF-06463922 is very active against ALK-dependent intracranial tumor models•PF-06463922 shows a high safety margin in preclinical studies Zou et al. show that PF-06463922, an ALK/ROS1 inhibitor, is effective against all known clinical ALK mutants. Moreover, PF-06463922 is effective against brain metastases of EML4-ALK-driven tumors and has high safety margins in preclinical studies.