P14.19 Preclinical and clinical efficacy of entrectinib in primary and metastatic brain tumors harboring NTRK, ROS1, or ALK gene fusions
Authors: S. Rangaraju, A. Farago, K. M. Heym, M. Ahn, A. Drilon, S. Potts, Z. Hornby, P. Multani, G. Li
Journal: Neuro-Oncology (2017)

Targeted therapies that effectively cross the blood-brain barrier to treat primary and metastatic brain tumors represent a critical unmet medical need in neuro-oncology. NTRK, ROS1, and ALK gene fusions are seen in over 40 primary solid tumor histologies, many of which may be complicated by brain metastases. An inhibitor with demonstrated brain tumor efficacy could be beneficial for these patient populations. Entrectinib (RXDX-101), an orally available, selective and potent kinase inhibitor of TRK, ROS1, and ALK, is specifically designed to cross the blood-brain barrier and is being developed in part to address this need. STARTRK-2 (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - 2) (NCT02568267) is an open-label, multi-center, global phase 2 pivotal basket study of oral entrectinib in adult patients with locally advanced or metastatic solid tumors, including primary and secondary brain lesions, harboring a gene fusion in NTRK, ROS1, or ALK. While NTRK, ROS1, or ALK gene fusions are rare in non-small cell lung cancer (NSCLC), colorectal cancer, and primary brain tumors, NTRK fusions are more frequent in rare cancers such as infantile fibrosarcoma, secretory breast cancer and mammary analog secretory carcinoma (MASC) of the salivary gland. We report the activity of entrectinib against metastatic brain lesions in preclinical models and clinical subjects bearing these gene fusions. Entrectinib demonstrated a CNS penetration with a brain/blood ratio of 0.4 in mouse, 0.6 - 1.0 in rat, and 1.4 - 2.2 in dog. In a mouse model of intracranial ALK-fusion-driven lung cancer, entrectinib led to a survival benefit of 57 days vs. 34 days (p < 5x10e-4), after 10 days of oral treatment. In phase 1 clinical studies of entrectinib, a total of 119 patients have been treated with entrectinib (as of March 7, 2016). In the subpopulation of 24 patients positive for NTRK, ROS1, or ALK gene fusions who were naïve to prior TRK-inhibitor treatment specific for their respective fusion, effective therapeutic dosing of entrectinib resulted in a 79% response rate, with a well-tolerated safety profile. Regression of primary and metastatic brain tumors was demonstrated in 100% of NTRK fusion positive patients with CNS disease (3/3). In an NSCLC patient with SQSTM1-NTRK1 gene fusion, entrectinib treatment led to a rapid and sustained clinical response systemically and in 15-20 secondary brain lesions. In multiple ROS1-rearranged NSCLC patients, entrectinib treatment also resulted in robust regression of metastatic brain lesions. Finally, compassionate use of entrectinib in a young patient with infantile fibrosarcoma harboring an ETV6-NTRK3 fusion led to a confirmed RECIST response of multiple CNS metastases. Together, these data provide compelling evidence to identify patients with primary or metastatic brain tumors harboring NTRK, ROS1, or ALK fusions for enrollment in the STARTRK-2 trial.