Here, we describe the dramatic response of a patient with an ETV6-NTRK3-driven mammary analogue secretory carcinoma to treatment with a pan-Trk inhibitor, and the development of acquired resistance linked to a novel NTRK3 mutation that interferes with drug binding. This case emphasizes how molecular profiling can identify therapies for rare diseases and dissect mechanisms of drug resistance.

Abstractsiii106 NEURO-ONCOLOGY • MAY 2017 age, KPS, EGFR and ALK status. Clinical outcome was evaluated by neurological examination and MRI at 2 months after RT and then every 3 months. RESULTS: From June 2009 to December 2015, 156 patients for 228 BMs treated were included in this evaluation. Fifty (32.1%) were female and 106 (67.9%) male with a median age of 62 years (range 27-93 years). The greater number of patients had a KPS 90-100, were in RPA class II, had DS-GPA score 2.5-3, and had 1-2 BMs (88.4%). Surgical resection only was performed in 3 cases, plus HSRS in 16 (19%) cases, and as rescue after local progression in 11 cases; SRS and HSRS only in 160 (70.1%) and 65 (28.5%), respectively. Eighty-four (53.8%) patients received systemic therapy after BMs treatment, consisted in chemotherapy platinum based in 56, mono-chemotherapy in 14, EGFR TKIs in 10 and ALK inhibitors in 4. The median follow-up time was 14.8 months (0.9-90.5 months) and 23.6 months (13.5-90.5 months) for alive patients. The 1 and 2 years LC rate were 87.2%±3 and 72.8%±5; the median BDF time and the 1 and 2 years BDF rate were 21.7 months, 30.8% ±4, 58.1%±6. The median OS time, the 1 and 2 years OS rate from BMs diagnosis were 15 months, 60.9%±3.9, 31.4%±4. On univariate analyses prognostic factors recorded as conditioning survival were age (p=0.01), presence of lymph-node involvement (p=0.03), KPS (p<<0.01), presence of extracranial metastases at the time of BMs treatment (p<0.01), and numbers of BMs (p=0.02), confirming the prognostic and predictive role of DS-GPA (p<<0.01). The treatment performed (surgery+HSRS) has proven to significantly improve OS (p<0.01) too. CONCLUSIONS: The choice of an adequate local treatment can impact on survival in patient with limited BMs from NSCLC. A careful evaluation of prognostic and predictive factors is a pivotal additional aid. 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 bloodbrain barrier and is being developed in part to address this need. STAR-TRK-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, ...