P14.19 Preclinical and clinical efficacy of entrectinib in primary and metastatic brain tumors harboring NTRK, ROS1, or ALK gene fusions

Abstract

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, ...

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

“…In addition, and consistent with these relative AP-ER values, entrectinib (despite not reaching steady state) showed a more favourable CSF-to-plasma unbound concentration ratio than crizotinib and larotrectinib (both of which reached steady state) following constant intravenous infusion for 4-6 h in an in vivo brain distribution study (> 0.2 vs ≈ 0.03 and ≈ 0.03) [11]. Entrectinib demonstrated CNS penetration [5,11] (e.g. steady-state brain/plasma ratios of 1.4-2.2, 0.6-1.0 and 0.4 following repeated daily oral administration in dog, rat and mouse, respectively [5]) and inhibited tumour growth and improved survival in murine models intracranially injected with human tumour cell lines driven by an NTRK [11] or ALK [24] fusion.…”

“…The diagnosis and treatment of solid tumours has firmly entered the era of personalized (or precision) medicine, with optimal patient management requiring molecular profiling aimed at identifying oncogenic driver mutations that are actionable or potential therapeutic targets [1][2][3][4]. In this regard, gene rearrangements (fusions) involving the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2 and NTRK3 [encoding the tropomyosin receptor kinase (TRK) receptors TRKA, TRKB and TRKC, respectively], the c-ros oncogene 1 receptor tyrosine kinase (ROS1) gene [encoding proto-oncogene tyrosine-protein kinase ROS (ROS1)] and the anaplastic lymphoma kinase gene (ALK; encoding the ALK receptor tyrosine kinase) are variously implicated, albeit often infrequently, in a broad range of (> 40) solid tumour types [5]. NTRK fusions, which are thought to be present in up to 1% of all solid tumours, are found in a wide variety of adult and paediatric tumour types; they are extremely common (incidence > 90%) in rare cancer types, such as infantile fibrosarcoma and mammary analogue secretory carcinoma (MASC), but rare (incidence predominantly < 1%) in more common cancer types, such as lung, breast and colorectal cancers, and melanomas [2,6,7].…”

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

“…Intratumoral target engagement remains one major obstacle for effective treatment of brain tumors, which are considered to be protected from anticancer drugs by the BBB. Entrectinib demonstrated CNS penetration capacity in preclinical models with repeated oral daily dosing [ 26 , 50 ]. In our study, we could demonstrate CSF penetrance of entrectinib in a patient for the first time.…”

Management of glioblastoma: State of the art and future directions

“…148,149 There were patients with glioblastoma on those trials, and subgroup analyses suggested a benefit from NTRK inhibitors in these patients. 150,151 There are also numerous FGFR TKIs in development, and there are documented cases of response. 152 Although many trials of targeted therapies to date have not demonstrated significant efficacy, better enrichment strategies using precision biomarkers will increase the chances of future success.…”