ELCC 2015 News: Brigatinib (AP26113) Shows Intracranial Anti-tumour Activity in ALK-positive NSCLC patients with Brain Metastasis Following Crizotinib

Efficacy data from Post hoc analysis shows intracranial disease control

More than 80% of patients with non-small-cell lung cancer (NSCLC) and brain metastases achieved intracranial disease control after treatment with brigatinib, formerly AP26113, an investigational ALK tyrosine kinase inhibitor that can be taken orally.

Central nervous system (CNS) progression has been observed in a significant proportion of patients treated with crizotinib for ALK-positive NSCLC, according to first author Dr David Kerstein, Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, USA. Dr Kerstein presented findings from this post hoc efficacy analysis during a Medical and Radiation Oncology poster discussion session at the European Lung Cancer Conference, held April 15 to 18, 2015 in Geneva, Switzerland.

The post hoc analysis was done on data from 45 of the 49 patients identified with baseline brain metastases that had evaluable data at cut-off. The patients were among participants in a larger phase 1/2 single-arm, multicentre study of brigatinib in patients with advanced malignancies. All patients received brigatinib at total daily doses of 30 to 300 mg orally once daily.

Brigatinib received breakthrough therapy designation by US FDA

European Lung Cancer Conference 2015: Abstract LBA4

Brigatinib activity in ALK+ NSCLC patients with measurable intracranial CNS metastases (n=15) in a phase 1/2 trial. Objective response was achieved by 8/15 (53%) patients.
© David Kerstein

Preclinical activity for brigatinib had been observed against mutated ALK and also in crizotinib-resistant tumours having a range of other mutations in patients with baseline intracranial CNS metastases, which led to Breakthrough Therapy designation by the US Food and Drug Administration (FDA) in 2014.

Contrast-enhanced magnetic resonance imaging of the brain was done at baseline and at follow-up that was centrally reviewed by blinded independent neuroradiologists. Lesions having a longest diameter of 10 mm or greater were defined as measurable lesions.

The 49 patients identified with baseline brain metastasis and having evaluable data were on study a median of 56.1 weeks. Measurable brain metastases were reported for 16 patients and non-measurable brain metastases for 33 patients. Following treatment, 45 patients overall with brain involvement and a follow-up scan achieved median intracranial progression–free survival (PFS) of 22.3 months and the median duration of intracranial response in 16 patients with a response and a follow-up scan was 18.9 months.

Intracranial response was reported for 8 (53%) patients with measurable brain metastases and for 9 (30%) patients identified with non-measurable lesions. Intracranial disease control was achieved by 13 (87%) patients with measurable and by 26 (87%) patients with non-measurable brain metastases.

Treatment-emergent adverse events were mild to moderate in severity and included nausea, diarrhoea, and fatigue that were reported by 29 (59%), 28 (57%) and 24 (49%) patients, respectively.

Prof. Giorgio Scagliotti from the University of Torino in Italy, who discussed the study results, said that a clinical development of ALK inhibitors is amazing in very short time period. Second generation of ALK inhibitors is characterised by high response rate and penetration into central nervous system with highly efficacy against untreated and treated brain metastases.


The investigators concluded that brigatinib demonstrated significant intracranial antitumor activity and durable responses in patients with ALK-positive NSCLC whose disease progressed following crizotinib therapy and demonstrated CNS metastases at baseline.

Based on results from this post hoc analysis, a prospective study of brigatinib in ALK-positive NSCLC patients with brain metastases participating in the phase II ALTA trial is underway.


LBA4. Evaluation of anaplastic lymphoma kinase (ALK) inhibitor brigatinib [AP26113] in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) and brain metastases.

The study sponsor was ARIAD Pharmaceuticals, Inc.