Brigatinib, an investigational ALK tyrosine kinase inhibitor, demonstrated significant intracranial antitumor activity in patients with ALK-positive nonâ€“small cell lung cancer and brain metastases.
Giorgio V. Scagliotti, MD, PhD
Brigatinib (AP26113), an investigational ALK tyrosine kinase inhibitor, demonstrated significant intracranial antitumor activity in patients with ALK-positive non—small cell lung cancer (NSCLC) and brain metastases, according to findings presented at the European Lung Cancer Conference.1
A post hoc analysis conducted by Ariad Pharmaceuticals, the company developing brigatinib, looked at 49 NSCLC patients identified as having baseline brain metastasis. The analysis determined that intracranial disease control was achieved with brigatinib in 87% of patients with measurable brain metastases and in 87% of patients with nonmeasurable brain metastases. Intracranial response was reported in 53% of patients with measurable brain metastases and in 30% of patients with nonmeasurable lesions.
Following treatment, 45 patients achieved median intracranial progression—free survival (PFS) of 22.3 months. The median duration of intracranial response was 18.9 months.
Adverse events were mild to moderate in severity and included nausea, diarrhea, and fatigue that were reported by 29 (59%), 28 (57%), and 24 (49%) patients, respectively.
Giorgio V. Scagliotti, MD, PhD, professor, University of Turin in Italy, who discussed the study results at the conference, described the clinical development of ALK inhibitors as shown in the analysis as “amazing” for the short time period. Second-generation ALK inhibitors are characterized by high response rate and penetration into the CNS, with high efficacy against untreated and treated brain metastases.
Brigatinib, received a Breakthrough Therapy designation by the FDA in 2014 for the treatment of patients with ALK-positive metastatic NSCLC whose tumors are resistant to crizotinib (Xalkori). This designation was based on results from the ongoing phase I/II trial that showed antitumor activity of brigatinib in patients with ALK-positive NSCLC, including patients with active brain metastases.
Ninety-one percent of the patients evaluated in the analysis were previously treated with crizotinib, which is the standard of care in this patient population. As a first-line treatment, crizotinib has been shown to improved PFS and objective response rate compared with standard chemotherapy in patients with advanced ALK-positive NSCLC. However, for ALK-positive NSCLC patients who are crizotinib-resistant, CNS progression is common.
The patients studied in the post hoc analysis were among participants in a larger phase I/II single-arm, multicenter study of brigatinib in patients with advanced malignancies, including ALK-positive NSCLC. The trial included 137 patients, 79 of whome had ALK-positive NSCLC and 71 who had received prior treatment with crizotinib.
All patients received brigatinib at total once daily doses of 30 to 300 mg. Patients were broken into three cohorts that received 90 mg, 90 to 180 mg (escalating after 7 days) or 180 mg of brigatinib.
Of the 14 patients receiving brigatinib at 90 mg, none experienced a complete response, 79% (11) had a partial response, and 7% (1) had stable disease. Progressive disease was seen in no patients.
In the 26 patients receiving brigatinib at 90 to 180 mg, 12% (3 patients) had a complete response, 69% (18) experienced a partial response, and 8% (2) had stable disease. Progressive disease was observed in one patient.
In 25 patients receiving brigatinib at 180 mg, 8% (2) had a complete response, 60% (15) had a partial response, and 12% (3) patients had stable disease. Progressive disease was observed in five patients.
There was a median of 12.9 months of PFS in patients receiving the lowest dose of brigatinib. Median PFS had not been reached in the 90-to-180-mg cohort, and the median PFS in patients in the 180 mg cohort was 11.1 months.2
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 diameter of 10 mm or greater were defined as measurable lesions. Forty-six of the ALK-positive NSCLC patients in the trial were identified with brain metastases at baseline. Median time on study was 51.4 weeks (n = 46).
Based on the results from this trial and the post hoc analysis, a phase II ALTA trial study of brigatinib in ALK-positive NSCLC patients with brain metastases is underway. This is a randomized, open-label, multicenter, international study to evaluate the efficacy and safety of two different dosing regimens of brigatinib in patients with ALK-positive, locally advanced or metastatic NSCLC who have previously been treated with crizotinib. Brigatinib will be administered at a dose of 90 mg per day, continuously in a 28-day cycle or at a dose of 90 mg per day for 7 days, then 180 mg per day, continuously.
Scientists at Ariad initially discovered brigatinib. Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of NSCLC and neuroblastomas, as well as anaplastic large-cell lymphoma. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.