Next-generation ALK-inhibitor brigatinib promising against NSCLC

CHICAGO, IL—The investigational drug brigatinib against ALK-positive non-small cell lung cancer (NSCLC) had promising results in a phase 1/2 clinical trial. The study found that 58 of 78 ALK-positive  patients responded to treatment, including 50 of 70 patients who had progressed after previous treatment with crizotinib, the first licensed ALK inhibitor. Progression-free survival (PFS) in patients previously treated with crizotinib was 13.4 months.

These findings were reported at the 2015 American Society for Clinical Oncology (ASCO) Annual Meeting.

"Although still only in an early phase trial, brigatinib is showing an objective response rate in approximately 70% of ALK-positive patients post-crizotinib and it's showing about a year of progression-free survival. These results are among the best in the field, offering a lot of hope to people with ALK-positive lung cancer," said principal investigator D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado Cancer Center in Aurora.

In addition, robust data is emerging on drug activity in patients with brain involvement of the disease. Many lung cancer trials have traditionally excluded patients with brain metastases at baseline, expecting that the presence of metastases would create negative results that could in turn create the appearance of drug failure.

Following early recognition of the importance of the brain as a potential differentiator between the activity of new drugs, the brigatinib trial included patients with untreated brain metastases. A greater than 30% decrease in size of brain tumors was found in 8 of 15 patients with brain tumors greater than 10 mm, along with the disappearance of brain metastases in 11 of 33 patients with smaller lesions only. Brain metastases remained controlled for a median 15.6 months.

Based on these promising early results, brigatinib, developed by Ariad Pharmaceuticals Inc, recently received Breakthrough Therapy designation by the US Food and Drug Administration (FDA) for the treatment of patients with ALK-positive metastatic NSCLC whose tumors are resistant to crizotinib.

"Many targeted cancer treatments come with an Achilles heel, a specific way or ways that the cancer can use to escape the drug, either through growth in the brain or via a range of different crizotinib-resistance mechanisms. We're now seeing that brigatinib covers a lot of these 'escape mechanisms,' potentially offering greater and more durable disease control," Camidge said.

The drug is an oral compound that inhibits the activity of ALK. When ALK is engaged through a gene rearrangement, it can drive the growth and survival of the cancer. ALK rearrangements occur in approximately 4% of lung cancers.

Brigatinib is generally well tolerated, but in a small proportion of cases early onset pulmonary symptoms can occur. These patients develop rapid shortness of breath and oxygen dependency. These symptoms were seen in 14% of patients treated with a starting dose of 180 mg, but in only 4% of patients who started with a 90-mg dose, including those patients who then escalated to 180 mg after 1 week of treatment.

A phase II trial comparing sustained 90 mg dosing of the drug, with 90 mg of the drug for 1 week followed by escalation to 180 mg is underway.

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