Promising data on Phase I/II clinical trials of the investigational drug brigatinib for non-small cell lung cancer (NSCLC) was recently presented at the American Society for Clinical Oncology (ASCO) 2015 Annual Meeting held in Chicago.
NSCLC is the most common type of lung cancer corresponding to about 85% of all lung cancers diagnosed. It has been reported that some NSCLC have a rearrangement in a gene called ALK (anaplastic lymphoma kinase), resulting in the production of an abnormal ALK protein that promotes cancer growth, survival and spread. Lung cancers with the ALK gene rearrangement, estimated to be around 4% of all lung cancers, are susceptible to treatment with ALK inhibitors.
Brigatinib is an oral drug able to inhibit ALK activity that was developed by Ariad Pharmaceuticals, Inc. At ASCO 2015, researchers showed that in a cohort of 78 ALK-positive NSCLC patients, 58 responded positively to treatment with brigatinib, including 50 out of 70 patients whose disease progressed after a previous treatment based on crizotinib, the first licensed ALK inhibitor. Progression-free survival (PFS) in these particular patients was found to be 13.4 months.
“Although still only in an early phase trial, brigatinib is showing an objective response rate in approximately 70 percent 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,” noted the trial’s principal investigator Dr. D. Ross Camidge, at the University of Colorado Cancer Center, in the press release.
Brigatinib has also been tested in lung cancer patients with untreated brain metastases. The team found that in 15 patients with brain tumors greater than 10 mm, 8 patients had a greater than 30% decrease in tumor size after treatment with brigatinib, while in 33 patients with smaller brain lesions, 11 patients experienced complete disappearance of brain metastases after treatment. Overall, brain metastases remained controlled for a median of 15.6 months.
“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,” said Dr. Camidge.
Based on these results, brigatinib recently received the Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of ALK-positive metastatic NSCLC patients whose cancer is resistant to crizotinib.
In terms of safety, brigatinib was found to be, in general, well-tolerated by the patients; however, in a small proportion of patients, early onset pulmonary symptoms were reported where the patients developed rapid shortness of breath and oxygen dependency. These symptoms were reported in 14% of patients receiving brigatinib starting dose of 180 mg, and in only 4% of the patients receiving 90 mg, including patients who received 180 mg after one week of treatment.
“Beyond the dose effect, another key breakthrough in managing this rare side effect came through careful management of a patient here in Colorado. By supporting him through the 3-5 days of his symptoms, he rapidly acclimatized and has been able to stay on the drug ever since without problems. The symptoms disappeared by themselves. This gave us the idea of maybe we could minimize the risk by getting folks through the early period at a lower dose and then escalating dosing once everything had settled down,” explained Dr. Camidge.
A phase II trial is currently being conducted where a sustained 90 mg brigatinib dose regimen is being compared to a 90 mg dose for one week followed by escalation to 180 mg.
