Brigatinib Offers Disease Control in Crizotinib-Refractory NSCLC

Higher doses of the kinase inhibitor brigatinib as second-line therapy for anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) may be an option for some patients. A new study published in the Journal of Clinical Oncology is suggesting that brigatinib may produce substantial whole-body and intracranial responses as well as robust progression-free survival (PFS). The researchers found that a lead-in dose of 180 mg showed consistently better efficacy than 90 mg, with acceptable safety.

The majority of patients with ALK-positive NSCLC eventually experience disease progression after treatment with crizotinib. Now, crizotinib-refractory, ALK-positive NSCLC patients appear to have a new treatment alternative that is highly effective and highly tolerable. Brigatinib, a next-generation ALK inhibitor, is the first agent to demonstrate over 1-year control of ALK-positive lung cancer post-crizotinib.

“Brigatinib has a broader spectrum of coverage of resistance mechanisms than many of these other next generation drugs, especially at the higher dose. So, the broader your spectrum of coverage of resistance mechanisms, the longer you control the disease,” said senior study author D. Ross Camidge, MD, PhD, who is the director of Thoracic Oncology at the CU School of Medicine in Denver.

The US Food and Drug Administration (FDA) granted accelerated approval for crizotinib to target ALK changes in 2011. However, crizotinib does not pass the blood-brain barrier and is unable to target ALK-positive lung cancer that has spread into the central nervous system. In addition, the genetic diversity of NSCLC leads to high rates of resistance to the drug.

The current multicenter phase II clinical trial examined brain metastases and best response to crizotinib. Patients were randomly assigned to oral brigatinib 90 mg once daily (n = 109) or 180 mg once daily (n = 110). Among all the patients, more than two-thirds had baseline brain metastases and three-fourths had received prior chemotherapy. The study demonstrated that those in the 90 mg dose arm had a 45% overall response rate (ORR) with 8-month median follow-up. Those on the higher dose had a 54% ORR.

The researchers found that the median PFS was 9.2 months in the 90 mg dose group and 12.9 months in the higher dose group. The most common treatment-related adverse events were mainly nausea, diarrhea, headache, and cough. Most of the adverse events were grades 1 or 2. However, a subset of pulmonary adverse events occurred within approximately 48 hours of starting the medication in 14 of 219 treated patients (all grades).

Camidge said many patients enrolled in this trial continue to experience cancer control and most recent results as of May 17, 2017, show that median PFS with brigatinib against ALK-positive lung cancer may be closer to 16 months. On April, 28, 2017, the FDA approved brigatinib as a second-line therapy for ALK-positive NSCLC patients.