The investigational ALK inhibitor brigatinib could be a promising treatment for non-small cell lung cancer (NSCLC) patients who have ALK rearrangements. It showed a favorable clinical activity and an acceptable safety profile in a Phase 1/2 clinical trial.
The findings, recently published in The Lancet Oncology in the study “Activity and safety of brigatinib in ALK-rearranged non-small cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial,” support brigatinib’s continued development as a potential new treatment option for patients with ALK-rearranged NSCLC.
“The publication reports the results of the first clinical evaluation of brigatinib in patients with advanced malignancies, including ALK+ NSCLC,” Scott N. Gettinger, MD, associate professor of medicine at Yale Cancer Center and the study’s lead author, said in a press release.
“Brigatinib yielded responses in the majority of patients with crizotinib-treated ALK+ NSCLC, with median progression-free survival of over one year,” he said. “Additionally, responses in the brain were achieved in this crizotinib refractory population. Early onset pulmonary adverse events, which occurred in 8 percent of patients, generally within 48 hours of first dose, appeared to be related to starting dose.”
Approximately 8 percent of patients with NSCLC have rearrangements in the ALK gene, which is known to be involved in the development of this cancer. Two ALK inhibitors are currently FDA-approved to treat ALK-positive NSCLC: Xalkori (crizotinib) and Zykadia (ceritinib).
Now, the investigational ALK inhibitor brigatinib has emerged as a potential treatment for patients who are resistant to other ALK inhibitors.
The Phase 1/2 trial (NCT01449461) is an ongoing, single-arm, open-label study assessing brigatinib patients with advanced malignancies, including ALK-rearranged NSCLC. Among the 79 patients with advanced ALK-rearranged NSCLC, all but eight had received prior Xalkori treatment.
After a median time on brigatinib of 15.4 months, the median progression-free survival (PFS) of patients who had received Xalkori therapy was 13.2 months, and for patients who hadn’t received Xalkori, the median PFS had not been reached at the time of analysis.
The objective response rate was 100 percent for patients who had never received an ALK inhibitor and 74 percent for those who had been previously treated with Xalkori.
Brain metastasis was identified in 63 percent of ALK-rearranged NSCLC, and treatment with brigatinib was associated with an intracranial overall response rate of 53 percent in the 15 evaluable patients with measurable brain metastasis.
The most common Grade 3 and Grade 4 treatment-related adverse events were shortness of breath, hypertention, and increased lipase. Serious adverse events included shortness of breath, pneumonia, and hypoxia (low levels of oxygen in the blood).
Based on data from this Phase 1/2 trial and the pivotal Phase 2 ALTA clinical trial (NCT02094573), Ariad recently submitted a new drug application (NDA) to the U.S. Food and Drug Administration requesting approval for brigatinib in patients with metastatic ALK-rearranged NSCLC patients who are resistant or intolerant to Xalkori.
The FDA has granted priority review status to Ariad’s request, which accelerates the review time from 10 months to six months, setting the FDA action date for April 29, 2017. Ariad is also planning to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency in early 2017.
“This in-depth publication provides a thorough review of the Phase 1/2 trial of brigatinib, ARIAD’s internally developed targeted cancer candidate under regulatory review,” said Timothy P. Clackson, PhD, president of research and development and chief scientific officer at ARIAD.
“We are excited to continue to work with academic collaborators to provide additional clinical detail on the brigatinib trials, including upcoming presentations at the World Conference on Lung Cancer in December,” he said.