The TKI brigatinib offered good response rates in a phase II trial of patients with ALK-positive non–small-cell lung cancer whose disease progressed on crizotinib.
The investigational tyrosine kinase inhibitor (TKI) brigatinib offered good response rates in a pivotal phase II trial of patients with ALK-positive non–small-cell lung cancer (NSCLC) whose disease progressed on crizotinib. The results were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 9007).
“Most ALK-positive NSCLC patients treated with crizotinib eventually progress, often due to acquired ALK resistance mutations and/or poor CNS drug penetration,” said Dong-Wan Kim, MD, PhD, of Seoul National University Hospital in South Korea, who presented the study.
Brigatinib, a next-generation ALK TKI designed to have broad activity against resistant ALK mutants, showed promising clinical activity in a phase I/II study of crizotinib-treated ALK-positive NSCLC patients. The new open-label phase II ALTA study included 222 patients with locally advanced or metastatic NSCLC who had progressive disease on crizotinib. Patients were randomized to two brigatinib treatment regimens: group A (112 patients) received oral brigatinib 90 mg once per day, and group B (110 patients) received the same dose for 7 days followed by 180 mg once per day.
The median age of patients was 50.5 years in group A, and 56.5 years in group B, and most patients (71% and 67%, respectively) had brain metastases at baseline. As of February 29, 2016, 57% of patients on the 90-mg dose and 69% of patients on the 180-mg dose remained on the study.
The objective response rate (ORR) in group A was 45%, including one confirmed complete response. In group B, the ORR was 54%, with four confirmed complete responses. The median progression-free survival (PFS) was 9.2 months with the 90-mg dose and 12.9 months with the higher dose. The median overall survival (OS) had not been reached in either group; the 1-year OS rate was 80% with the higher dose, compared with 71% with the 90-mg dose.
Kim noted that among patients with measurable active brain metastases at baseline, the ORR was higher with the 180-mg dose, at 73% vs 37%. The intracranial PFS was 15.6 months with the 90-mg dose, and the median had not been reached in the 180-mg group.
The most common grade 3 or higher treatment-emergent adverse events included hypertension (6% in both groups), dyspnea (3% in group A and 2% in group B), increased blood creatine phosphokinase (3% and 9%, respectively), and others. In group A, 3% of patients required a discontinuation, and 7% required a dose reduction; in group B, these rates were 8% and 20%, respectively.
“Brigatinib demonstrated substantial efficacy and an acceptable safety profile in both arms,” Kim said. “A consideration of efficacy outcomes and adverse events supports the choice of the 180-mg regimen in future development. Brigatinib has the potential to be a promising new treatment option for patients with crizotinib-resistant ALK-positive NSCLC.”
A phase III study of brigatinib using the escalating dose schedule and compared with crizotinib in TKI-naive, advanced ALK-positive NSCLC has been initiated.
The discussant for the session, Shirish M. Gadgeel, MD, of the Karmanos Cancer Institute at Wayne State University in Detroit, said, “I think it has become even more imperative that we make efforts to define which particular patient benefits the most from which particular drug.” He also noted that pulmonary adverse events were seen with brigatinib in 6% of patients, which is of some concern. But based on these data, he predicted that the drug will be approved by the US Food and Drug Administration; it received Breakthrough Designation in 2014, and Orphan Drug Status in May of this year.