FDA Approves Fourth ALK Inhibitor for Lung Cancer
Last week, the U.S. Food and Drug Administration (FDA) approved brigatinib (Alunbrig), a molecularly targeted therapeutic, for treating certain patients with metastatic non-small cell lung cancer (NSCLC). Specifically, brigatinib is approved for patients whose NSCLC is driven by mutations in the ALK gene and whose disease is not responding to treatment with crizotinib (Xalkori).
Brigatinib and crizotinib are part of a family of molecularly targeted therapeutics known as ALK inhibitors, which target the signaling protein ALK. This protein is aberrantly active in 3 to 7 percent of NSCLCs due to mutations in the ALK gene. Crizotinib, the first ALK inhibitor approved by the FDA in August 2011, is the standard of care for patients with metastatic ALK-positive NSCLC. However, most patients experience disease progression within a year of starting treatment due to tumor resistance.
The approval of brigatinib was based on results from the phase II ALTA clinical trial. The FDA reported that 48 percent of patients receiving 90 mg of brigatinib once daily and 53 percent of those receiving 180 mg once daily after a 7-day lead-in at 90 mg once daily experienced complete or partial tumor shrinkage. Additionally, brigatinib showed promising antitumor activity in patients with brain metastases, with 42 percent and 67 percent of patients in the 90 mg and 180 mg arms, respectively, experiencing complete or partial shrinkage of their brain tumors.
Despite these encouraging results, brigatinib's manufacturer, Takeda, is required to conduct further studies to confirm the therapeutic's clinical benefits, as the FDA approval was based on objective response rate data rather than overall survival. Among these studies is the ALTA 1L trial, a randomized phase III trial comparing brigatinib with crizotinib in patients who have not previously received medication for ALK-positive NSCLC.
The order in which the four FDA-approved ALK inhibitors should be used to maximize patient benefit remains a key question for oncologists. Preclinical studies published in the AACR journal Clinical Cancer Research suggest that brigatinib is a more potent in vitro ALK inhibitor than crizotinib, ceritinib, and alectinib, and it can inhibit ALK mutations that drive resistance to these previously approved inhibitors.