Alectinib and Brigatinib: New Second-Generation ALK Inhibitors for the Treatment of Non–Small Cell Lung Cancer

The treatment of non–small cell lung cancer (NSCLC) has been revolutionized by the discovery of genetic driver mutations and associated targeted therapies. Anaplastic lymphoma kinase (ALK) mutations are present in about 5% of NSCLC cases, and treatment with the first-generation ALK inhibitor crizotinib has shown better progression-free survival (PFS) and response rate compared to traditional chemotherapy. However, eventually, ALK-mutated NSCLC develops resistance to treatment with crizotinib, and second-generation ALK inhibitors such as ceritinib, brigatinib, and alectinib have been shown to be effective in the second-line setting after progression on crizotinib. In the second-line setting, alectinib showed an objective response rate (ORR) of 45% and PFS of 8 to 12 months. Brigatinib showed an ORR of 45% to 54% with a PFS of 9.2 to 12.9 months in the second-line setting. A more recent trial compared alectinib to crizotinib in the treatment-naive setting and showed a significant PFS benefit to treatment with alectinib. The second-generation ALK inihibitors brigatinib and alectinib offer new options for the treatment of ALK mutation–positive NSCLC.