The FDA has granted breakthrough therapy status to the anaplastic lymphoma kinase (ALK) inhibitor alectinib (Alecensa, Chugai/Roche) for the first-line treatment of patients with ALK-positive non–small-cell lung cancer (NSCLC).
The FDA’s decision was based on results from the phase 3 J-ALEX trial, which was an open-label, randomized study designed to compare the efficacy and safety of alectinib with that of crizotinib (Xalkori, Pfizer/EMD Serono). The trial enrolled 207 ALK inhibitor-naïve patients with ALK fusion gene-positive advanced or recurrent NSCLC who had not received chemotherapy or who had received one chemotherapy regimen. The study’s primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, the objective response rate, and safety. In February 2016, an independent data monitoring committee recommended that the J-ALEX study be discontinued early for benefit, based on the results of a predetermined interim analysis.
The PFS hazard ratio of the alectinib arm compared with the crizotinib arm was 0.34, and alectinib demonstrated significantly prolonged PFS (99.68%; P
Alectinib is a highly selective ALK inhibitor. It has been reported that 2% to 5% of patients with NSCLC express a chromosomal rearrangement that leads to fusion of the ALK gene with another gene. ALK kinase signaling is constantly active in cells with such fusion genes, resulting in uncontrolled growth of tumor cells and transforming the cells into tumor cells. Alectinib exerts its antitumor effect by selectively interfering with ALK kinase activity to inhibit tumor-cell proliferation and induce cell death. In addition, alectinib is not recognized by the transporter proteins in the blood–brain barrier that actively pump molecules out of the brain. Alectinib is active in the central nervous system and has proven activity against brain metastases.
In the United States, alectinib was approved in December 2015 for the treatment of patients with ALK-positive, metastatic NSCLC who have progressed on or are intolerant of crizotinib.
The breakthrough therapy designation was adopted as part of the FDA Safety and Innovation Act (FDASIA), enacted in July 2012, which was designed to expedite the development and review of drugs for the treatment of severe or life-threatening diseases or symptoms.
Source: Chugai Pharmaceutical Co.; October 4, 2016.