%0 Journal Article
%T Editorial on the article entitled ¡°brigatinib efficacy and safety in patients with anaplastic lymphoma kinase ( ALK )-positive nonsmall cell lung cancer in a phase I/II trial¡±
%A David Planchard
%A Ivana Sullivan
%J SCIE-indexed Journal
%D 2016
%R 10.21037/jtd.2016.10.57
%X Anaplastic lymphoma kinase (ALK)-rearrangements occur in 3¨C7% of patients with non-small cell lung cancer (NSCLC) and are more common among patients with a never/light smoking history, adenocarcinoma histology, youngers and in tumors wild-type for EGFR and KRAS genes (1-4). Crizotinib (Xalkori£¿; PF-02341066; Pfizer), a small molecule inhibitor of ALK, ROS1 and MET (5-7), was the first tyrosine kinase inhibitor (TKI) approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) for patients with NSCLC who have the ALK gene rearrangement, because it induces rapid tumor regression and objective responses around 70% in the majority of such patients, both in first and second line settings (8,9). Unfortunately, as occurred with other TKIs, the disease progressed within the first 12 months and the central nervous system (CNS) is one of the most common first sites of progression. Within different mechanisms of resistance, the emergence of acquired crizotinib-resistance mutations, such as the ¡®gate-keeper¡¯ L1196M, the G1269A, C1156Y and G1202R mutations, among others, are the main cause of crizotinib-resistant disease (10-15). In light of its limitations, several next-generation ALK-inhibitors were rapidly developed. Ceritinib (Zykadia£¿; LDK378; Novartis) was the first FDA and EMA drug approved for patients who have experienced progression on or are intolerant to crizotinib. Ceritinib has shown objective response rates (ORR) around 60% across its ¡°ASCEND¡± development (16-19). Unlike crizotinib, ceritinib exhibited higher incidence of gastrointestinal adverse events. While the majority of crizotinib-resistant patients respond to ceritinib, acquired secondary resistance has been reported (20). Within the most developed second-generation ALK-inhibitors beyond ceritinib, alectinib (Alecensa£¿; CH5424802/RO5424802; Chugai-Roche), based on two phase II trials, was approved by the FDA: one was performed in a global population (21), and the other one was conducted in the United States and Canada (22). In addition, alectinib is the first ALK-inhibitor that has demonstrated superior efficacy against crizotinib in a head to head phase III trial. A multicenter randomized, open-label phase III trial (J-ALEX; JapicCTI-132316) was conducted in Japan by Nokihara and colleagues, to compare alectinib (300 mg twice daily) versus crizotinib (250 mg twice daily) in 207 ALK+ NSCLC patients who had received ¡Ü1 prior chemotherapy regimen and no prior ALK-inhibitors. Of note, Japan regulates alectinib to a lower dose than does the rest of the world, which uses
%U http://jtd.amegroups.com/article/view/10043/html