O10.1 - Next generation ALK inhibitors and mechanisms of resistance to therapy

Abstract

ABSTRACT Anaplastic lymphoma kinase (ALK) gene rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that impart sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Indeed, crizotinib is now considered a standard of care for ALK-positive NSCLC patients based upon randomized trials in which crizotinib produced significant improvements in objective response rate (ORR) and progression-free survival (PFS) compared to first- and second-line cytotoxic chemotherapy. Nonetheless, patients almost invariably relapse on crizotinib—typically within 1-2 years. Molecular mechanisms of resistance to crizotinib include: 1) acquired secondary mutations in the ALK kinase domain (e.g., L1196M, G1269A), 2) ALK fusion gene amplification, and 3) activation of bypass signaling pathways, such as EGFR and c-KIT. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and/or structurally distinct, next-generation ALK inhibitors. Ceritinib (LDK378) is one such next-generation ALK inhibitor that recently gained accelerated regulatory approval in the United States. In a recent phase I study, ceritinib was associated with an ORR of 58% among 114 patients receiving at least 400 mg per day. Importantly, among patients previously treated with crizotinib, the response rate to ceritinib was 56%. Similarly, the next-generation ALK inhibitor alectinib has shown impressive activity in ALK-positive NSCLC. In a phase I/II study conducted in Japan, alectinib was associated with an ORR of 93.5% in TKI-naive patients. More recently, data on alectinib in the crizotinib-resistant setting has also emerged. Among 44 patients previously treated with crizotinib, the ORR on alectinib was 55%. Of note, both alectinib and ceritinib have also shown activity against central nervous system metastases—an important sanctuary site in ALK-positive NSCLC. Finally, at least 6 other ALK inhibitors are currently in clinical development. Determining the mechanisms of resistance to these agents as well as the optimal sequencing of ALK inhibitors in the clinic are important emerging questions.