Current Status of Targeted Therapy for Anaplastic Lymphoma Kinase–Rearranged Non–Small Cell Lung Cancer

Abstract

The identification of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in ~3-5% of non-small cell lung cancer (NSCLC) tissues and the demonstration that the first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. Single-arm studies demonstrating rapid and durable responses in the majority of ALK-positive NSCLC patients treated with crizotinib have been followed by a randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients. However, despite the initial responses, most patients develop acquired resistance to crizotinib. Several novel therapeutic approaches targeting ALK-positive NSCLC are currently under evaluation in clinical trials, including second-generation ALK inhibitors, such as LDK378, CH5424802 (RO5424802802), and AP26113, and heat shock protein 90 inhibitors.

Ceritinib for the Treatment of Late-Stage (Metastatic) Non–Small Cell Lung Cancer

“…AP26113 is a novel TKI that potently inhibits mutant activated forms of the ALK and EGFR genes as well as TKI-resistant forms, including L1196M of the ALK gene and T790M of the EGFR gene (29). Preliminary data for an ongoing dose-finding phase I/II study of AP26113 for advanced malignancy refractory to standard treatment showed the efficacy and safety of the compound in patients with NSCLC previously treated with ALKi or EGFR-TKIs.…”

Alectinib Shows Potent Antitumor Activity againstRET-Rearranged Non–Small Cell Lung Cancer

“…[20][21][22]. In contrast, crizotinib hardly inhibited RET (IC 50 ¼ 3,200 nmol/L) and LDK378, a second-generation ALK inhibitor (23,24), did not inhibit RET kinase activity (IC 50 , >5,000 nmol/L). In addition, ATPcompetitive binding assay showed that alectinib bound to RET at a dissociation constant (K D ) value of 7.6 nmol/L.…”

Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

“…[94][95][96][97][98][99][100][101][102][103][104] Ceritinib is an orally active TKI of ALK, which also inhibits the insulin-like growth factor 1 (IGF-1) receptor but not MET. An expanded phase I trial showed that ceritinib was very active in 122 patients with locally advanced or metastatic NSCLC who have ALK gene rearrangements.…”