Chapter 11 - Diagnosis and treatment of anaplastic lymphoma kinase (ALK) rearranged non−small cell lung cancer

Abstract

The identification of anaplastic lymphoma kinase (ALK) rearrangement and subsequent development of ALK tyrosine kinase inhibitors (TKIs) established ALK+ non–small cell lung cancer (NSCLC) as a separate and unique subset of NSCLC. It is important that all patients with NSCLC and adenocarcinoma histology undergo testing for ALK rearrangements or ALK protein expression. A number of tests are available including fluorescence in situ hybridization, immunohistochemistry, next-generation sequencing, and circulating tumor DNA. Crizotinib demonstrated superior efficacy and better tolerability as first-line and second-line therapy compared with chemotherapy metastatic ALK+ NSCLC. Next-generation ALK TKIs were developed with greater potency and ALK selectivity and better central nervous system penetration. These agents have activity against the ALK tyrosine kinase mutations, which are a mechanism of resistance to crizotinib. Next-generation ALK TKIs demonstrated clinically relevant activity in patients with disease progression after crizotinib, including central nervous system responses. More recently, phase 3 trials with these agents (alectinib, brigatinib, ceritinib, ensartinib, and lorlatinib) have demonstrated superiority as first-line therapy compared with crizotinib or platinum-pemetrexed. Lorlatinib is available for patients who experience disease progression after next-generation ALK TKIs. The activity of single-agent immunotherapy has been disappointing, but the chemotherapy and immunotherapy combination of carboplatin, paclitaxel, bevacizumab, and atezolizumab demonstrated activity in a subset analysis of a phase 3 trial in patients with disease progression on an ALK TKI.