Management of acquired resistance to ALK inhibitors: repeat biopsy to characterize mechanisms of resistance significantly impacts clinical outcomes

The discovery of anaplastic lymphoma kinase (ALK) rearrangements in patients with non-small cell lung cancer (NSCLC) in 2007 and the subsequent development of ALK tyrosine kinase inhibitors (TKI) paved the way for precision oncology in the treatment of NSCLC (1). Crizotinib, a multi-kinase inhibitor with activity against ALK and mesenchymal epithelial transition (MET) receptors, was the first TKI to be approved by the US Food and Drug Administration (FDA) for treatment of ALK-rearranged (ALK+) NSCLC, based on PROFILE1007 and 1014 trials (2,3). The second generation ALK TKIs, ceritinib, alectinib and brigatinib are more selective and potent when compared to crizotinib. Alectinib and brigatinib have demonstrated superior efficacy in patients with ALK+ NSCLC when compared to crizotinib in treatment naïve patients (4-6). Both are now FDA approved for use in treatment naïve patients with ALK+ NSCLC. Ceritinib is also FDA approved in the first line setting based on superior progression free survival (PFS) when compared to platinum doublet chemotherapy (7). Recently, lorlatinib, a third generation ALK inhibitor showed improved PFS compared to crizotinib in treatment naïve patients (8). Moreover, next generation ALK TKIs have superior intracranial efficacy compared to crizotinib. Despite a growing portfolio of selective ALK TKIs, resistance mechanisms inevitably develop and challenges in management of disease progression remain. Herein we discuss the crucial role repeat tumor biopsy has in impacting the clinical outcomes of patients with ALK+ NSCLC. ALK resistance mechanisms and management