The identification of anaplastic lymphoma kinase (ALK), an oncogenetic driver 
mutation, in lung cancer has paved the way for a new era in the treatment of 
non-small cell lung cancer (NSCLC). Targeting ALK using tyrosine kinase 
inhibitors (TKI) has dramatically improved the prognosis of patients with 
ALK-rearranged NSCLC. However, most patients relapse on ALK-TKI therapy within a 
few years because of acquired resistance. One mechanism of acquiring resistance 
is a second mutation on the ALK gene, and the representative mutation is L1996M 
in the gatekeeper residue. In particular, the solvent-front ALK G1202R mutation 
is the common cause of resistance against first- and second-generation ALK-TKIs. 
Another major concern regarding ALK-TKI is metastasis to the central nervous 
system, commonly observed in patients relapsing after ALK-TKI therapy. The 
next-generation ALK inhibitor lorlatinib (PF-06463922) has therefore been 
developed to inhibit resistant ALK mutations, including ALK G1202R, and to 
penetrate the blood-brain barrier. In a Phase I/II trial, the safety and 
efficacy of lorlatinib were demonstrated in patients with advanced ALK-positive 
NSCLC, most of whom had central nervous system metastases and had previous 
ALK-TKI treatment. In this review, we discuss the structure, pharmacodynamics, 
and pharmacokinetics of lorlatinib and compare its characteristics with those of 
other ALK inhibitors. Furthermore, clinical trials for lorlatinib are 
summarized, and future perspectives in the management of patients with 
ALK-rearranged NSCLC are discussed.