Spotlight on lorlatinib and its potential in the treatment of NSCLC: the evidence to date

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.