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

OncoTargets and Therapy
Takaki AkamineTakashi Seto

Abstract

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 treatme...Continue Reading

Citations

Jun 30, 2019·Neurology·Alessia PellerinoRiccardo Soffietti
Dec 9, 2020·International Journal of Biological Macromolecules·Yuping ZhaoHafiz M N Iqbal
Feb 5, 2021·Frontiers in Oncology·Yalin KangXianglin Yuan
Jun 3, 2021·Journal of Medicinal Chemistry·Jennifer Alisa AmrheinThomas Hanke

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Methods Mentioned

BETA
xenograft
biopsy

Clinical Trials Mentioned

NCT01970865
NCT03052608
NCT02604342

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