Lorlatinib for the treatment of ALK-positive metastatic non-small cell lung cancer

ABSTRACT

Introduction: The treatment of lung cancer has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) that target sensitizing somatic (gene) activations including anaplastic lymphoma kinase (ALK)-rearrangements. Despite remarkable initial responses, patients develop progressive disease via various resistance mechanisms, some of which are ALK dependent. Various next-generation ALK TKIs have been developed to improve on central nervous system (CNS) activity and also target the multitude of acquired resistance mechanisms. Of these, lorlatinib has the greatest spectrum of clinical activity against multiple ALK resistance mutations and has also demonstrated promising efficacy in patients with known brain metastases.

Areas covered: We discuss the structure, pharmacology and efficacy of lorlatinib and also provide future perspectives in the management of patients with ALK-rearranged non-small cell lung cancer (NSCLC).

Expert opinion: Patients invariably develop resistance during treatment with lorlatinib. Unique combinations of ALK resistance mutations may confer sensitivity to alternate ALK TKIs. There is a move toward individualized biomarker-driven treatment strategies to identify the select group of candidates that can benefit from existing therapies.

KEYWORDS:

• Lorlatinib
• third-generation ALK-TKI
• G1202R
• sequencing
• liquid biopsy

Declaration of Interest

RA Soo has received honoraria from Astra-Zeneca, BMS, Boehringer Ingelheim, Eli-Lilly, Merck, Novartis, Pfizer, Roche, Taiho and a research grant from Astra-Zeneca. RA Soo is also supported by the National Medical Research Council NMRC/CG/012/2013, the National Research Foundation Singapore, and the Singapore Ministry of Education. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer on this manuscript has attended editorial activities sponsored by Roche and BMS.

Peer reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper received no funding.