An update on lorlatinib: a novel first line treatment for ALK-positive advanced lung cancer

ABSTRACT

Introduction

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of ALK-rearranged non-small cell lung cancer (NSCLC), but these patients will eventually develop resistance and progression of disease after 10 months of first-generation and more than 30 months after second-generation TKIs. Lorlatinib is a third-generation highly selective ALK-TKI capable of inducing significant and durable CNS responses and overcoming known ALK resistance mutations.

Areas covered

This review summarizes the mechanism of action, efficacy, and safety of lorlatinib in ALK-positive NSCLC. The authors provide their expert opinions on the use of this drug, including its future prospects.

Expert opinion

Lorlatinib has shown good efficacy and safety in ALK-positive NSCLC patients progressing to first- and second-generation ALK-TKIs. The phase III trial CROWN evaluating lorlatinib as first-line therapy has provided promising results; however, the comparing arm was crizotinib, supplanted now by second-generation agents. Whether lorlatinib can replace them as upfront strategy is a relevant question that still remains open. In our opinion, longer follow-up and face-to-face studies are required to determine which is the best treatment sequence strategy. The advent of liquid biopsy will contribute to treatment tailoring according to the genomic profile at progression.

KEYWORDS:

• anaplastic lymphoma kinase
• non-small cell lung cancer
• resistance ALK mutations
• tyrosine kinase inhibitors

Article highlights

• Lorlatinib is a potent and highly selective third-generation ALK inhibitor able to overcome the ALK resistance mutations (G1202R) developed after second-generation ALK-TKIs.

• It presents a favorable PK profile with a marked activity on brain metastasis.

• Lorlatinib is the preferred option after second-generation ALK-TKIs’ failure with an ORR of 47% and a median PFS of 7.3 months.

• Lorlatinib presents the highest intracranial response rate (82%) when administered as first-line therapy, with a comparable ORR among other ALK-TKIs.

• Lorlatinib has a particular toxicity profile, and the most common AEs are hypercholesterolemia, hypertriglyceridemia, and increased weight.

Declaration of interest

D Planchard declares consulting, advisory role, or lectures: AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Merck, Novartis, Pfizer, Roche, Janssen, and AbbVie. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Janssen, and AbbVie. Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen, and AbbVie. Travel, Accommodations, and Expenses: AstraZeneca, Roche, Novartis, and Pfizer. 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.