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An update on lorlatinib: a novel first line treatment for ALK-positive advanced lung cancer
Mariona Riudavets1, David Planchard1
1Cancer Medicine Department, Gustave Roussy Cancer Campus, Villejuif, France.
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.
Insights
Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, shows efficacy in ALK-positive non-small cell lung cancer (NSCLC) progressing on earlier TKIs. Further studies are needed to establish its role as a first-line therapy.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have transformed outcomes for ALK-rearranged non-small cell lung cancer (NSCLC).
- Resistance to first- and second-generation ALK-TKIs is a significant clinical challenge, occurring after approximately 10 and 30 months, respectively.
- Lorlatinib is a third-generation, highly selective ALK-TKI designed to overcome resistance mutations and achieve central nervous system (CNS) responses.
Conclusions:
- Lorlatinib is an effective option for patients with advanced ALK-positive NSCLC progressing on earlier generation TKIs.
- The optimal role of lorlatinib as a first-line agent requires further investigation with longer follow-up and head-to-head comparisons against newer agents.
- Liquid biopsy may facilitate personalized treatment strategies by guiding therapy selection based on genomic profiles at progression.
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