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Lorlatinib in Advanced NSCLC With ALK Resistance Mutations

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Key Points

  • Among patients with crizotinib-resistant disease, lorlatinib showed similar efficacy among those with vs without ALK mutations.
  • Among patients for whom treatment with one or more second-generation ALK tyrosine kinase inhibitors failed, lorlatinib showed greater efficacy in patients with vs without ALK mutations.

In a study reported in the Journal of Clinical Oncology, Shaw et al found that lorlatinib showed greater efficacy in patients with vs without anaplastic lymphoma kinase (ALK) resistance mutations among patients with advanced ALK-positive non–small cell lung cancer (NSCLC) in whom one or more second-generation ALK tyrosine kinase inhibitors failed.

Study Details

The study involved baseline plasma and tumor tissue samples from 198 patients with ALK-positive NSCLC from the registrational phase II study of lorlatinib. Plasma DNA was analyzed for ALK mutations using Guardant360; tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay.

Treatment Outcomes

Approximately one-quarter of patients had ALK resistance mutations detected by plasma (24%) or tissue (24%) genotyping. Among patients with crizotinib-resistant disease, objective response rates were comparable among patients with vs without ALK mutations using plasma (73% vs 75%) or tissue (73% vs 74%) genotyping. Among patients in whom treatment with one or more second-generation ALK tyrosine kinase inhibitors failed, objective response rate was higher among patients with vs without ALK mutations in plasma (62% vs 32%) and in tissue (69% vs 27%). Progression-free survival was similar in patients with vs without ALK mutations in plasma (median = 7.3 vs 5.5 months, hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.50–1.31) but significantly longer in patients with vs without ALK mutations in tissue genotyping (median = 11.0 vs 5.4 months, HR = 0.47, 95% CI = 0.27–0.83).

The investigators concluded: “In patients who have failed one or more second-generation ALK tyrosine kinase inhibitor(s), lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation tyrosine kinase inhibitor may identify patients who are more likely to derive clinical benefit from lorlatinib.”

Alice T. Shaw, MD, PhD, of Massachusetts General Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Pfizer and a grant from the National Cancer Institute. The study authors’ full disclosures can be found at jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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