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Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration
Alexander Drilon1,2, Jeffrey W Clark3, Jared Weiss4
1Memorial Sloan Kettering Cancer Center, New York, NY, USA. drilona@mskcc.org.
Abstract:
MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)1. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition2. Crizotinib is a multikinase inhibitor with potent activity against MET3. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.
Insights
MET exon 14 alterations drive non-small-cell lung cancer (NSCLC). Crizotinib showed antitumor activity in advanced NSCLC patients with these alterations, indicating MET inhibition is a viable targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MET exon 14 alterations are key drivers in non-small-cell lung cancer (NSCLC).
- These alterations lead to increased MET activity and sensitivity to MET inhibitors.
- Crizotinib is a multikinase inhibitor demonstrating potent activity against MET.
Purpose of the Study:
- To assess the antitumor activity and safety of crizotinib in patients with advanced NSCLCs harboring MET exon 14 alterations.
- To determine the efficacy of MET inhibition in a specific molecular subgroup of NSCLC.
Main Methods:
- A clinical study evaluated 69 patients with advanced NSCLCs and MET exon 14 alterations.
- Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) were key endpoints.
- Analysis considered molecular heterogeneity, including splice-site region, mutation type, MET copy number, and circulating tumor DNA.
Main Results:
- The ORR was 32% (95% CI, 21-45) in 65 response-evaluable patients.
- Responses were consistent across different molecular characteristics of the MET exon 14 alteration.
- Median DoR was 9.1 months (95% CI, 6.4-12.7) and median PFS was 7.3 months (95% CI, 5.4-9.1).
Conclusions:
- MET exon 14 alteration defines a molecular subgroup of NSCLC responsive to MET inhibition.
- Crizotinib demonstrates activity in this NSCLC subset, addressing an unmet need for targeted therapy.
- These findings support the expansion of genomically driven therapies for NSCLC.
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