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Safety, Efficacy, and Biomarker Analysis of Crizotinib in MET-Mutated Non-Small Cell Lung Cancer-Results from the
Karlijn Verkerk1,2, Tijmen J W T van der Wel3, Laurien J Zeverijn1,2
1Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Purpose:
To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse.
Patients And Methods:
In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit [CB: RECIST v1.1 confirmed partial response, complete response (CR), or stable disease ≥16 weeks] and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage I and if ≥1/8 patients had CB, 24 patients in stage II. Whole-genome sequencing and RNA sequencing were performed on baseline biopsies.
Results:
Between September 2018 and October 2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, 13 (54.2%) partial response, and two (8.3%) stable disease. The CB rate was 70.8% [95% confidence interval (CI), 48.9-87.4], and the objective response rate was 62.5% (95% CI, 40.6-81.2). After 21.2-month median follow-up, median duration of response, progression-free survival, and overall survival were 9.3 (95% CI, 6.5-not available), 10.2 (95% CI, 6.0-20.1), and 13.0 months (95% CI, 9.0-not available), respectively. Twenty-three treatment-related grade ≥ 3 adverse events occurred in 12/30 patients (40%), causing treatment discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), and all other patients had MET exon 14 skipping mutations.
Conclusions:
Crizotinib is a valuable treatment option in METmut aNSCLC.
Insights
Crizotinib shows significant clinical benefit for patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC). This study confirms its efficacy and safety, offering a valuable treatment option for this patient group.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) represents a specific subset of lung cancer.
- Targeted therapies are crucial for improving outcomes in patients with actionable molecular profiles.
- Crizotinib is an established tyrosine kinase inhibitor with activity against MET alterations.
Purpose of the Study:
- To evaluate the efficacy and safety of crizotinib in patients with METmut aNSCLC.
- To provide access to crizotinib for patients with METmut aNSCLC.
- To identify potential biomarkers predicting nonresponse to crizotinib.
Main Methods:
- A Simon-like two-stage design was employed in the Drug Rediscovery Protocol (NCT0295234).
- Patients received crizotinib 250 mg BID until disease progression or toxicity.
- Clinical benefit (CB) and safety were primary endpoints; whole-genome and RNA sequencing were performed on baseline biopsies.
Main Results:
- A clinical benefit rate of 70.8% and an objective response rate of 62.5% were observed in 24 response-evaluable patients.
- Median progression-free survival was 10.2 months and median overall survival was 13.0 months.
- Treatment-related grade ≥3 adverse events occurred in 40% of patients, leading to discontinuation in 10%.
Conclusions:
- Crizotinib demonstrates significant efficacy and a manageable safety profile in METmut aNSCLC.
- The study substantiates crizotinib as a valuable treatment option for this patient population.
- Further research may elucidate biomarkers for nonresponse to optimize treatment strategies.
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