Related Experiment Videos
Crizotinib
David F Heigener1, Martin Reck2
1Department of Thoracic Oncology, LungenClinic Grosshansdorf, Grosshansdorf, Germany. D.heigener@lungenclinic.de.
Abstract:
Crizotinib is an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases (RTK) C-Met, ALK and ROS1. There is a robust effectiveness in non-small-cell lung cancer (NSCLC) harbouring EML4-ALK-rearrangements resulting in constitutional activation of the ALK-RTK. The drug is approved for this entity, which represents no more than 3-5% of all NSCLC. However, in this population, impressive response rates are generated. The same is true for ROS-1 rearrangements; however, these only occur in approximately 1% of all NSCLC. In small series, efficacy is also reported in patients, whose tumours harbour a MET Exon 4 skipping mutation (approx. 3% of all NSCLC). Toxicities include visual impairment, nausea, peripheral edema, QT-prolongation and liver-enzyme elevation. Also, the occurrence of renal cysts is reported. The detection of ALK-protein by immunohistochemistry is a predictor of efficacy for crizotinib. In cases of doubt, fluorescence in situ hybridisation (FISH) detecting the ALK-rearrangement has to be performed on tumour tissue. FISH is also the method of choice to detect ROS1-rearrangement, whereas MET-mutations are detected by sequencing methods. The high efficacy of crizotinib in ALK- and ROS-rearranged as well as MET mutated lung cancer as new molecular targets beside the epidermal growth factor receptor (EGFR) underscores the importance of molecular typing in NSCLC.
Insights
Crizotinib shows high effectiveness in non-small-cell lung cancer (NSCLC) with specific ALK, ROS1, or MET mutations. Molecular typing is crucial for identifying patients who will benefit from this targeted therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Non-small-cell lung cancer (NSCLC) harbors specific genetic alterations, including EML4-ALK rearrangements, ROS1 rearrangements, and MET Exon 4 skipping mutations.
- These alterations lead to constitutive activation of receptor tyrosine kinases (RTKs), driving tumor growth.
- Crizotinib targets these activated RTKs, offering a personalized treatment approach.
Purpose of the Study:
- To evaluate the efficacy of crizotinib in NSCLC patients with specific molecular alterations.
- To highlight the importance of molecular diagnostics in NSCLC treatment selection.
- To review the known toxicities associated with crizotinib therapy.
Main Methods:
- Utilized immunohistochemistry (IHC) to detect ALK-protein expression as a predictive biomarker.
- Employed fluorescence in situ hybridization (FISH) for detecting ALK and ROS1 rearrangements.
- Applied sequencing methods to identify MET mutations.
Main Results:
- Crizotinib demonstrates robust effectiveness in NSCLC with EML4-ALK rearrangements (3-5% of NSCLC), yielding impressive response rates.
- Significant efficacy is also observed in patients with ROS1 rearrangements (approx. 1% of NSCLC).
- Crizotinib shows efficacy in a subset of patients with MET Exon 4 skipping mutations (approx. 3% of NSCLC).
Conclusions:
- Crizotinib is a highly effective targeted therapy for NSCLC harboring ALK, ROS1, or MET mutations.
- Molecular typing of NSCLC is essential for identifying patients who can benefit from targeted treatments like crizotinib.
- Crizotinib expands the landscape of molecularly targeted therapies beyond EGFR inhibitors in NSCLC.