crizotinib

Overview

Crizotinib is a first-generation multi-target tyrosine kinase inhibitor of ALK, ROS1, and MET. It is FDA-approved for ALK-positive and ROS1-positive non-small cell lung cancer.

Evidence in the corpus

• In a patient with MET exon 14 skipping mutation-positive lung cancer and CNS metastases, serial CSF ctDNA profiling detected emergence of the MET p.Y1230N resistance mutation while on crizotinib, prompting a treatment switch to capmatinib PMID:39289779.
• CSF ctDNA sequencing via MSK-IMPACT identified resistance mutations arising during crizotinib therapy, demonstrating the utility of CSF liquid biopsy for monitoring on-target resistance in the CNS compartment PMID:39289779.
• Referenced as an example of acquired resistance in targeted therapy (ALK-fusion lung cancer + crizotinib), used to motivate anticipatory combination regimens and second-generation inhibitor strategies for HCC PMID:24735922
• ALK/ROS1/MET inhibitor used as targeted therapy for ALK rearrangements (>80% EML4-ALK) over-represented in young-onset NSCLC; CROWN trial subgroup analyses showed consistent outcomes by age PMID:27346245
• Matched therapy for ROS1 fusions in 860-patient MSK-IMPACT LUAD cohort; two ROS1-fusion patients died before crizotinib FDA approval (March 2016) for ROS1 indication; ALK fusions also matched to crizotinib with 90.9% uptake and 93.3% clinical benefit PMID:28336552.
• Flagged as the approved ALK inhibitor for 20 ALK-fusion samples spanning 8 cancer types (5 in LUAD) in the TCGA pan-cancer fusion atlas (n=9,624); EML4 was the dominant 5’ partner (7/17 ALK fusions), and ALK overexpression was copy-number neutral — consistent with fusion-driven promoter capture rather than amplification PMID:29617662

Resistance mechanisms

• MET p.Y1230N resistance mutation detected in CSF ctDNA during crizotinib treatment of a MET exon 14 skipping-positive lung cancer patient PMID:39289779.
• ALK p.G1202R and p.G1269A resistance mutations were detected in CSF ctDNA from ALK-rearranged lung cancer patients on targeted therapy (including ALK inhibitors); these mutations confer resistance to first-generation ALK inhibitors such as crizotinib PMID:39289779.

Cancer types (linked)

• NSCLC
• LUAD

Sources

• PMID:39289779

This page was processed by crosslinker on 2026-04-11. - PMID:24735922

This page was processed by wiki-cli on 2026-05-11. - PMID:27346245

This page was processed by wiki-cli on 2026-05-14. - PMID:28336552 - PMID:29617662 — Gao et al. 2018, Cell Reports. TCGA pan-cancer fusion atlas (n=9,624); crizotinib flagged for 20 ALK-fusion samples across 8 cancer types; EML4-ALK dominant partner; ALK overexpression copy-number neutral.

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