crizotinib — Drug Monograph

Brand names: Xalkori

Drug class: ALK Inhibitor

Mechanism of Action

Crizotinib is a first-generation ATP-competitive small-molecule inhibitor that targets ALK, ROS1, and MET receptor tyrosine kinases. It binds to the ATP-binding pocket of the ALK kinase domain, preventing autophosphorylation and downstream activation of pro-survival signaling cascades including RAS/MAPK, PI3K/AKT, and JAK/STAT3 pathways. Inhibition of ROS1 and MET kinases similarly abrogates oncogenic signaling driven by ROS1 rearrangements and MET amplification or mutation. The net effect is suppression of tumor cell proliferation and induction of apoptosis in ALK-, ROS1-, or MET-driven…

FDA Indications

• Metastatic non-small cell lung cancer (NSCLC) that is ALK-positive — 1st-line approval (2013, PROFILE 1014 trial)
• Metastatic NSCLC that is ALK-positive — after prior chemotherapy (2011 accelerated approval, expanded 2013; PROFILE 1007 trial)
• Metastatic NSCLC whose tumors are ROS1-rearranged (2016, PROFILE 1001 expansion cohort)

Common Side Effects

• Visual disturbances (photopsia, blurred vision, vitreous floaters) — up to 60–70%
• Nausea
• Diarrhea
• Vomiting
• Constipation
• Peripheral edema
• Fatigue
• Elevated transaminases (ALT/AST)
• Decreased appetite
• Dizziness
• Dysgeusia

Clinical Pearl

Crizotinib was the first ALK inhibitor approved and established the paradigm of biomarker-driven therapy in NSCLC, yet its CNS penetration is limited, making it less effective for brain metastases. It has been largely superseded by second- and third-generation ALK inhibitors (alectinib, brigatinib, lorlatinib) which demonstrate superior PFS, better CNS activity, and broader resistance mutation coverage; crizotinib is now rarely used first-line. Unique among ALK inhibitors, crizotinib also has…

Related Therapies & Mechanisms

• Brigatinib (Alunbrig) — ALK Inhibitor · NSCLC
• Ceritinib (Zykadia) — ALK Inhibitor · NSCLC
• Lorlatinib (Lorbrena) — ALK Inhibitor · NSCLC
• Adagrasib (Krazati) — NSCLC