Detailed Chinese instructions for the targeted drug crizotinib

1. Generic name: Crizotinib,Crizotinib

Product name:Xalkori, Xalkori

All names: Crizotinib, Crizotinib, Crizotinib, XALKORI, XALKORI

2. Indications:

1. ALK or ROS1-positive metastatic non-small cell lung cancer (NSCLC): Crizotinib is suitable for the treatment of adult patients with metastatic non-small cell lung cancer whose tumors have been tested to be anaplastic lymphoma kinase (ALK) or ROS1 positive.

2. Relapsed or refractory (R/R) systemic ALK-positive anaplastic large cell lymphoma (ALCL): Crizotinib is suitable for the treatment of pediatric patients and adolescent patients 1 year old and above with ALK-positive relapsed or refractory systemic anaplastic large cell lymphoma.

3. Unresectable, recurrent or refractory (R/R) ALK-positive inflammatory myofibroblastic tumor (IMT): Crizotinib is indicated for the treatment of adult and pediatric patients 1 year and older with ALK-positive unresectable, recurrent or refractory inflammatory myofibroblastic tumor.

Limitations of Use: The safety and efficacy of crizotinib in older adults with relapsed or refractory systemicALK-positive ALCL have not been established.

3. Usage and dosage:

1. Before treatment: Before starting treatment, doctors will select patients with metastatic non-small cell lung cancer (NSCLC) to use crizotinib based on the presence of ALK or ROS1 positivity in the tumor specimens.

1. Recommended testing during treatment: Patients should monitor liver function tests every 2 weeks during the first 2 months of treatment, then monthly; monitor complete blood counts during the first month of treatment, then monthly; and more frequently if grade 3 or 4 abnormalities, fever, or infection occur. For pediatric and young adult patients with ALK-positive anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumor (IMT), perform baseline and follow-up ophthalmic examinations, including retinal examinations, within 1 month after starting crizotinib and every 3 months thereafter.

2. Management: Crizotinib capsule preparations can usually be taken with or without food, and the capsules should not be chewed, crushed or split; Crizotinib granules can be administered in two ways, such as pouring the contents directly into the patient's mouth, or pouring the contents into the provided oral administration aids (such as spoons, medicine cups). Deliver the granules directly into the patient's mouth via an administration aid (e.g., spoon, medicine cup). Administer immediately after administration with sufficient water to ensure that all medication is swallowed.

3. Recommended dosage:

（1) ALK or ROS1-positive metastatic NSCLC: For adult patients, the recommended dose of crizotinib is 250 mg orally twice daily; for patients unable to swallow capsules, the recommended dose for granules is 250 mg (2*50mg+1*150mg) orally twice daily until disease progression or unacceptable toxicity occurs.

(2) Relapsed or refractory (R/R) systemic ALK-positive ALCL: The recommended dose for pediatric patients and young adults is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity.

(3) Unresectable, recurrent, or refractory (R/R) ALK-positive IMT: The recommended dose for adult patients is 250 mg orally twice daily; for pediatric patients, the recommended dose is 280 mg/m2 orally twice daily.

4. Dose adjustment: If a patient develops adverse reactions after treatment with crizotinib, the doctor may adjust the drug dose according to the severity of the condition. The first dose will be reduced to 200 mg twice a day; the second dose will be reduced to 250 mg once a day; if 250 mg once a day is intolerable, please permanently discontinue crizotinib.

4. Adverse reactions:

In clinical studies of crizotinib treatmentIn adult patients with ALK- or ROS1-positive non-small cell lung cancer, the most common side effects were visual disturbances, nausea, diarrhea, vomiting, edema, constipation, increased liver enzymes in the blood, fatigue, decreased appetite, dizziness, and neuropathy (pain caused by nerve damage); the most serious side effects were liver damage, pneumonia, neutropenia, and QT interval prolongation. In children and adolescents with ALK-positive ALCL or IMT, the most common side effects are increases in liver enzymes in the blood, vomiting, neutropenia, nausea, diarrhea, and leukopenia; the most common serious side effect is neutropenia.

5. Storage:

Crizotinib may be stored20°C to 25°C (68°F to 77°F); tolerances allowed are 15°C to 30°C (59°F to 86°F).

6. Mechanism of action:

Inhibitors of crizotinib receptor tyrosine kinases, includingALK, hepatocyte growth factor receptor (HGFR, c-Met), ROS1 (c-ros), and Nantai receptor (RON). Translocations can affect the ALK gene, leading to the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of gene expression and signaling, which contributes to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts expressing echinoderm microtubule-associated protein-like 4 (EML 4) or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

In vitro, crizotinib induced apoptosis and inhibited proliferation and ALK-mediated signaling in ALCL-derived cell lines (containing NPM-ALK) at clinically achievable exposures. In vivo data obtained in an ALCL mouse model showed complete tumor regression at a dose of 100 mg/kg once daily.