Crizotinib

Crizotinib is a selective small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase and of its oncogenic variants (ALK fusion events and selected ALK mutations). It also inhibits the hepatocyte growth factor receptor (HGFR, c-Met), ROS1 (c-ros) and the Recepteur d’Origine Nantais (RON) receptor tyrosine kinases.

Mechanism of Action

• Kinase inhibition: crizotinib inhibited the kinase activity of ALK, ROS1 and c-Met in a concentration-dependent way in biochemical assays, and inhibited phosphorylation in cell-based assays.
• Effect on tumour cells: it stopped growth and induced apoptosis in tumour cell lines with ALK fusions (including EML4-ALK and NPM-ALK), ROS1 fusions, or amplification of the ALK or MET gene.
• Animal models: in mice, it had marked, dose-dependent antitumour activity against xenografts expressing ALK fusion proteins and against xenografts engineered to express key human ROS1 fusions, correlating with inhibition of ALK or ROS1 phosphorylation in the tumours.
• Lymphoma cell lines: in two ALCL-derived cell lines carrying NPM-ALK it induced apoptosis, and in one of them it inhibited proliferation and ALK-mediated signalling at clinically achievable concentrations.
• Active metabolite (DrugBank): one active metabolite (PF-06260182, two diastereomers) has been identified; in vitro it is about 3- to 8-fold less potent than crizotinib against ALK and 2.5- to 4-fold less potent against c-Met.

Pharmacokinetics

• Absorption (hard capsules): after a single dose in the fasted state, peak concentrations are reached after a median of 4 to 6 hours; steady state is reached within 15 days of twice-daily dosing. Absolute bioavailability is 43% after a single 250 mg dose. A high-fat meal lowered AUC and Cmax by about 14%, so the capsules can be taken with or without food.
• Absorption (granules in capsules for opening): bioequivalent to the capsules in the fasted state. A high-fat, high-calorie meal reduced AUC and Cmax by about 15% and 23%; they too can be taken with or without food.
• Distribution: steady-state volume of distribution 1,772 L after an intravenous dose, indicating extensive tissue distribution; 91% bound to plasma proteins in vitro, independent of concentration. Crizotinib is a P-glycoprotein substrate in vitro.
• Metabolism: mainly by CYP3A4/5. The main pathways are oxidation of the piperidine ring to crizotinib lactam, and O-dealkylation followed by phase 2 conjugation. In vitro, crizotinib is a time-dependent inhibitor of CYP2B6 and CYP3A and a weak inhibitor of UGT1A1 and UGT2B7; clinical interactions through CYP1A2, 2C8, 2C9, 2C19 or 2D6 are unlikely.
• Elimination (DrugBank): terminal half-life about 42 hours after a single dose; apparent clearance about 60 L/h at steady state (about 100 L/h after a single dose, possibly because of CYP3A auto-inhibition). After a radiolabelled 250 mg dose in healthy subjects, 63% was recovered in faeces (53% as unchanged drug) and 22% in urine (2.3% unchanged).
• Special populations: mild or moderate renal impairment did not change steady-state exposure meaningfully; concentrations may rise in severe renal impairment. Hepatic impairment is covered under Administration and Dosage. DrugBank adds that age, sex and ethnicity had no clinically significant effect, and that in patients under 18 years higher body weight was associated with lower exposure.

Xalkori is indicated as monotherapy for:

• ALK-positive advanced NSCLC, first-line: first-line treatment of adults with ALK-positive advanced non-small cell lung cancer (NSCLC).
• ALK-positive advanced NSCLC, previously treated: treatment of adults with previously treated ALK-positive advanced NSCLC.
• ROS1-positive advanced NSCLC: treatment of adults with ROS1-positive advanced NSCLC.
• ALK-positive ALCL in children: treatment of paediatric patients (age ≥1 to under 18 years) with relapsed or refractory systemic ALK-positive anaplastic large cell lymphoma (ALCL).
• ALK-positive IMT in children: treatment of paediatric patients (age ≥1 to under 18 years) with recurrent or refractory ALK-positive unresectable inflammatory myofibroblastic tumour (IMT).

• Hypersensitivity to crizotinib or to any of the excipients.

In adults (1,722 patients with ALK-positive or ROS1-positive advanced NSCLC taking 250 mg twice daily), the most serious reactions were hepatotoxicity, interstitial lung disease (ILD)/pneumonitis, neutropenia and QT interval prolongation. The most common (25% or more) were vision disorder, nausea, diarrhoea, vomiting, oedema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness and neuropathy. Neutropenia (11%), elevated transaminases (7%), vomiting (5%) and nausea (4%) were the most frequent reasons for interrupting treatment, and elevated transaminases (4%) and neutropenia (3%) for dose reduction. Adverse events of any cause led to permanent discontinuation in 18% of patients; the most frequent were ILD and elevated transaminases (1% each).

Adults with NSCLC (frequencies in brackets):

Very common (≥1/10): neutropenia (22%), anaemia (15%), leukopenia (15%); decreased appetite (30%); neuropathy (25%), dysgeusia (21%); vision disorder (63%); dizziness (26%), bradycardia (13%); vomiting (51%), diarrhoea (54%), nausea (57%), constipation (43%), abdominal pain (21%); elevated transaminases (32%); rash (13%); oedema (47%), fatigue (30%).

Common (≥1/100 to <1/10): hypophosphataemia (6%); cardiac failure (1%), QT prolongation on the electrocardiogram (4%), syncope (3%); interstitial lung disease (3%); oesophagitis (2%), dyspepsia (8%); increased blood alkaline phosphatase (7%); renal cyst (3%), increased blood creatinine (8%); decreased blood testosterone (2%).

Uncommon (≥1/1,000 to <1/100): gastrointestinal perforation, hepatic failure, photosensitivity, acute renal failure, renal failure, increased blood creatine phosphokinase (all below 1%).

Selected reactions in adults:

• Hepatotoxicity: fatal drug-induced liver injury occurred in 0.1% of patients; grade 3 or 4 ALT or AST elevations occurred in 11% and 6%. Elevations usually appear within the first 2 months (median onset 23 days for grade 1 or 2, 43 days for grade 3 or 4) and were generally reversible on interruption.
• ILD/pneumonitis: 3% of patients, grade 3 or 4 in 1%, fatal in under 1%; generally within 3 months of starting.
• QT prolongation: QTcF of 500 msec or more in 2.1% of patients with a post-baseline ECG, and a rise of 60 msec or more from baseline in 5.0%.
• Vision disorder: 63%, 95% of them mild; mostly visual impairment, photopsia, blurred vision and vitreous floaters, usually starting within the first week. Grade 4 visual field defect with visual loss was reported in 4 patients (0.2%).
• Gastrointestinal effects: nausea and vomiting start at a median of 3 days and become less frequent after 3 weeks; diarrhoea and constipation start at a median of 13 and 17 days. Gastrointestinal perforation occurred, including fatal cases after marketing.
• Other: complex renal cysts in 3% (local cystic invasion beyond the kidney in some); grade 3 or 4 neutropenia in 12% (median onset 89 days), febrile neutropenia in under 0.5%.

Paediatric patients (safety analysis of 110 children aged 1 to under 18 years with various tumour types, 41 of them with ALK-positive ALCL or IMT): the profile was generally consistent with that in adults. Grade 3 or 4 neutropenia, leukopenia and diarrhoea were at least 10% more frequent than in adults with NSCLC.

Very common (≥1/10): neutropenia (71%), leukopenia (63%), anaemia (52%), thrombocytopenia (21%); hypophosphataemia (30%), decreased appetite (39%); neuropathy (26%), dysgeusia (10%); vision disorder (44%); bradycardia (14%), dizziness (16%); vomiting (77%), diarrhoea (69%), nausea (71%), constipation (31%), dyspepsia (10%), abdominal pain (43%); elevated transaminases (87%), increased blood alkaline phosphatase (19%); increased blood creatinine (45%); oedema (20%), fatigue (46%).

Common (≥1/100 to <1/10): QT prolongation on the electrocardiogram (4%), oesophagitis (4%), rash (3%).

In the 41 children with ALCL or IMT, vomiting (95%), diarrhoea (85%) and nausea (83%) were the most frequent gastrointestinal events, and vision disorder occurred in 61% (all grade 1 or 2 except one grade 3 myopic optic nerve disorder already present at baseline). Neutropenia was the most frequent grade 3 or 4 reaction.

Interaction studies were done in adults.

• Strong CYP3A inhibitors (atazanavir, ritonavir, cobicistat, itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, erythromycin): ketoconazole raised single-dose crizotinib exposure (AUC) about 3.2-fold and Cmax 1.4-fold; itraconazole at steady state raised AUC 1.6-fold and Cmax 1.3-fold. Avoid the combination unless the benefit outweighs the risk, and then monitor closely for adverse events.
• Moderate CYP3A inhibitors (for example diltiazem, verapamil): simulations predicted a 17% rise in steady-state AUC; use with caution.
• CYP3A inducers: strong and moderate CYP3A4 inducers should be avoided. St John’s wort may lower crizotinib concentrations and should be avoided.
• CYP3A4 substrates with a narrow therapeutic index: avoid concomitant use.
• Bradycardic agents (beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin): avoid where possible because of the risk of symptomatic bradycardia.
• QT-prolonging medicines and antiarrhythmics: avoid the combination (see QT Interval Prolongation below).
• Grapefruit and grapefruit juice: may raise crizotinib concentrations and should be avoided.
• Other interactions, including the effect of crizotinib on CYP2B6, CYP3A and UGT substrates, are covered in section 4.5 of the SmPC.

Treatment must be started and supervised by a physician experienced in the use of anticancer medicinal products. A validated assay for ALK or ROS1 is needed to select patients: ALK-positive NSCLC, ROS1-positive NSCLC, ALK-positive ALCL or ALK-positive IMT status must be established before starting, in laboratories with proven proficiency in the technology used.

Adults with ALK-Positive or ROS1-Positive Advanced NSCLC

• 250 mg twice daily (500 mg daily), taken continuously, as hard capsules.

Paediatric Patients with ALK-Positive ALCL or IMT

• Starting dose: 280 mg/m² orally twice daily until disease progression or unacceptable toxicity, set by body surface area (BSA). Combine capsule strengths as needed. Children are treated under adult supervision.
• BSA 1.34 m² or more (hard capsules): BSA 1.34–1.51 m², 400 mg twice daily (2 × 200 mg), 800 mg a day; BSA 1.52–1.69 m², 450 mg twice daily (1 × 200 mg + 1 × 250 mg), 900 mg a day; BSA 1.70 m² or more, 500 mg twice daily (2 × 250 mg), 1,000 mg a day.
• BSA 0.38 to 1.33 m² (granules in capsules for opening, 20, 50 and 150 mg; no more than 4 capsules per dose), twice daily:
  • 0.38–0.46 m²: 120 mg (1 × 20 mg + 2 × 50 mg)
  • 0.47–0.51 m²: 140 mg (2 × 20 mg + 2 × 50 mg)
  • 0.52–0.61 m²: 150 mg (1 × 150 mg)
  • 0.62–0.80 m²: 200 mg (1 × 50 mg + 1 × 150 mg)
  • 0.81–0.97 m²: 250 mg (2 × 50 mg + 1 × 150 mg)
  • 0.98–1.16 m²: 300 mg (2 × 150 mg)
  • 1.17–1.33 m²: 350 mg (1 × 50 mg + 2 × 150 mg)
• The dose for BSA below 0.38 m² has not been established.
• Supportive care: antiemetics before and during treatment are recommended, with standard antiemetic and antidiarrhoeal agents for gastrointestinal toxicity, and hydration, electrolyte and nutritional support as indicated.

How to Take It

• Hard capsules: swallowed whole, preferably with water; not crushed, dissolved or opened.
• Granules in capsules for opening: not chewed, crushed or sprinkled on food. The capsule shell is not swallowed. Hold the capsule with the printed “Pfizer” at the top and tap it so the granules sit in the lower half; gently squeeze the bottom, twist top and bottom in opposite directions and pull apart. Empty the contents straight into the patient’s mouth or into a dry dosing aid (spoon or medicine cup) and then into the mouth, tapping the capsule so all granules are given. If the whole dose cannot be taken at once, give it in portions, with enough water after each portion to be sure everything is swallowed. The package leaflet has pictograms.
• Both forms can be taken after a meal or fasted. Avoid grapefruit or grapefruit juice and St John’s wort.

Missed Dose

Take a missed dose as soon as it is remembered, unless the next dose is due in under 6 hours, in which case skip it. Never take two doses at once to make up for a missed dose.

Dose Adjustments

• Adults, dose steps (from 250 mg twice daily): first reduction 200 mg twice daily; second reduction 250 mg once daily; stop permanently if 250 mg once daily is not tolerated.
• Adults, blood toxicity (except lymphopenia unless linked to clinical events such as opportunistic infection): grade 3, withhold until grade 2 or lower and resume at the same dose; grade 4, withhold until grade 2 or lower and resume at the next lower dose. If grade 4 recurs, resume at 250 mg once daily after recovery, and stop permanently if it recurs again.
• Adults, other toxicity: grade 3 or 4 ALT or AST rise with bilirubin grade 1 or lower: withhold until grade 1 or baseline, resume at 250 mg once daily and escalate to 200 mg twice daily if tolerated. Grade 2 to 4 ALT or AST rise with grade 2 to 4 bilirubin rise (without cholestasis or haemolysis): stop permanently. Any-grade ILD/pneumonitis: withhold if suspected, stop permanently if treatment-related. Grade 3 QTc prolongation: withhold until grade 1 or lower, correct electrolytes, resume at the next lower dose; grade 4: stop permanently. Symptomatic bradycardia (grade 2 or 3): withhold until grade 1 or lower or heart rate 60 or above, review contributing medicines, then resume at the previous dose if a contributing medicine was stopped or adjusted, otherwise at a reduced dose. Life-threatening (grade 4) bradycardia: stop permanently unless a contributing medicine is found and stopped, in which case resume at 250 mg once daily with frequent monitoring (stop permanently on recurrence). Grade 4 visual loss: discontinue during evaluation.
• Paediatric dose steps (twice daily; stop permanently if not tolerated after 2 reductions). Hard capsules: BSA 1.34–1.69 m², 250 mg then 200 mg; BSA 1.70 m² or more, 400 mg then 250 mg. Granules (first, then second reduction): 0.38–0.46 m², 90 mg then 70 mg; 0.47–0.51 m², 100 mg then 80 mg; 0.52–0.61 m², 120 mg then 90 mg; 0.62–0.80 m², 150 mg then 120 mg; 0.81–0.97 m², 200 mg then 150 mg; 0.98–1.16 m², 220 mg then 170 mg; 1.17–1.33 m², 250 mg then 200 mg.
• Paediatric blood toxicity: complete blood counts with differential are checked weekly for the first month and at least monthly after that. Grade 4 neutropenia: withhold until grade 2 or lower and resume at the next lower dosage; permanent discontinuation for a recurrence complicated by febrile neutropenia or infection (an uncomplicated recurrence may be stopped permanently or managed by withholding and reducing). Grade 3 low platelets with bleeding or grade 3 anaemia: withhold until grade 2 or lower and resume at the same dosage; grade 4: withhold, resume at the next lower dosage, and stop permanently on recurrence.
• Paediatric other toxicity: the same liver, ILD and QTc rules apply as in adults (for grade 3 QTc, resume once the QTc is below 481 ms or back to baseline). For symptomatic bradycardia, resume once resting heart rate is back to the age norm (1 to under 2 years, 91 bpm or above; 2 to 3 years, 82; 4 to 5 years, 72; 6 to 8 years, 64; over 8 years, 60). Grade 3 nausea, or grade 3 or 4 vomiting or diarrhoea despite maximum medical therapy: withhold until resolved, then resume at the next lower dose level. Grade 3 or 4 visual loss: withhold pending evaluation and stop permanently if no other cause is found.

Special Populations

• Hepatic impairment (adults): mild (AST above ULN and bilirubin at or below ULN, or bilirubin up to 1.5 × ULN): no starting dose change. Moderate (bilirubin above 1.5 and up to 3 × ULN): 200 mg twice daily. Severe (bilirubin above 3 × ULN): 250 mg once daily. Children: moderate impairment starts at the first dose-reduction level for their BSA and severe at the second.
• Renal impairment (adults): no adjustment for mild (creatinine clearance 60 to under 90 mL/min) or moderate (30 to under 60 mL/min) impairment. Severe (under 30 mL/min) not needing dialysis: 250 mg once daily, which may be increased to 200 mg twice daily after at least 4 weeks if tolerated. Children: severe impairment starts at the second dose-reduction level and may move to the first after at least 4 weeks.
• Elderly: no starting dose adjustment.
• Paediatric use: safety and efficacy in children with ALK-positive or ROS1-positive NSCLC are not established. In ALCL they are established from 3 to under 18 years and in IMT from 2 to under 18 years; no data exist for ALCL below 3 years or IMT below 2 years.

ALK and ROS1 Testing

A well-validated and robust method must be used to avoid false negative or false positive results.

Hepatotoxicity

Drug-induced hepatotoxicity, with fatal cases in adults, has been reported. ALT, AST and total bilirubin are checked weekly for the first 2 months, then monthly and as clinically indicated, more often after grade 2, 3 or 4 elevations.

Interstitial Lung Disease/Pneumonitis

Severe, life-threatening or fatal ILD/pneumonitis can occur. Patients with pulmonary symptoms are monitored, treatment is withheld if it is suspected, and crizotinib is permanently stopped if treatment-related ILD/pneumonitis is diagnosed after other causes are excluded.

QT Interval Prolongation

QTc prolongation can increase the risk of ventricular tachyarrhythmias (such as torsade de pointes) or sudden death. Benefit and risk are weighed before starting in patients with bradycardia, a history of or predisposition to QTc prolongation, antiarrhythmics or other QT-prolonging medicines, significant heart disease or electrolyte disturbances. ECG and electrolytes (calcium, magnesium, potassium) are checked as close as possible before the first dose and periodically, particularly with vomiting, diarrhoea, dehydration or impaired renal function. If the QTc rises by 60 msec or more from baseline but stays below 500 msec, crizotinib is withheld and a cardiologist consulted; at 500 msec or more, cardiologist advice is needed immediately.

Bradycardia and Cardiac Failure

• Bradycardia: reported in 13% of adults and 17% of children with ALCL or IMT. Symptomatic bradycardia (syncope, dizziness, hypotension) can occur, and the full effect on heart rate may not appear until several weeks into treatment. Heart rate and blood pressure are monitored regularly; no dose change is needed for asymptomatic bradycardia.
• Cardiac failure: severe, life-threatening or fatal cases were reported in adults. Patients are monitored for dyspnoea, oedema and rapid weight gain from fluid retention, and interruption, reduction or discontinuation is considered.

Neutropenia and Leukopenia

Grade 3 or 4 neutropenia was very common in adults (12%) and in children with ALCL or IMT (68%); grade 3 or 4 leukopenia occurred in 3% of adults and 24% of children. Complete blood counts with differential are monitored, more often if grade 3 or 4 abnormalities, fever or infection occur.

Gastrointestinal Perforation and Renal Effects

• Perforation: fatal cases occurred after marketing. Use caution in patients at risk (for example history of diverticulitis, gastrointestinal metastases, or medicines with a recognised perforation risk); stop crizotinib if it occurs, and tell patients to seek help quickly at the first signs.
• Kidney: raised creatinine, reduced creatinine clearance, renal failure (including fatal cases and cases needing haemodialysis) and grade 4 hyperkalaemia were seen in adults. Renal function is monitored at baseline and during treatment, especially with risk factors or past renal impairment. Periodic imaging and urinalysis should be considered in patients who develop renal cysts.

Visual Effects

Optic atrophy and optic nerve disorder have been reported as possible causes of visual loss. Children with ALCL or IMT need an eye examination before starting, a follow-up including the retina within 1 month, then every 3 months and with any new visual symptom. For grade 2 disorders, symptoms are monitored and reported to an eye specialist and a dose reduction considered; for grade 3 or 4, crizotinib is withheld pending evaluation. In any patient with new severe visual loss (best corrected visual acuity below 6/60 in one or both eyes), treatment is stopped and a full eye evaluation done.

Photosensitivity

Patients should avoid prolonged sun exposure and, outdoors, use protective clothing or sunscreen.

Gastrointestinal Toxicity in Children

Crizotinib can cause severe gastrointestinal toxicity in children with ALCL or IMT (vomiting in 95%, diarrhoea in 85%). Antiemetics are used before and during treatment, with antidiarrhoeal agents, hydration and nutritional support as needed.

Non-Adenocarcinoma NSCLC

Information in ALK-positive and ROS1-positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma, is limited.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant during treatment. Adequate contraception is used during therapy and for at least 90 days after it ends.
• Pregnancy: crizotinib may cause foetal harm, and animal studies showed reproductive toxicity. There are no data in pregnant women. It should not be used in pregnancy unless the mother’s condition requires treatment. Pregnant women, patients who become pregnant on treatment, and treated men whose partners are pregnant should be told of the hazard to the foetus.
• Breastfeeding: it is not known whether crizotinib or its metabolites pass into human milk; mothers should avoid breastfeeding during treatment.
• Fertility: non-clinical findings suggest male and female fertility may be compromised, and both men and women should seek advice on fertility preservation before treatment.

Sodium and Sucrose

Each hard capsule contains less than 1 mmol (23 mg) sodium, so it is essentially sodium-free. The granule capsules contain sucrose (6 mg, 14 mg and 43 mg in the 20 mg, 50 mg and 150 mg capsules); patients with rare hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take them.

Effect on Driving

Xalkori has a minor influence on the ability to drive and use machines. Take care, as symptomatic bradycardia (syncope, dizziness, hypotension), vision disorder or fatigue may occur.

• Hard capsules (200 mg, 250 mg): no special storage conditions. They are supplied in HDPE bottles with a polypropylene closure containing 60 capsules, or in PVC-foil blisters of 10 capsules (carton of 60).
• Granules in capsules for opening (20 mg, 50 mg, 150 mg): store below 25 °C. They are supplied in HDPE bottles with a child-resistant closure and an induction seal, containing 60 capsules.
• Not all pack sizes may be marketed.

Hard capsules (200 mg and 250 mg): 4 years. Granules in capsules for opening (20 mg, 50 mg and 150 mg): 2 years.

Prescription only (Rx), on the prescription of a specialist experienced in the use of anticancer medicinal products. Xalkori is taken at home, by the patient or, for children, by a caregiver under adult supervision, so it is supplied to the patient or to the treating clinic on prescription.