Crizotinib, an inhibitor of multiple receptor tyrosine kinases including anaplastic lymphoma kinase ( ALK ) and c-ros oncogene-1 ( ROS-1 ), is an antineoplastic agent.1, 2, 3, 4, 5, 7, 15, 16, 44
Crizotinib is used for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose cancer is anaplastic lymphoma kinase ( ALK )- or c-ros oncogene-1 ( ROS-1 )-positive as detected by an FDA-approved diagnostic test.1, 15, 42, 43, 44 The drug has been designated an orphan drug by the FDA for use in this condition.12 Use of crizotinib for the treatment of metastatic NSCLC is supported by several randomized controlled trials.38, 46, 48, 49, 52 Guidelines generally support use of crizotinib for the treatment of stage IV NSCLC when other ALK inhibitors are unavailable or were previously used in the first-line setting.35
The current indication for crizotinib in the treatment of ALK - or ROS-1 -positive metastatic NSCLC is based principally on the results of 2 multicenter, open-label, randomized, phase 3 studies (PROFILE 1014 and PROFILE 1007)42, 43 and a multicenter, open-label, noncomparative study (PROFILE 1001).1, 44
In the PROFILE 1014 study, 343 adults with previously untreated ALK -positive metastatic NSCLC were randomized (stratified by Eastern Cooperative Oncology Group [ECOG] performance status, race, and presence of brain metastases) in a 1:1 ratio to receive either crizotinib (250 mg orally twice daily) alone or standard chemotherapy (pemetrexed 500 mg/m2 IV and either cisplatin 75 mg/m2 IV or carboplatin at the dose required to obtain an AUC of 5-6 mg/mL per minute IV every 3 weeks for up to 6 cycles).1, 42 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 42 At the time of documented disease progression, patients randomized to chemotherapy were offered crizotinib.1 The primary measure of efficacy was progression-free survival as assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1); additional outcome measures included objective response rate, duration of response, and overall survival.1, 42 Presence of ALK rearrangement was determined using an FDA-approved diagnostic test (i.e., Vysis ALK Break-Apart fluorescence in situ hybridization [FISH] probe kit).1, 42
The median age of patients enrolled in the PROFILE 1014 study was 53 years; 51% of patients were white, 46% were Asian, 62% were female, 95% had an ECOG performance status of 0 or 1, 64% had never smoked, 92% had adenocarcinoma histology, 27% had brain metastases, and 7% had received adjuvant or neoadjuvant chemotherapy.1 At the time of final analysis for overall survival, 84% of patients previously randomized to receive standard chemotherapy subsequently received crizotinib therapy.1 At a median follow-up of 17.4 months for those receiving crizotinib and 16.7 months for those receiving chemotherapy, median progression-free survival was prolonged in patients receiving crizotinib compared with those receiving standard chemotherapy (10.9 versus 7 months; hazard ratio: 0.45).1, 42 Objective response rate in patients receiving crizotinib or standard chemotherapy was 74 or 45%, respectively; complete response was achieved in 2 or 1% of patients, respectively.1, 42 At the time of analysis, the median duration of response in patients receiving crizotinib or standard chemotherapy was 11.3 or 5.3 months, respectively.1, 42 No substantial difference in overall survival was observed between patients receiving crizotinib and those receiving standard chemotherapy.1, 42 In a final overall survival analysis (median duration of follow-up of 46 months), no substantial difference in overall survival was observed; however, analysis adjusted for crossover demonstrated an overall survival benefit with crizotinib therapy.46 Results of an exploratory analysis (based on patient-reported symptoms) suggested that crizotinib therapy delayed the time to new onset or worsening of dyspnea compared with chemotherapy; however, because patients were not blinded to treatment assignment, differences in patient-related symptoms cannot be assessed reliably.1
In the PROFILE 1007 study, 347 adults with ALK -positive metastatic NSCLC previously treated with one platinum-containing regimen were randomized (stratified by ECOG performance status, presence of brain metastases, and prior epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor therapy) in a 1:1 ratio to receive either crizotinib (250 mg orally twice daily) or standard chemotherapy (pemetrexed 500 mg/m2 IV or docetaxel 75 mg/m2 IV every 21 days).1, 43 Treatment was continued until unacceptable toxicity or disease progression occurred or the patient was no longer experiencing clinical benefit.1, 43 The primary measure of efficacy was progression-free survival as assessed by an independent review committee according to RECIST 1.1; additional outcome measures included objective response rate, duration of response, and overall survival.1, 43 Presence of ALK rearrangement was determined using an FDA-approved diagnostic test (i.e., Vysis ALK Break-Apart FISH probe kit).1, 43
The median age of patients enrolled in the PROFILE 1007 study was 50 years; 52% of patients were white, 45% were Asian, 56% were female, 90% had an ECOG performance status of 0 or 1, and 63% had never smoked.1 Most patients (approximately 95%) had metastatic disease and at least 93% had adenocarcinoma histology.1 At the time of final analysis for overall survival, 89% of patients previously randomized to receive standard chemotherapy subsequently received crizotinib therapy.1 At a median follow-up of 12.2 months for those receiving crizotinib and 12.1 months for those receiving standard chemotherapy, median progression-free survival was prolonged in patients receiving crizotinib compared with those receiving standard chemotherapy (7.7 versus 3 months; hazard ratio: 0.49).1, 43 Objective response rate in patients receiving crizotinib or standard chemotherapy was 65 or 20%, respectively; complete response was achieved in one crizotinib-treated patient and none of those receiving standard chemotherapy.1, 43 At the time of analysis, the median duration of response in patients receiving crizotinib or standard chemotherapy was 7.4 or 5.6 months, respectively.1 No substantial difference in overall survival was observed between patients receiving crizotinib and those receiving chemotherapy.1, 43
In the PROFILE 1001 study, 50 patients with ROS-1 -positive metastatic NSCLC received crizotinib (250 mg orally twice daily) until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 44 The primary measures of efficacy were objective response rate according to RECIST 1.1 and duration of response.1, 44 Presence of ROS-1 rearrangement was determined by reverse transcription-polymerase chain reaction (RT-PCR) or FISH (defined as ROS-1 rearrangement on at least 15% of at least 50 tumor cells).1 The median age of patients enrolled in the study was 53 years; 54% of patients were white, 42% were Asian, 56% were female, 98% had an ECOG performance status of 0 or 1, and 78% had never smoked.1, 44 Most patients (92%) had metastatic disease and 96% had adenocarcinoma histology.1 The majority (80%) of patients had previously received platinum-based chemotherapy for metastatic disease.1 At the time of analysis, objective response rate as assessed by an independent review committee (IRC) or the investigator was 66 or 72%, respectively; complete response was achieved in 1 or 5 patients, respectively.1, 44 The median duration of IRC-assessed response was 18.3 months; median duration of investigator-assessed response had not been reached at the time of analysis.1
Crizotinib also has been compared with alectinib, brigatinib, and lorlatinib in clinical trials enrolling ALK inhibitor-naïve NSCLC patients.48, 49, 51, 52
A relatively small subset of patients with NSCLC have ALK - or ROS-1 -positive disease (approximately 3-7% or 1-2%, respectively), which indicates potential responsiveness to ALK or ROS-1 inhibitor therapy.36, 38, 39, 40, 42, 43, 44, 45 Patients with these forms of lung cancer typically are nonsmokers or have a history of light smoking, are female, and are younger in age and often have adenocarcinoma histology.3, 4, 6, 7, 10, 13, 38, 39, 40, 41, 42, 44 Although crizotinib is highly active in patients with ALK -positive NSCLC, most patients treated with the drug eventually experience disease progression, limiting the drug's long-term therapeutic potential.36, 38, 39, 41 Disease progression in patients receiving crizotinib can result from acquired resistance mutations in ALK , amplification of gene expression, activation of alternate signaling pathways, and/or progression of brain metastases (because of poor distribution of crizotinib into the CSF).36, 37, 38, 39, 41
ALK -positive Non-small Cell Lung Cancer
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as ALK mutations.35 ASCO/OH state that alectinib or brigatinib should be offered in the first-line setting in patients with stage IV NSCLC and driver alterations in ALK .35 If alectinib or brigatinib are not available, ceritinib or crizotinib should be offered in the first-line setting.35
In the second-line setting, ASCO/OH state that alectinib, brigatinib, or ceritinib should be offered in patients who received initial therapy with crizotinib.35
ROS-1 -positive Non-small Cell Lung Cancer
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as ROS-1 mutations.35 ASCO/OH state that crizotinib or entrectinib may be offered in patients with driver alterations in ROS-1 .35 ASCO/OH also state that if nontargeted therapy was given in the first-line setting in patients with ROS-1 -positive NSCLC, ceritinib, crizotinib, or entrectinib may be offered in the second-line setting.35
Anaplastic Large Cell Lymphoma
Crizotinib is used for the treatment of pediatric patients ≥1 year of age and young adults with relapsed or refractory ALK -positive systemic anaplastic large cell lymphoma (ALCL).1, 53 The drug has been designated an orphan drug by the FDA for use in this condition.12 The principal efficacy study did not include any patients >21 years of a the manufacturer states that safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory systemic ALK -positive ALCL.1
Safety and efficacy of crizotinib for the treatment of relapsed or refractory systemic ALK -positive ALCL are based principally on the results of a multicenter, single-arm, open-label study in 26 patients 1-21 years of age with systemic ALK -positive ALCL that relapsed or was refractory to at least 1 systemic treatment.1, 53 Patients with primary cutaneous ALCL or CNS involvement by lymphoma were excluded.1 In this study, patients received crizotinib 280 mg/m2 (20 patients) or 165 mg/m2 (6 patients) orally twice daily until disease progression or unacceptable toxicity occurred.1 Discontinuance of crizotinib therapy was permitted to undergo hematopoietic stem cell transplantation (HSCT).1 The median age of patients enrolled in the study was 11 years (range, 3 to 20); 69% were male, 54% were white, 19% were Black, and 8% were Asian.1 All patients had received systemic combination therapy, 8% had previously undergone HSCT, and 15% had received at least 3 prior therapies.1 The objective response rate was 88% (95% confidence interval, 71-96%); complete response occurred in 81% of patients and partial response occurred in 8% of patients.1 Of those with an objective response, 57% maintained a response at 3 months, 39% maintained a response at 6 months, and 22% maintained a response at 12 months.1
Anaplastic large cell lymphoma occurs in approximately 2 and 15% of adult and pediatric patients with non-Hodgkin lymphoma, respectively.54 The prevalence of ALK -positive ALCL is unknown, but the disease typically affects children and young adults.55 Anthracycline-based therapy is generally considered first-line treatment for ALCL.54, 56 Hematopoietic stem cell transplantation (HSCT) may be considered in specific patients and may improve survival; however, the clinical role of HSCT in patients with relapsed or refractory ALCL remains unclear.54 Targeted therapy and immunotherapy, including ALK inhibitors such as crizotinib, histone deacetylase inhibitors, and brentuximab vedotin, are generally considered emerging therapies for ALCL and have demonstrated high rates of response and survival in patients with ALK -positive or CD30-positive relapsed or refractory ALCL.54
Inflammatory Myofibroblastic Tumor
Crizotinib is used for the treatment of adult and pediatric patients ≥1 year of age with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.1 The drug has been designated an orphan drug by the FDA for use in this condition.12 Efficacy of crizotinib for treatment of ALK -positive IMT was established in 2 separate clincial studies; one study was conducted in patients 1 to ≤21 years of age and the other study was conducted in adults.1
The efficacy of crizotinib for treatment of ALK -positive IMT for pediatric patients 1 to ≤21 years of age was evaluated in a multicenter, single-arm, open-label study that included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT.1 Twelve patients received crizotinib 280 mg/m2twice daily until disease progression or unacceptable toxicity; 2 patients received a lower dose.1 The median age of patients in this study was 6.5 years (range: 2 to 13); 64% were female, 71% were white, 7% were Black, and 71% had a Lansky/Karnofsky Score of 100.1 A total of 12 (86%) patients received prior therapy; the most common prior therapy was surgery (57%).1 The primary efficacy outcome was objective response rate with 86% of patients having a complete (36%) or partial (50%) response rate.1 The duration of response was ≥6 and 12 months in 58% of the patients.1
The efficacy of crizotinib for treatment of ALK -positive IMT for adult patients was evaluated in a multicenter, single-arm, open-label study that included 7 adult patients with unresectable, recurrent, or refractory ALK-positive IMT.1 Patients received crizotinib 250 mg twice daily.1 The median age of patients was 38 years (range: 23 to 73); 57% were male, 57% were white, 43% were Asian, and 86% had an ECOG performance status of 0 or 1.1 Two (29%) patients had at least one prior systemic treatment.1 The primary efficacy outcome was objective response rate with 5 patients experiencing a response, including 1 complete response.1 The duration of response was ≥6 months for all 5 patients and ≥12 months for 2 patients.1
Inflammatory myofibroblastic tumors (IMTs) occur throughout the body, with the lungs as the most commonly involved organ.57 If possible, surgical resection is the treatment of choice as patients with completely resected tumors have an excellent prognosis.57 Molecular rearrangement of the ALK locus on chromosome 2p23 is seen in approximately 50% of IMT cases; therefore, patients with unresectable or recurrent tumors may respond to crizotinib if the ALK mutation is present and crizotinib administration is followed by complete or incomplete resection.57
Dispensing and Administration Precautions
Crizotinib is administered orally twice daily without regard to meals.1 The capsules should be swallowed whole; do not crush, chew, or split.1
The pellets are supplied encapsulated in shells.1 Do not chew or crush the pellets and do not swallow pellets encapsulated in the shell.1
Crizotinib pellets may be administered by opening the shells containing the pellets and emptying the contents directly into the patient's mouth or by emptying the contents into an oral dosing aid (e.g., spoon, medicine cup) and administering the pellets via the dosing aid directly into the patient's mouth.1 Give the patient a sufficient amount of water immediately after administration to ensure that all medication is swallowed.1
If a dose of crizotinib is missed, take it as soon as it is remembered unless the next dose is due within 6 hours.1
If a dose of crizotinib is vomited after administration, an additional dose should not be administered to replace the vomited dose.1 The next dose should be administered at the next scheduled time.1
Store capsules and pellets at room temperature (20°-25°C); excursions permitted between 15°-30°C.1
The recommended adult dosage of crizotinib for the treatment of ALK - or ROS-1 -positive metastatic NSCLC is 250 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Anaplastic Large Cell Lymphoma
The recommended dosage of crizotinib in pediatric patients ≥1 year of age and young adults with anaplastic large cell lymphoma (ALCL) is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity occurs.1 The recommended dosage of crizotinib is based on body surface area (BSA).1 See Table 1.
Body Surface Area (m2) | Recommended Dosage (280 mg/m2 twice daily) |
|---|---|
0.38-0.46 | 120 mg twice daily |
0.47-0.51 | 140 mg twice daily |
0.52-0.61 | 150 mg twice daily |
0.62-0.80 | 200 mg twice daily |
0.81-0.97 | 250 mg twice daily |
0.98-1.16 | 300 mg twice daily |
1.17-1.33 | 350 mg twice daily |
1.34-1.51 | 400 mg twice daily |
1.52-1.69 | 450 mg twice daily |
≥1.7 | 500 mg twice daily |
Inflammatory Myofibroblastic Tumor
The recommended dosage of crizotinib in pediatric patients ≥1 year of age with IMT is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity occurs.1 The recommended dosage of crizotinib is based on BSA.1 See Table 1.
The recommended adult dosage of crizotinib in patients with IMT is 250 mg orally twice daily until disease progression or unaceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur during crizotinib therapy, temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of crizotinib should be reduced as described in Table 2 in adult patients with NSCLC or IMT or in Table 3 for pediatric patients with ALCL or IMT and young adults with ALCL; the recommended dosage modifications for pediatric patients with ALCL or IMT and young adults with ALCL are based on BSA.1
Dose Reduction Level | Dosage Reduction after Recovery from Toxicity (Initial Adult Dosage = 250 mg twice daily) |
|---|---|
First | Resume at 200 mg twice daily |
Second | Resume at 250 mg once daily |
Third | Permanently discontinue drug |
Body Surface Area (m2) | First Dose Reduction | Second Dose Reductiona |
|---|---|---|
0.38-0.46 | 90 mg twice daily | 70 mg twice daily |
0.47-0.51 | 100 mg twice daily | 80 mg twice daily |
0.52-0.61 | 120 mg twice daily | 90 mg twice daily |
0.62-0.80 | 150 mg twice daily | 120 mg twice daily |
0.81-0.97 | 200 mg twice daily | 150 mg twice daily |
0.98-1.16 | 220 mg twice daily | 170 mg twice daily |
1.17-1.33 | 250 mg twice daily | 200 mg twice daily |
1.34-1.69 | 250 mg twice daily | 200 mg twice daily |
≥1.7 | 400 mg twice daily | 250 mg twice daily |
aPermanently discontinue in patients who are unable to tolerate crizotinib therapy after 2 dose reductions.
In adult patients receiving crizotinib for the treatment of NSCLC or IMT:
If grade 3 hematologic toxicity occurs, withhold crizotinib therapy until the hematologic toxicity resolves to ≤grade 2, then resume therapy at the same dosage.1
If grade 4 hematologic toxicity occurs, withhold crizotinib therapy until the hematologic toxicity resolves to ≤grade 2, then resume therapy at the next lower dosage.1
Dosage modification is not recommended for lymphopenia unless it is associated with clinical events (e.g., opportunistic infections).1
In pediatric and young adult patients receiving crizotinib for the treatment of ALCL or pediatric patients with IMT:
If absolute neutrophil count (ANC) <500/mm3 occurs, withhold crizotinib until ANC recovers to >1000/mm3, then resume crizotinib at the next lower dosage.1 If ANC <500/mm3 recurs, permanently discontinue crizotinib if recurrence is complicated by febrile neutropenia or infection.1 If uncomplicated grade 4 neutropenia occurs, withhold therapy until ANC recovers to >1000/mm3 and then resume at the next lower dosage or permanently discontinue therapy.1 Permanently discontinue crizotinib in patients who are unable to tolerate the drug after 2 dosage reductions, unless indicated otherwise.1
If platelet count of 25,000-50,000/mm3 occurs with concurrent bleeding, withhold crizotinib until platelet count recovers to >50,000/mm3 and bleeding resolves, then resume at the same dosage.1 If platelet count <25,000/mm3 occurs, withhold crizotinib until platelet count recovers to >50,000/mm3, then resume at the next lower dosa permanently discontinue for recurrence.1
If hemoglobin concentration <8 g/dL occurs, withhold crizotinib until hemoglobin concentration recovers to ≥8 g/dL, then resume at the same dosage.1 If life-threatening anemia occurs and urgent intervention is needed, withhold crizotinib until hemoglobin recovers to ≥8 g/dL, then resume at the next lower dosage.1 If life-threatening anemia recurs, permanently discontinue crizotinib therapy.1
If elevations in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations exceeding 5 times the upper limit of normal (ULN) with total bilirubin concentrations ≤1.5 times the ULN occur, withhold crizotinib therapy until liver function test results return to baseline values or improve to ≤3 times the ULN.1 Crizotinib therapy may then be resumed at the next lower dosage.1
If elevations in ALT or AST concentrations exceeding 3 times the ULN with total bilirubin concentrations exceeding 1.5 times the ULN (in the absence of cholestasis or hemolysis) occur, permanently discontinue crizotinib therapy.1
If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue crizotinib therapy.1
If corrected QT (QTc) interval exceeds 500 msec on at least 2 separate electrocardiograms (ECGs), withhold crizotinib therapy until the QTc-interval returns to baseline values or improves to <481 msec.1 Crizotinib therapy may then be resumed at the next lower dosage.1
If QTc interval exceeds 500 msec or a change from baseline of ≥60 msec occurs with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, permanently discontinue crizotinib therapy.1
If symptomatic, but non-life-threatening , bradycardia requiring medical intervention occurs, withhold therapy with crizotinib until recovery to a resting heart rate according to the patient's age (based on the 2.5th percentile per age-specific norms) as seen in Table 4.1 If concomitant drugs known to cause bradycardia are identified and discontinued or their dosage is adjusted, crizotinib therapy may be resumed at the same dosage upon recovery to asymptomatic bradycardia or to the age-specific heart rate.1 If no concomitant drugs known to cause bradycardia are identified or if discontinuance or dosage adjustment of such concomitant drugs is not possible, resume crizotinib at the next lower dosage upon recovery to asymptomatic bradycardia or to the age-specific heart rate.1
If life-threatening bradycardia requiring urgent intervention occurs in patients not receiving concomitant contributory drugs, permanently discontinue crizotinib therapy.1 If concomitant drugs known to cause bradycardia are identified and discontinued or their dosage is adjusted, crizotinib therapy may be resumed at the second dose reduction level in Table 2 or 3 upon recovery to asymptomatic bradycardia or to the heart rate criteria listed for management of symptomatic, but non-life-threatening bradycardia, with frequent monitoring.1 Permanently discontinue crizotinib therapy for recurrence.1
Age (years) | Resting Heart Rate |
|---|---|
1 to <2 | ≥91 beats/minute |
2-3 | ≥82 beats/minute |
4-5 | ≥72 beats/minute |
6-8 | ≥64 beats/minute |
>8 | ≥60 beats/minute |
If visual loss (grade 3 or 4 ocular disorder, marked decrease in vision) occurs, discontinue crizotinib therapy and perform an ophthalmologic evaluation.1 Permanently discontinue crizotinib for grade 3 or 4 ocular disorders or severe visual loss if no other etiology is discovered during the ophthalmologic evaluation.1
If visual symptoms (grade 1 or 2 ocular toxicity) occur, monitor symptoms and consult an eye specialist; consider dosage reduction of crizotinib for grade 2 visual disorders.1 I
In pediatric and young adult patients receiving crizotinib for the treatment of ALCL or pediatric patients with IMT:
If grade 3 nausea occurs, withhold crizotinib until symptoms resolve and then resume at the next lower dosage level.1
If grade 3 or 4 vomiting occurs, withhold crizotinib until symptoms resolve and then resume at the next lower dosage level.1
If grade 3 or 4 diarrhea occurs, withhold crizotinib until symptoms resolve and then resume at the next lower dosage level.1
In patients experiencing GI toxicity who are unable to tolerate crizotinib after 2 dosage reductions, permanently discontinue crizotinib unless otherwise indicated.1
Concomitant Use of Drugs or Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of crizotinib with potent cytochrome P-450 (CYP) isoenzyme 3A inhibitors should be avoided.1 If concomitant use of a potent CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dose of crizotinib to the second dose reduction (see Table 2 for adults with NSCLC or IMT and Table 3 for pediatric patients with ALCL or IMT and young adults with ALCL).1 When concomitant use of the potent CYP3A inhibitor is discontinued, resume the crizotinib dosage used prior to initiation of the potent CYP3A inhibitor.1
For adult patients with severe preexisting hepatic impairment (total bilirubin concentration exceeding 3 times the upper limit of normal [ULN] with any AST concentration), the manufacturer recommends a crizotinib dosage of 250 mg once daily in patients with NSCLC or IMT and reducing the dosage according to the second dosage reduction level in pediatric and young adult patients with ALCL or pediatric patients with IMT (see Table 3).1
For adult patients with moderate preexisting hepatic impairment (total bilirubin concentration exceeding 1.5 times ULN, but no more than 3 times ULN, with any AST concentration), the manufacturer recommends a crizotinib dosage of 200 mg twice daily in patients with NSCLC or IMT and reducing the dosage according to the first dosage reduction level in pediatric and young adult patients with ALCL or pediatric patients with IMT (see Table 3).1
No dosage adjustment is necessary in patients with mild preexisting hepatic impairment (AST concentration exceeding the ULN with total bilirubin concentration no more than the ULN, or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration).1
For adult patients with severe renal impairment (creatinine clearance <30 mL/minute, calculated using the modified Cockroft-Gault equation) who do not require dialysis, the manufacturer recommends a crizotinib dosage of 250 mg once daily in patients with NSCLC or IMT .1
For patients with severe renal impairment (creatinine clearance <30 mL/minute, calculated using the modified Cockroft-Gault equation for adults and the Schwartz equation for pediatric patients) who do not require dialysis, the manufacturer recommends a crizotinib dosage according to the second dosage reduction level in pediatric and young adult patients with ALCL or pediatric patients with IMT (see Table 3).1
No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Drug-induced hepatotoxicity with fatal outcome has occurred; such cases were reported in 0.1% of patients receiving crizotinib in clinical trials.1 Concurrent alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations of ≥3 times the upper limit of normal (ULN) and total bilirubin elevations of ≥2 times the ULN with normal alkaline phosphatase concentrations occurred in less than 1% of crizotinib-treated patients in clinical trials.1 ALT or AST elevations occurred in 11 or 6% of patients, respectively, in clinical trials in patients with NSCLC.1 ALT or AST elevations exceeding 5 times the ULN occurred in 4 or 4% of patients, respectively, in clinical trials in patients with ALCL.1 In clinical trials in patients with IMT treated with crizotinib, AST or ALT elevations occurred in 71% and 71% of pediatric patients, respectively and 57% and 43% of adult patients, respectively.1 Permanent discontinuance of crizotinib was required in 1% of patients with elevated ALT or AST concentrations in clinical trials in patients with NSCLC.1 Elevations in aminotransferase concentrations usually occurred within the first 2 months of treatment.1
The manufacturer states that liver function tests, including ALT, AST, and total bilirubin, should be monitored every 2 weeks during the first 2 months of therapy, monthly thereafter, and as clinically indicated.1 More frequent repeat testing for increased aminotransferases, alkaline phosphatase, or total bilirubin is necessary in patients who develop aminotransferase elevations during therapy.1 If hepatotoxicity occurs, temporary interruption, dosage reduction, or discontinuance of crizotinib may be necessary.1
Severe, life-threatening, or fatal interstitial lung disease or pneumonitis can occur in patients treated with crizotinib.1 In patients with NSCLC receiving crizotinib in clinical studies, grade 3 or 4 interstitial lung disease occurred in 1% of patients and fatal interstitial lung disease occurred in 0.5% of patients.1, 4 Interstitial lung disease generally occurred within the first 3 months of therapy.1 In clinical studies of patients 1 to ≤21 years of age with relapsed or refractory tumors, including ALCL and IMT, interstitial lung disease occurred in 0.8% of patients.1
Patients receiving the drug should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis, and other causes of interstitial lung disease or pneumonitis should be excluded.1 Crizotinib should be permanently discontinued in patients who are diagnosed with treatment-related interstitial lung disease or pneumonitis.1
Prolongation of the corrected QT (QTc) interval has been observed in crizotinib-treated patients.1 The prolongation appears to occur in a plasma concentration-dependent manner.1 An increase in the QTc interval (corrected for heart rate using Fridericia's formula [QTcF]) of ≥60 msec from baseline occurred in 5% of patients receiving crizotinib 250 mg twice daily, and QTcF intervals of ≥500 msec occurred in 2.1% of crizotinib-treated patients.1 Prolongation of the QTc interval occurred in 8% of patients with ALCL and 7% of pediatric patients with IMT in clinical studies.1
Crizotinib should be avoided in patients with congenital long QT syndrome.1 Electrocardiograms (ECGs) and serum electrolytes should be monitored in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval.1
If QTc-interval prolongation occurs, temporary interruption, dosage reduction, or discontinuance of crizotinib may be necessary.1
Symptomatic bradycardia has been observed in crizotinib-treated patients.1 In clinical studies, bradycardia occurred in 13% of crizotinib-treated patients with NSCLC.1 Grade 3 syncope was reported in 2.4 or 0.6% of patients receiving crizotinib or standard chemotherapy, respectively.1 Bradycardia (all grade 1 severity) occurred in 19% of crizotinib-treated patients with ALCL in clinical studies.1 In pediatric patients with IMT treated with crixotinib, bradycardia occured in 14% of patients, including grade 3 bradycardia in 0.8% of patients.1
Crizotinib should be avoided in patients who are receiving other drugs known to cause bradycardia (e.g., β-adrenergic blockers, nondihydropyridine calcium-channel blockers, clonidine, digoxin) when possible.1
Heart rate and blood pressure should be monitored regularly during crizotinib therapy.1 If symptomatic or life-threatening bradycardia occurs, temporary interruption, dosage reduction, or discontinuance of crizotinib may be necessary depending on concomitant use of other drugs known to cause bradycardia.1
Visual disturbances, which may result in partial or complete loss of vision in one or both eyes, have been observed in crizotinib-treated patients; visual disturbances generally occur within 1 week of initiating therapy.1 In clinical studies, grade 4 visual field defects leading to vision loss occurred in 0.2% of crizotinib-treated patients with NSCLC.1 Visual disorders occurred in 65% of crizotinib-treated patients with ALCL and 50% of patients with IMT in clinical studies.1 Optic atrophy and optic nerve disorder also may cause vision loss.1
In pediatric and young adult patients with ALCL or pediatric patients with IMT, perform ophthalmologic examination prior to starting crizotinib.1 Follow-up ophthalmologic examination including retinal examination is recommended within 1 month of treatment initiation, every 3 months thereafter.1 Assess visual symptoms monthly for all patients during treatment.1 If visual disturbances occur, consult an eye specialist.1 Permanently discontinue crizotinib for any grade 3 or 4 ocular disorders or for severe vision loss (best corrected vision less than 20/200 in one or both eyes) unless other etiology is identified.1 The manufacturer states that insufficient data are available to determine the risks of resuming crizotinib in patients who develop severe vision loss; the potential benefit of the drug to the patient must be carefully weighed against the potential risks of continued therapy.1
Severe GI toxicities have been observed in pediatric and young adult patients with ALCL or in pediatric patients with IMT receiving crizotinib.1 GI toxicity has been reported in all patients receiving crizotinib for the treatment of ALCL; grade 3 toxicity (i.e., diarrhea, nausea, vomiting, stomatitis) has been reported in 27% of patients.1 In pediatric patients with IMT, vomiting occurred in 93%, nausea occurred in 86%, and diarrhea occurred in 64% of patients.1 Provide standard antiemetic and antidiarrheal agents for GI toxicities in pediatric and young adult patients with ALCL and pediatric patients with IMT.1
Antiemetics are recommended prior to and during treatment with crizotinib to prevent nausea and vomiting.1 In patients who develop grade 3 nausea lasting 3 days or grade 3 or 4 diarrhea or vomiting despite maximum medical therapy, withhold crizotinib until symptoms resolve, and then resume at the next lower dosage level.1 When clinically indicated, consider supportive care such as hydration, electrolyte supplementation, and nutritional support.1
Fetal/Neonatal Morbidity and Mortality
Crizotinib may cause fetal harm if administered to pregnant women; the drug has been shown to be embryotoxic and fetotoxic in animals.1 There are no adequate and well-controlled studies in humans.1
Pregnancy should be avoided during therapy.1 Advise females of reproductive potential to use effective contraception during treatment with crizotinib and for 45 days following the last dose.1 Advise male patients with female partners of reproductive potential to use condoms during treatment with crizotinib and for 90 days after the last dose.1 If crizotinib is used during pregnancy or if the patient or their partner becomes pregnant during therapy, the patient should be apprised of the potential fetal hazard.1
Crizotinib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1
It is not known whether crizotinib is distributed into human milk.1 Because of the potential for serious adverse reactions to crizotinib in nursing infants, females should be advised not to breast-feed while receiving the drug and for 45 days after the drug is discontinued.1
Females and Males of Reproductive Potential
The manufacturer states that a pregnancy test should be performed prior to initiation of crizotinib in females of reproductive potential and that such females should use effective contraceptive methods while receiving the drug and for at least 45 days after the drug is discontinued.1 Males with female partners should use condoms during and for at least 90 days after discontinuance of the drug.1
Based on findings from animal studies, crizotinib may impair male and female fertility.1
In repeat-dose toxicity studies, testicular pachytene spermatocyte degeneration and single-cell necrosis of ovarian follicles were observed in male and female rats, respectively, receiving crizotinib at exposure levels exceeding human exposure at the recommended dosa whether these effects on fertility are reversible has not been established.1
Safety and efficacy of crizotinib have been established in pediatric patients ≥12 months of age with relapsed or refractory systemic anaplastic lymphoma kinase ( ALK )-positive ALCL or with unresectable, recurrent, or refractory ( ALK )-positive IMT.1 Safety and efficacy have not been established in pediatric patients <12 months of age with ALCL or IMT or in any pediatric patients with NSCLC.1
In a study of crizotinib in combination with chemotherapy in pediatric patients with newly diagnosed ALCL, 20% of patients experienced a grade 2 or higher thromboembolic event, including pulmonary embolism in 6% of the patients.1 The safety and efficacy of crizotinib in combination with chemotherapy have not been established in patients with newly diagnosed ALCL.1
Decreased bone formation in growing long bones has been observed in immature rats receiving crizotinib for 28 days (at a dosage of 150 mg/kg daily, approximately 5.4 times the recommended human dosage based on AUC); other toxicities of potential concern in pediatric patients have not been evaluated to date in juvenile animal studies.1
In clinical studies, 16% of patients with anaplastic lymphoma kinase ( ALK )-positive metastatic NSCLC receiving crizotinib were ≥65 years of age and 3.8% were ≥75 years of age.1 No overall differences in safety or efficacy were observed between these geriatric patients and younger adults.1
Clinical studies evaluating crizotinib in patients with c-ros oncogene-1 ( ROS-1 )-positive metastatic NSCLC did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1
Dosage of crizotinib should be reduced in patients with preexisting moderate or severe hepatic impairment.1 Systemic exposure to crizotinib was increased in patients with moderate (total bilirubin concentration exceeding 1.5 times the upper limit of normal [ULN], but not exceeding 3 times ULN, with any AST concentration) or severe (total bilirubin concentration exceeding 3 times the ULN with any AST concentration) hepatic impairment; dosage adjustment is necessary in patients with preexisting moderate or severe hepatic impairment.1 Following administration of a reduced crizotinib dosage of 200 mg twice daily in patients with moderate hepatic impairment, mean AUC and peak plasma concentrations at steady state were increased by 14 and 9%, respectively, compared with patients with normal hepatic function receiving the recommended dosage of crizotinib (250 mg twice daily).1 Following administration of a reduced crizotinib dosage of 250 mg once daily in patients with severe hepatic impairment, mean AUC and peak plasma concentrations were decreased by 35 and 27%, respectively, compared with patients with normal hepatic function receiving the recommended dosage of crizotinib (250 mg twice daily).1
Mean AUC and peak plasma concentrations of crizotinib at steady state were decreased by 9% in patients with mild hepatic impairment (AST concentration exceeding the ULN with total bilirubin concentration no more than the ULN, or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration) compared with patients with normal hepatic function following the recommended dosage of crizotinib (250 mg twice daily); no dosage adjustment is necessary in patients with preexisting mild hepatic impairment.1
Following administration of a single 250-mg dose of crizotinib in patients with severe renal impairment (creatinine clearance <30 mL/minute) who did not require dialysis, mean peak plasma concentrations and AUC of crizotinib were increased by 34 and 79%, respectively, compared with patients with normal renal function; similar effects on the AUC and peak plasma concentrations of the active metabolite of crizotinib were observed in patients with severe renal impairment.1 The manufacturer recommends dosage adjustment in patients with severe renal impairment.1
Systemic exposure of crizotinib was unaffected following administration of the drug in patients with mild (creatinine clearance 60-89 mL/minute) or moderate (creatinine clearance 30-59 mL/minute) renal impairment.1
Adverse effects reported in ≥25% of patients receiving crizotinib for the treatment of ALK -positive metastatic NSCLC include vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated aminotransferase concentrations, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.1
Adverse effects reported in ≥35% of pediatric patients receiving crizotinib for the treatment of IMT include vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache.1 Adverse effects reported in ≥20% of adult patients receiving crizotinib for the treatment of IMT include vision disorders, nausea, and edema.1
Adverse effects reported in ≥35% of patients receiving crizotinib for the treatment of ALCL include diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus.1
Grade 3 or 4 laboratory abnormalities reported in ≥15% of patients receiving crizotinib for the treatment of ALCL include include neutropenia, lymphopenia, and thrombocytopenia.1
Crizotinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1 In vitro studies indicate that crizotinib is an inhibitor of CYP isoenzyme 2B6.1 Crizotinib does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, or 2D6, or uridine diphosphate-glucuronosyl transferases (UGT) 1A1, 1A4, 1A6, 1A9, or 2B7.1 The drug also does not induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A.1
In vitro, crizotinib is an inhibitor and substrate of P-glycoprotein (P-gp).1 Crizotinib inhibits organic cation transporter (OCT) 1 and OCT2, but does not inhibit organic anion transport protein (OATP) B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, or bile salt export pump (BSEP).1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of crizotinib with potent inhibitors of CYP3A may result in increased systemic exposure to crizotinib and possible toxicity.1 When the potent CYP3A inhibitor ketoconazole was administered concomitantly with crizotinib (single 150-mg dose), peak plasma concentration and area under the concentration-time curve (AUC) of crizotinib were increased by 44 and 216%, respectively, compared with crizotinib administration alone.1 When the potent CYP3A inhibitor itraconazole was administered concomitantly with crizotinib (250 mg once daily), peak plasma concentration and AUC of crizotinib were increased by 33 and 57%, respectively, compared with crizotinib administration alone.1
Concomitant use of crizotinib with potent CYP3A inhibitors (e.g., ketoconazole, itraconazole) should be avoided.1 If concomitant use of a potent CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of crizotinib to 250 mg once daily in adult patients with NSCLC or IMT and reducing the dosage according to the second dosage reduction level in pediatric and young adult patients with ALCL or pediatric patients with IMT (see Table 3).1 When concomitant use of the potent CYP3A inhibitor is discontinued, the crizotinib dosage should be returned to the dosage used prior to initiation of the potent CYP3A inhibitor.1
Caution should be exercised with concomitant use of crizotinib and moderate CYP3A inhibitors.1
Grapefruit products are CYP3A inhibitors and should be avoided because of the potential for increased plasma crizotinib concentrations during concurrent use.1
Concomitant use of crizotinib with potent inducers of CYP3A may result in decreased plasma concentrations of crizotinib and reduced crizotinib efficacy.1 When the potent CYP3A inducer rifampin was administered concomitantly with crizotinib (250 mg twice daily), AUC and peak plasma concentration of crizotinib were decreased by 84 and 79%, respectively, compared with crizotinib administration alone.1
Concomitant use of crizotinib with potent CYP3A4 inducers should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of crizotinib and substrates of CYP3A may result in increased plasma concentrations of the CYP3A substrate and possible toxicity.1 When the CYP3A substrate midazolam was administered concomitantly with crizotinib (250 mg twice daily for 28 days), AUC of midazolam increased 3.7-fold compared with midazolam administration alone.1
Concomitant use of crizotinib with CYP3A substrates that have a narrow therapeutic index should be avoided.1 If concomitant use of CYP3A substrates that have a narrow therapeutic index cannot be avoided, the manufacturer recommends reducing the dosage of the substrate drug.1
Drugs that Prolong the QT Interval
Because crizotinib has been associated with QT-interval prolongation, the manufacturer recommends that concomitant use of crizotinib with other drugs known to prolong the QT interval be avoided.1 If concomitant use of other drugs known to prolong the QT interval cannot be avoided, the manufacturer recommends monitoring electrocardiograms (ECGs) and serum electrolytes.1, 18, 19
Drugs Associated with Bradycardia
Because crizotinib has been associated with bradycardia, concomitant use of crizotinib with other drugs known to cause bradycardia (e.g., β-adrenergic blocking agents, nondihydropyridine calcium-channel blocking agents, clonidine, digoxin) should be avoided, when possible.1
Drugs Affecting Gastric Acidity
Concomitant administration of crizotinib and the proton-pump inhibitor esomeprazole did not substantially affect the pharmacokinetics of crizotinib.1
Crizotinib, an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-Met), c-ros oncogene-1 (ROS-1), and recepteur d'origine nantais (RON), is an antineoplastic agent.1, 2, 4, 5, 7, 15, 16, 42, 43, 44, 45 Activating mutations or translocations of the ALK gene have been identified in several malignancies2 and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).1, 3, 6, 15, 16 Such ALK gene rearrangements have been identified in approximately 3-7% of patients with non-small cell lung cancer (NSCLC).36, 38, 39, 40, 42, 43 Approximately 1-2% of patients with NSCLC have ROS-1 -positive disease.44, 45 Formation of ALK fusion proteins such as EML4-ALK results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.1, 2, 6, 16 In vitro, crizotinib has demonstrated concentration-dependent inhibition of ALK, ROS-1, and c-Met phosphorylation.1, 8 The drug has also demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4-ALK or nucleophosmin (NPM)-ALK fusion proteins or c-Met.1 In vitro, crizotinib induced apoptosis and inhibited proliferation and ALK-mediated signaling in anaplastic large cell lymphoma (ALCL)-derived cell lines at clinically achievable exposures.1
Although crizotinib has demonstrated improved outcomes in patients with NSCLC harboring ALK mutations, secondary resistance to crizotinib eventually develops, generally within the first 1-2 years of treatment.36, 38, 39, 41 Clinical resistance to crizotinib has been attributed to several possible mechanisms, including acquired resistance mutations of ALK , amplification of gene expression, and activation of alternate signaling pathways.36, 38, 39, 41 Secondary mutations of ALK are responsible for about 30% of cases of acquired crizotinib resistance and gene amplification is implicated in 9% of these cases.36, 37, 41 The CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF;36, 38, 39, 41 development and/or progression of brain metastases occurs in approximately one-half of patients during crizotinib treatment.36, 38
Crizotinib is predominantly metabolized by the cytochrome P-450 (CYP) isoenzyme 3A.1 Following oral administration of a single 250-mg radiolabeled dose of crizotinib, approximately 63% of the radioactivity was recovered in feces and 22% was recovered in urine; unchanged drug accounted for 53% of the dose recovered in feces and 2.3% of the dose recovered in urine.1 The mean terminal half-life of crizotinib is 42 hours.1, 5 The mean absolute bioavailability of crizotinib following oral administration as capsules is approximately 43%.1 Bioavailability of the oral pellets is comparable to that of the oral capsules.1 Following administration of a single capsule dose of crizotinib, peak plasma concentrations of the drug are achieved in a median of 4-6 hours.1 In vitro, crizotinib is 91% bound to plasma proteins, and binding is independent of crizotinib concentration.1 Following administration of crizotinib over the dose range of 200 to 300 mg twice daily, trough plasma concentrations and AUC increase in a greater than dose-proportional manner; steady-state concentrations of the drug are achieved in 15 days, with a median accumulation ratio of 4.8.1 AUC and peak plasma concentrations were reduced by approximately 14% when crizotinib in the capsule formulation was administered with a high-fat meal; for the pellet formulation, AUC and peak plasma concentrations were reduced by 15% and 23%, respectively.1 The pharmacokinetics of crizotinib are not affected by age, sex, or ethnicity (Asian or non-Asian).1 In patients ≤18 years of age, crizotinib exposure is lower in patients with higher body weight.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Crizotinib is available only from designated specialty pharmacies.17 Consult the manufacturer's website for additional information.17
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions February 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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