Ceritinib, an inhibitor of several receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), is an antineoplastic agent.1, 2, 3
Ceritinib is used for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose cancer is anaplastic lymphoma kinase ( ALK )-positive as detected by an FDA-approved diagnostic test.1, 2, 3, 43 Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at [Web].1 Ceritinib has been designated an orphan drug by the FDA for this use.4 Guidelines for the treatment of patients with stage IV NSCLC with driver alterations in ALK generally support the use of ceritinib as an option in the first-line setting if alectinib and brigatinib are not available; ceritinib also may be offered in the second-line setting if crizotinib was given in the first-line setting.35
Efficacy and safety of ceritinib for the treatment of ALK -positive metastatic NSCLC are based principally on the results of a multicenter, open-label, randomized phase 3 study (ASCEND-4) in patients with previously untreated advanced disease and a multicenter, single-arm, open-label study (ASCEND-1) in patients whose cancer had progressed during crizotinib therapy or who were intolerant to crizotinib.1, 2, 43
In the ASCEND-4 study, 376 adults with previously untreated ALK -positive metastatic NSCLC were randomized (stratified by World Health Organization [WHO] performance status, prior chemotherapy, and presence of brain metastases) in a 1:1 ratio to receive either ceritinib (750 mg orally once daily in a fasted state) 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 4 cycles followed by maintenance therapy with pemetrexed 500 mg/m2 IV every 3 weeks).1, 43 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 43 The primary measure of efficacy was progression-free survival as assessed by a blinded independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1); additional outcome measures included overall survival, overall response rate, duration of response, intracranial overall response rate, and duration of intracranial response.1 Presence of ALK rearrangement was determined using an FDA-approved diagnostic test (Ventana ALK [D5F3] CDx assay).1 The median age of patients enrolled in the study was 54 years; 54% of patients were white, 42% were Asian, 57% were female, 61% had never smoked, and 97% had adenocarcinoma histology.1 At the time of analysis, 43% of patients previously randomized to receive standard chemotherapy had subsequently received ceritinib therapy.1
In the ASCEND-4 study, median progression-free survival was prolonged in patients receiving ceritinib compared with those receiving standard chemotherapy (16.6 versus 8.1 months; hazard ratio: 0.55).1, 43 Overall response rate in patients receiving ceritinib or standard chemotherapy was 73 or 27%, respectively; complete response was achieved in 1 or 0% of patients, respectively.1, 43 At the time of analysis, the median duration of response in patients receiving ceritinib or standard chemotherapy was 23.9 or 11.1 months, respectively.1 No substantial difference in overall survival was observed between patients receiving ceritinib and those receiving standard chemotherapy at the time of an interim analysis.1 In the subgroup of 55 patients with measurable brain metastases at baseline, intracranial overall response rate was 57 or 22% in patients receiving ceritinib or standard chemotherapy, respectively; complete responses were achieved in 7% of patients in both treatment groups.1 The median duration of intracranial response had not been reached in patients receiving standard chemotherapy, but was 16.6 months in ceritinib-treated patients.1 Results of an exploratory analysis (based on patient-reported symptoms) suggested that ceritinib therapy delayed the time to new onset or worsening of shortness of breath compared with standard chemotherapy; however, because patients were not blinded to treatment assignment, differences in patient-related symptoms cannot be assessed reliably.1
In the ASCEND-1 study, 163 adults with metastatic ALK -positive NSCLC whose cancer had progressed with or who were intolerant of crizotinib received ceritinib 750 mg once daily in a fasted state.1 The primary efficacy end point was overall response rate as assessed by a blinded independent review committee (IRC) according to RECIST 1.1; an additional outcome measure was duration of response.1 The median age of patients enrolled in the study was 52 years; 91% of patients had experienced disease progression during crizotinib therapy and 93% had adenocarcinoma histology.1 At the time of analysis, overall response rate in patients receiving ceritinib was 44%; complete responses were achieved in 2.5% of patients.1 Median duration of response was 7.1 months.1 Effects of ceritinib on investigator-assessed progression-free survival and IRC-assessed progression-free survival were comparable.1
Use of ceritinib also was investigated in ASCEND-7, a 5-arm, multicenter, open-label phase 2 study in 156 patients with ALK-positive NSCLC with active brain and/or leptomeningeal metastases.47 The study arms were defined as follows: arm 1 (patients previously treated with radiation to the brain and with prior exposure to an ALK inhibitor [ALKi]), arm 2 (patients previously not treated with radiation to the brain but with prior exposure to an ALKi), arm 3 (patients previously treated with radiation to the brain but no prior ALKi exposure), arm 4 (patients previously not treated with radiation to the brain and no prior ALKi exposure), and arm 5 (patients with leptomeningeal carcinomatosis).47 Patients in each arm were treated with ceritinib 750 mg orally once daily, in a fasted state; treatment was continued until disease progression, discontinuation, or withdrawal of study consent.47
The median age of patients ranged from 46 to 53.5 years and the majority of patients in arms 1, 2, and 5 had received crizotinib previously.47 The primary efficacy endpoint was investigator-assessed overall response rate according to RECIST 1.1.47 A key secondary outcome was investigator-assessed whole-body disease control rate.47
At the time of analysis, overall response rate was higher in arm 4 (59.1%) compared to other arms: arm 1 (35.7%), arm 2 (30%), arm 3 (50%), and arm 5 (16.7%).47 Investigator-assessed whole-body disease control rate was highest in arm 2 (82.5%) compared to other arms.47
Approximately 60% of patients with lung cancer have driver alterations (e.g., in the epidermal growth factor receptor and ALK and BRAF genes).35 A relatively small subset of patients with NSCLC (approximately 3-7%) have ALK-positive disease, which indicates potential responsiveness to ALK inhibitor therapy (e.g., alectinib, brigatinib, ceritinib, crizotinib).48, 50, 51, 52 Patients with this form 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.50, 51, 52, 53 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.48, 50, 41, 53 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).48, 49, 50, 51, 53
The American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO) March 2021 guideline addresses treatment of stage IV NSCLC with driver alterations, including ALK-positive disease.35 For patients with stage IV NSCLC and driver alterations in ALK, alectinib or brigatinib should be offered in the first-line setting.35 If alectinib and brigatinib are not available, ceritinib or crizotinib should be offered.35 In the second-line setting, alectinib, brigatinib, or ceritinib should be offered if crizotinib was given in the first-line setting.35
Ceritinib is administered orally once daily with food.1
If a dose of ceritinib is missed, the missed dose should be taken as soon as it is remembered unless the next dose is due within 12 hours.1
If a dose of ceritinib 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 ceritinib tablets and capsules at 20-25°C (excursions permitted between 15-30°C).1
The recommended adult dosage of ceritinib for the treatment of ALK -positive metastatic NSCLC is 450 mg once daily with food.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur during ceritinib 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 ceritinib should be reduced as described in Table 1.1 Ceritinib should be discontinued if patients are unable to tolerate 150 mg once daily.1
Dose Reduction Level | Dosage Reduction after Recovery from Toxicity (Initial Dosage = 450 mg once daily) |
|---|---|
First | Resume at 300 mg once daily |
Second | Resume at 150 mg once daily |
In patients experiencing severe or intolerable nausea, vomiting, or diarrhea despite optimal antiemetic or antidiarrheal therapy, ceritinib therapy should be withheld until improvement of GI symptoms.1 Ceritinib may then be resumed at the next lower dosage as described in Table 1.1
If an elevation in serum ALT or AST concentrations exceeding 5 times the upper limit of normal (ULN) occurs with an elevation in total bilirubin concentrations no more than 2 times the ULN, ceritinib therapy should be withheld until the liver function test results return to baseline values or decrease to no more than 3 times the ULN.1 Ceritinib therapy may then be resumed at the next lower dosage as described in Table 1.1
If an elevation in ALT or AST concentrations exceeding 3 times the ULN occurs with an elevation in total bilirubin concentrations exceeding 2 times the ULN in the absence of cholestasis or hemolysis, therapy with ceritinib should be permanently discontinued.1
Interstitial Lung Disease/Pneumonitis
If treatment-related interstitial lung disease/pneumonitis of any grade occurs, ceritinib therapy should be permanently discontinued.1
If corrected QT (QTc) interval exceeds 500 msec on at least 2 separate ECGs, ceritinib therapy should be withheld until the QTc interval is less than 481 msec or returns to baseline (if baseline QTc interval is 481 msec or more).1 Ceritinib therapy may then be resumed at the next lower dosage as described in Table 1.1
If QTc-interval prolongation occurs concurrently with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, ceritinib therapy should be permanently discontinued.1
If symptomatic, but non-life-threatening, bradycardia (heart rate less than 60 beats/minute) occurs, therapy with ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of at least 60 beats/minute.1 If no concomitant drugs known to cause bradycardia are identified, ceritinib therapy may be resumed at the next lower dosage as described in Table 1.1
If clinically important bradycardia requiring intervention or life-threatening bradycardia occurs in patients receiving concomitant drugs known to cause bradycardia or hypotension, ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of at least 60 beats/minute.1 If such concomitant drugs are discontinued or the dosage adjusted, ceritinib therapy may be resumed at the next lower dosage as described in Table 1 with frequent monitoring.1
If life-threatening bradycardia occurs in patients not receiving concomitant drugs known to cause bradycardia or hypotension, ceritinib therapy should be permanently discontinued.1
If persistent hyperglycemia with serum glucose concentrations exceeding 250 mg/dL occurs despite optimal antidiabetic agent therapy, ceritinib therapy should be withheld until adequate control of the hyperglycemia is achieved.1 Ceritinib therapy may then be resumed at the next lower dosage as described in Table 1.1 If hyperglycemia persists despite optimal medical management, ceritinib therapy should be discontinued.1
If elevation in serum lipase or amylase concentration exceeding 2 times the ULN occurs, ceritinib therapy should be withheld until serum lipase or amylase concentrations improve to less than 1.5 times the ULN.1 Ceritinib therapy may then be resumed at the next lower dosage as described in Table 1.1
Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of ceritinib with drugs that are potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided.1 If concomitant use of a potent CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the daily dosage of ceritinib by approximately 33% and rounding dosage to the nearest 150-mg strength of ceritinib capsules or tablets (e.g., from 450 mg daily to 300 mg daily).1 If concomitant use of the potent CYP3A inhibitor is discontinued, the ceritinib dosage should be returned to the dosage used prior to initiation of the potent CYP3A inhibitor.1
Patients with hepatic impairment may have an increased exposure to ceritinib.1 The manufacturer recommends reducing the daily dosage of ceritinib by approximately 33% and rounding dosage to the nearest 150-mg strength of ceritinib capsules or tablets (e.g., from 450 mg daily to 300 mg daily) in patients with severe hepatic impairment (Child-Pugh class C).1 No dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe adverse GI effects may occur in patients receiving ceritinib.1 In clinical trials evaluating ceritinib 750 mg once daily, diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of patients receiving the drug in a fasting state, including severe cases in 14% of these patients; permanent discontinuance of ceritinib therapy or dosage modification (i.e., temporary interruption of therapy, dosage reduction) was necessary in 1.6 or 36%, respectively, of patients receiving the drug.1 In a dose-optimization study (ASCEND-8), the incidence and severity of adverse GI effects were reduced in patients receiving ceritinib 450 mg daily with food.1 In the ASCEND-8 study, diarrhea, nausea, vomiting, or abdominal pain occurred in 79% of 108 patients receiving ceritinib 450 mg daily with food; 53% of these cases were grade 1 in severity.1 Grade 3 diarrhea and grade 3 vomiting each occurred in one patient.1 Diarrhea or nausea resulted in temporary interruption of ceritinib therapy in 10% of patients receiving the drug; no dosage reduction was necessary in patients experiencing these adverse GI effects.1
Patients receiving ceritinib should be monitored for development of GI toxicity and treated as necessary with appropriate therapy (e.g., antidiarrhea agents, antiemetics, fluid replacement).1 Temporary interruption followed by dosage reduction or discontinuance of ceritinib may be necessary depending on the severity of the GI toxicity.1
Drug-induced hepatotoxicity has occurred in patients receiving ceritinib.1 In clinical trials evaluating ceritinib 750 mg once daily, elevations in ALT or AST concentrations exceeding 5 times the upper limit of normal (ULN) were reported in 28 or 16%, respectively, of patients receiving the drug in a fasting state.1 Concurrent elevations in ALT concentrations exceeding 3 times the ULN and total bilirubin concentrations exceeding 2 times the ULN with alkaline phosphatase concentrations less than 2 times the ULN have been reported in 0.3% of ceritinib-treated patients.1 Permanent discontinuance of the drug due to hepatotoxicity was necessary in approximately 1% of patients.1
The manufacturer states that liver function tests (i.e., ALT, AST, total bilirubin) should be monitored once monthly and as clinically indicated during ceritinib therapy, with more frequent testing in patients who develop aminotransferase elevations during therapy.1 Temporary interruption followed by dosage reduction or permanent discontinuance of ceritinib may be necessary depending on the severity of the hepatic toxicity.1
Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis may occur in patients receiving ceritinib.1 In clinical trials evaluating ceritinib 750 mg once daily, ILD or pneumonitis occurred in 2.4% of patients receiving the drug in a fasting state; grade 3 or 4 ILD or pneumonitis occurred in 1.3% of patients and fatal ILD or pneumonitis was reported in 0.2% of patients.1 Discontinuance of ceritinib due to ILD or pneumonitis occurred in 10 (1.1%) patients in these clinical trials.1
Patients receiving ceritinib should be monitored for pulmonary symptoms indicative of ILD or pneumonitis, and other potential causes of ILD or pneumonitis should be excluded.1 Ceritinib should be permanently discontinued in patients who are diagnosed with treatment-related ILD or pneumonitis.1
Prolongation of the corrected QT (QTc) interval, which may increase the risk for ventricular arrhythmias (e.g., torsades de pointes) or sudden death, has been reported in patients receiving ceritinib.1 The prolongation appears to occur in a plasma concentration-dependent manner.1 In clinical trials, an increase in the QTc interval exceeding 60 msec from baseline occurred in 6% of patients receiving ceritinib.1 QTc interval exceeding 500 msec has been reported in approximately 1.3% of patients receiving ceritinib 750 mg once daily in a fasting state.1 Discontinuance of ceritinib due to prolongation of the QTc interval was necessary in 0.2% of patients in clinical trials.1
Ceritinib should be avoided in patients with congenital long QT syndrome, if possible.1 The manufacturer recommends periodic monitoring of ECGs and serum electrolytes during ceritinib therapy in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval.1
Temporary interruption followed by dosage reduction or discontinuance of ceritinib may be necessary depending on the severity of the prolongation of QTc interval.1
Hyperglycemia has been reported in patients receiving ceritinib.1 In clinical trials evaluating ceritinib 750 mg once daily, grade 3 or 4 hyperglycemia occurred in 13% of patients receiving the drug in a fasting state.1 The risk of hyperglycemia may be increased in patients with diabetes mellitus or glucose intolerance and in those concurrently receiving corticosteroids.1
Fasting serum glucose concentrations should be monitored prior to initiation of ceritinib, during therapy, and as clinically indicated.1 Antidiabetic agents should be initiated or optimized as necessary.1 Temporary interruption followed by dosage reduction or discontinuance of ceritinib may be necessary depending on the severity of the hyperglycemia.1
Ceritinib may cause bradycardia.1 In clinical trials evaluating ceritinib 750 mg once daily, sinus bradycardia (defined as a heart rate of less than 50 beats/minute) was reported as a new finding in 1.1% of patients receiving the drug in a fasting state; bradycardia was reported as an adverse drug reaction in 1% of patients.1 In patients experiencing bradycardia, temporary interruption of ceritinib therapy followed by dosage reduction was necessary in 0.1% of patients receiving the drug; discontinuance of ceritinib therapy was not required in any patients experiencing bradycardia.1
Ceritinib should be avoided in patients who are receiving other drugs known to cause bradycardia when possible.1
Heart rate and blood pressure should be monitored regularly in all patients receiving ceritinib.1 Temporary interruption followed by dosage reduction or discontinuance of ceritinib may be necessary depending on the severity of bradycardia.1
Pancreatitis, sometimes fatal, has been reported in patients receiving ceritinib.1 In clinical trials, pancreatitis occurred in less than 1% of ceritinib-treated patients; grade 3 or 4 elevations of serum amylase or lipase concentrations were reported in 7 or 14% of patients, respectively.1
Serum lipase and amylase concentrations should be monitored prior to initiation of ceritinib, periodically during therapy, and as clinically indicated.1 Temporary interruption followed by dosage reduction or discontinuance of ceritinib may be necessary depending on the severity of the toxicity.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, ceritinib may cause fetal harm if administered to pregnant women.1 Ceritinib produced developmental toxicity, including dose-related skeletal abnormalities (e.g., delayed or incomplete ossification, skeletal variations) and a low incidence of visceral abnormalities, when administered to pregnant animals in dosages associated with exposure levels lower than those associated with the recommended human dosa maternal toxicity, abortion, and embryolethality also were observed.1
Pregnancy should be avoided during therapy.1 (See Females and Males of Reproductive Potential under Cautions.)
Ceritinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) If ceritinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
It is not known whether ceritinib or its metabolites are distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Because of the potential for serious adverse reactions to ceritinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 2 weeks after the drug is discontinued.1
Females and Males of Reproductive Potential
Prior to initiation of ceritinib therapy, verify pregnancy status of females of reproductive potential.1 Females of reproductive potential should be advised to use effective methods of contraception while receiving the drug and for 6 months after the drug is discontinued.1 Men who are partners of such women should use effective contraceptive methods during and for 3 months after discontinuance of the drug.1
Safety and efficacy of ceritinib have not been established in pediatric patients.1
In clinical trials evaluating ceritinib 750 mg once daily in patients with ALK -positive non-small cell lung cancer (NSCLC), 18% of patients were ≥65 years of age and 5% were ≥75 years of age.1 No substantial differences in safety or efficacy of ceritinib were observed between geriatric patients and younger adults.1
In pharmacokinetic population analyses, age did not have a clinically important effect on the systemic exposure of ceritinib in adults.1
Following administration of a single 750-mg dose of ceritinib in a fasting state in individuals with severe hepatic impairment (Child-Pugh class C), mean systemic exposure to total and unbound ceritinib was increased by 66 and 108%, respectively, compared with exposure in individuals with normal hepatic function.1 Systemic exposure to total and unbound ceritinib in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B) was similar to that observed in individuals with normal hepatic function.1
The manufacturer recommends dosage adjustment in patients with severe hepatic impairment.1
Population pharmacokinetic analysis suggests that systemic exposure to ceritinib is not substantially altered in patients with mild to moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 Patients with severe renal impairment (creatinine clearance less than 30 mL/minute) were not included in the clinical trials.1
Adverse effects reported in ≥25% of patients receiving ceritinib 450 mg with food include nausea, diarrhea, vomiting, abdominal pain, and fatigue.1
Ceritinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1 In vitro, ceritinib is a substrate of P-glycoprotein (P-gp).1 In vitro studies also indicate that ceritinib may inhibit CYP isoenzymes 3A and 2C9 at clinically relevant concentrations.6 In vitro, ceritinib induces CYP3A4, but does not induce CYP isoenzymes 1A2, 2B6, or 2C9.6
In vitro, ceritinib is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, organic cation transporter (OCT) 1, organic anion transporter (OAT) 2, or organic anion transport protein (OATP) 1B1.1 Ceritinib is unlikely to inhibit P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2 in vitro at clinically relevant concentrations.1
Drugs or Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of ceritinib with potent inhibitors of CYP3A may result in increased systemic exposure of ceritinib and possible toxicity.1 When the potent CYP3A and P-gp inhibitor ketoconazole (200 mg twice daily for 14 days)6 was administered concomitantly with ceritinib (as a single 450-mg dose in a fasted state) in healthy individuals, AUC and peak plasma concentrations of ceritinib increased by 2.9-fold and 22%, respectively.1 The steady-state AUC of ceritinib following concomitant administration of the drug at a dosage of 450 mg once daily in a fasted state and ketoconazole for 14 days is expected to be similar to the steady-state AUC of ceritinib alone at a dosage of 750 mg once daily in a fasted state.1
Concomitant use of potent CYP3A inhibitors should be avoided during ceritinib therapy.1 If concomitant use of a potent CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the daily dosage of ceritinib by approximately 33% and rounding to the nearest 150-mg strength of ceritinib capsules or tablets (e.g., from 450 mg daily to 300 mg daily).1 If concomitant use of the potent CYP3A inhibitor is discontinued, the ceritinib dosage should be returned to the dosage used prior to initiation of the potent CYP3A inhibitor.1
Grapefruit products are CYP3A inhibitors and should be avoided because of the potential for increased plasma ceritinib concentrations during concomitant use.1
Concomitant use of ceritinib with potent inducers of CYP3A may result in decreased systemic exposure to ceritinib and reduced ceritinib efficacy.1 When the potent CYP3A4 and P-gp inducer rifampin (600 mg daily for 14 days)6 was administered concomitantly with ceritinib (as a single 750-mg dose) in healthy individuals, AUC and peak plasma concentrations of ceritinib decreased by 70 and 44%, respectively.1
Concomitant use of ceritinib with potent CYP3A inducers should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Ceritinib may inhibit CYP3A at clinically relevant concentrations and potentially can increase plasma concentrations of other drugs metabolized by CYP3A.1 When a single dose of the sensitive CYP3A substrate midazolam was administered concomitantly with ceritinib (750 mg once daily in a fasted state for 3 weeks), AUC and peak plasma concentration of midazolam increased 5.4- and 1.8-fold, respectively, compared with midazolam alone.1
Concomitant use of ceritinib with CYP3A substrates with a narrow therapeutic index (e.g., midazolam) should be avoided.1 If concomitant use of CYP3A substrates with a narrow therapeutic index cannot be avoided, a dosage reduction of the CYP3A substrate should be considered.1
Ceritinib may inhibit CYP2C9 at clinically relevant concentrations and potentially can increase plasma concentrations of other drugs metabolized by CYP2C9.1 When a single dose of the CYP2C9 substrate warfarin was administered concomitantly with ceritinib (750 mg once daily in a fasted state for 3 weeks), AUC of S -warfarin increased by 54% and peak plasma concentrations remained unchanged compared with warfarin alone.1 Concomitant use of ceritinib with CYP2C9 substrates that have a narrow therapeutic index (e.g., warfarin) should be avoided.1 If concomitant use of warfarin cannot be avoided, the manufacturer recommends more frequent INR monitoring for increased anticoagulant effects.1 If concomitant use of CYP2C9 substrates with a narrow therapeutic index cannot be avoided, a dosage reduction of the CYP2C9 substrate should be considered.1
Drugs Affecting Efflux Transport Systems
Ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp).1 If ceritinib is administered with drugs that inhibit P-gp (e.g., ketoconazole), increased concentrations of ceritinib may occur.1
Drugs Associated with QT Prolongation
Because ceritinib has been associated with QT-interval prolongation, the manufacturer recommends that concomitant use of ceritinib with other drugs known to prolong the QT interval be avoided, if possible.1 If concomitant use of other drugs known to prolong the QT interval cannot be avoided, the manufacturer recommends periodic monitoring of electrocardiograms (ECGs) and serum electrolytes.1
Drugs Associated with Bradycardia
Because ceritinib has been associated with bradycardia, the manufacturer recommends that concurrent use with other drugs known to cause bradycardia (e.g., β-adrenergic blocking agents, nondihydropyridine calcium-channel blocking agents [e.g., diltiazem, verapamil], clonidine, digoxin) be avoided, if possible.1
Drugs Affecting Gastric Acidity
Concomitant use of ceritinib with drugs that increase gastric pH (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) may decrease the solubility of ceritinib and subsequently reduce its bioavailability.1, 6 When ceritinib (single 750-mg dose in fasted state) was administered concomitantly with the proton-pump inhibitor esomeprazole for 6 days in healthy individuals, AUC and peak plasma concentration of ceritinib decreased by 76 and 79%, respectively.1 However, in the ASCEND-1 study, decreases in ceritinib AUC and peak plasma concentration were only 30 and 25%, respectively, in a subgroup of patients who received ceritinib (single 750-mg dose in a fasted state) with a proton-pump inhibitor (for a duration of 6 days); no clinically meaningful effect on the pharmacokinetics of ceritinib were observed in these patients at steady state.1
Ceritinib, an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), insulin-like growth factor 1 receptor (IGF-1R), insulin receptor, and c-ros oncogene-1 (ROS-1), is an antineoplastic agent.1 Among these tyrosine kinases, ceritinib is most active against ALK.1
Activating mutations or translocations of the ALK gene have been identified in several malignancies7, 17 and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).3, 8, 9, 10, 11, 15 Such ALK gene rearrangements have been identified in approximately 3-7% of patients with NSCLC.36, 38, 39 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.2, 6, 7, 9, 11 In vitro and in vivo, ceritinib has demonstrated inhibition of ALK phosphorylation,1, 3, 16 ALK-mediated phosphorylation of the downstream signaling protein signal transducer and activator of transcription-3 (STAT-3), and proliferation of ALK-dependent cancer cells.1 In vitro, ceritinib inhibited proliferation of cell lines that expressed EML4-ALK and nucleophosmin (NPM)-ALK fusion proteins.1 The drug also has demonstrated dose-dependent inhibition of EML4-ALK in mice and rats bearing NSCLC tumor xenografts that expressed EML4-ALK.1 In vitro, ceritinib is approximately 20-fold more potent than crizotinib in its activity against ALK.16
At clinically relevant concentrations, ceritinib has demonstrated dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts that expressed EML4-ALK with demonstrated resistance to crizotinib.1 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.15, 16, 36, 38, 39, 41 Limited data to date suggest that secondary mutations of ALK (e.g., L1196M, G1269A) are responsible for only about 30% of cases of acquired crizotinib resistance.15, 16 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 In preclinical studies in cell-line models, ceritinib inhibited several crizotinib-resistant ALK kinase domain mutant forms.16
Peak plasma concentrations of ceritinib are achieved about 4-6 hours following single-dose, oral administration of the drug.1 Following repeated administration of ceritinib 50-750 mg once daily, systemic exposure increases in a greater than dose-proportional manner.1 Following multiple-dose administration of ceritinib 750 mg daily, steady-state concentrations of the drug were achieved in approximately 15 days.1 Systemic exposure to ceritinib is increased when the drug is administered with food.1 Oral administration of a single 500-mg dose of ceritinib with a low-fat (approximately 330 calories and 9 g of fat) or high-fat meal (approximately 1000 calories and 58 g of fat) resulted in increases in systemic exposure of 58 or 73%, respectively, and increases in peak plasma concentrations by 43 or 41%, respectively, compared with the fasted state.1 Oral administration of a single 750-mg dose of ceritinib with a low- or high-fat meal resulted in increases in systemic exposure of 39 or 64%, respectively, and increases in peak plasma concentrations of 42 or 58%, respectively, compared with the fasted state.1 Systemic exposure to ceritinib was not substantially altered following oral administration of ceritinib 450 mg daily with food compared with administration of ceritinib 750 mg daily in a fasted state.1 Ceritinib is predominantly metabolized by the cytochrome P-450 (CYP) isoenzyme 3A.1 The drug is 97% bound to plasma proteins.1 Following oral administration of a single 750-mg radiolabeled dose of ceritinib, 92% of the dose was recovered in feces and 1.3% was recovered in urine; unchanged drug accounted for 68% of the dose recovered in feces.1 The mean terminal half-life of ceritinib is 41 hours.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. 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.
Ceritinib is available only from designated specialty distributors and pharmacies. The manufacturer should be contacted for additional information.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions October 17, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Novartis Pharmaceuticals Corporation. Zykadia® (ceritinib) capsules and tablets prescribing information. East Hanover, NJ: 2021 Oct. [Web]
2. Shaw AT, Kim DW, Mehra R et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med . 2014; 370:1189-97. [PubMedCentral][PubMed 24670165]
3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205755Orig1s000: Summary review. From FDA website. [Web]
4. US Food and Drug Administration. FDA Application: Search Orphan Drug Designations and approvals. Rockville, MD. From FDA web site. [Web]
6. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205755Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
7. Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med . 2010; 363:1693-703. [PubMedCentral][PubMed 20979469]
8. Pearson R, Kolesar JM. Targeted therapy for NSCLC: ALK inhibition. J Oncol Pharm Pract . 2011; 18:271-4. [PubMed 21844131]
9. Sasaki T, Jänne PA. New strategies for treatment of ALK-rearranged non-small cell lung cancers. Clin Cancer Res . 2011; 17:7213-8. [PubMedCentral][PubMed 22010214]
10. Food and Drug Administration. FDA news release: FDA approves Xalkori with companion diagnostic test for a type of late-stage lung cancer. Rockville, MD; 2011 Aug 26. From FDA web site. [Web]
11. Husain H, Rudin CM. ALK-targeted therapy for lung cancer: ready for prime time. J Oncology . 2011; 25:1-6.
12. Tiseo M, Gelsomino F, Bartolotti M et al. Anaplastic lymphoma kinase as a new target for the treatment of non-small-cell lung cancer. Expert Rev Anticancer Ther . 2011; 11:1677-87. [PubMed 22050016]
13. Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol . 2011; 3:113-25. [PubMedCentral][PubMed 21904575]
14. Garber K. ALK, lung cancer, and personalized therapy: portent of the future?. J Natl Cancer Inst . 2010; 102:672-5. [PubMed 20460631]
15. Iwama E, Okamoto I, Harada T et al. Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer. Onco Targets Ther . 2014; 7:375-385. [PubMedCentral][PubMed 24623980]
16. Friboulet L, Li N, Katayama R et al. The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non-Small Cell Lung Cancer. Cancer Discov . 2014; 4:662-73. [PubMedCentral][PubMed 24675041]
17. Marsilje TH, Pei W, Chen B et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem . 2013; 56:5675-90. [PubMed 23742252]
18. LDK378 versus chemotherapy in ALK rearranged (ALK positive) patients previously treated with chemotherapy (platinum doublet) and crizotinib. From ClinicalTrials.gov registry. Accessed 2014 Jun 5. [Web]
19. Pfizer Inc. New York, NY: Personal communication (crizotinib).
20. Crinò L, Kim D, Riely GJ, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol . 2011; 29 (American Society of Clinical Oncology Annual Meeting Abstracts):Abstr. No. 7514.
21. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK -positive non-small cell lung cancer (NSCLC). J Clin Oncol . 2011; 29 (Suppl.): Abstr. No. 2501.
22. Doebele RC, Pilling AB, Aisner DL et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res . 2012; 18:1472-82. [PubMedCentral][PubMed 22235099]
23. Katayama R, Shaw AT, Khan TM et al. Mechanisms of acquired crizotinib resistance in ALK -rearranged lung cancers. Sci Trans Med . 2012; 4:120ra17.
24. Anon. Ceritinib (Zykadia) for non-small cell lung cancer. Med Lett Drugs Ther . 2014; 56:62-3. [PubMed 25046419]
25. Forest Pharmaceuticals, Inc. Celexa® (citalopram hydrobromide) tablets and oral solution prescribing information. St. Louis, MO; 2012 Mar.
26. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol . 2010; 70:16-23. [PubMedCentral][PubMed 20642543]
27. LDK378 versus chemotherapy in previously untreated patients with ALK rearranged non-small cell lung cancer. From ClinicalTrials.gov registry. Accessed 2014 Aug 12. [Web]
35. Hanna NH, Robinson AG, Temin S, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol . 2021;39(9):1040-1091. doi:10.1200/JCO.20.03570
36. Zhang S, Anjum R, Squillace R et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res . 2016; 22:5527-5538. [PubMed 27780853]
37. Sabari JK, Santini FC, Schram AM et al. The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers. Onco Targets Ther . 2017; 10:1983-1992. [PubMed 28435288]
38. Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol . 2016; 8:32-47. [PubMed 26753004]
39. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol . 2014; 12:429-39. [PubMed 25322323]
41. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol . 2016; 9:19. [PubMed 26951079]
43. Soria JC, Tan DSW, Chiari R et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet . 2017; 389:917-929. [PubMed 28126333]
46. Cho BC, Kim DW, Bearz A et al. ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol . 2017; 12:1357-1367. [PubMed 28729021]
47. Chow LQM, Barlesi F, Bertino EM, et al. ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients With ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges [published online ahead of print January 28, 2022]. Clin Cancer Res . doi: 10.1158/1078-0432.CCR-21-1838
48. Zhang S, Anjum R, Squillace R et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res . 2016; 22:5527-5538. [PubMed]
49. Sabari JK, Santini FC, Schram AM et al. The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers. Onco Targets Ther . 2017; 10:1983-1992. [PubMed]
50. Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol . 2016; 8:32-47. [PubMed]
51. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol . 2014; 12:429-39. [PubMed]
52. Sasaki T, Jänne PA. New strategies for treatment of ALK-rearranged non-small cell lung cancers. Clin Cancer Res . 2011; 17:7213-8. [PubMed]
53. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol . 2016; 9:19. [PubMed]