Alectinib hydrochloride, an inhibitor of several receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), is an antineoplastic agent.1, 6, 8, 9, 11
Alectinib is used for the treatment of metastatic non-small cell lung cancer (NSCLC) in adult patients whose cancer is anaplastic lymphoma kinase ( ALK )-positive as detected by an FDA-approved diagnostic test.1, 2, 3 The drug has been designated an orphan drug by FDA for use in this condition.4 Alectinib is also used as adjuvant treatment in adults following tumor resection of ALK -positive NSCLC (tumors ≥4 cm or node positive), as detected by an FDA-approved test.1
Treatment of Metastatic ALK-Positive NSCLC
The indication for alectinib in the treatment of ALK -positive metastatic NSCLC is based principally on the results of a multicenter, open-label, randomized phase 3 study (ALEX) in patients with previously untreated metastatic disease and 2 noncomparative phase 2 studies (NP28761 and NP28673) in patients whose cancer had progressed during crizotinib therapy.1, 2, 3, 38
In the ALEX study, 303 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 alectinib (600 mg orally twice daily) or crizotinib (250 mg orally twice daily) until disease progression or unacceptable toxicity.1, 38 The primary measure of efficacy was progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1); additional outcome measures included time to progression of brain metastases as assessed by an independent review committee (IRC), overall response rate, duration of response, overall survival, and IRC-assessed progression-free survival.1, 38 Presence of ALK rearrangement was determined using an FDA-approved diagnostic test (e.g., Ventana ALK [D5F3] CDx assay).1 The median age of patients enrolled in the study was 56 years; 50% of patients were white, 46% were Asian, 56% were female, 63% had never smoked, and 92% had adenocarcinoma histology.1, 38 Approximately one-half (40%) of patients had brain metastases at baseline and 35% of these patients had measurable brain metastases at baseline.1
In the ALEX study, median IRC-assessed progression-free survival was prolonged in patients receiving alectinib compared with those receiving crizotinib (25.7 versus 10.4 months; hazard ratio: 0.53).1, 38 Overall response rate (as assessed by the IRC) in patients receiving alectinib or crizotinib was 79 or 72%, respectively; complete response was achieved in 13 or 6% of patients receiving these respective treatments.1 At the time of analysis, 82, 64, or 37% of patients who responded to alectinib had durable responses of 6, 12, or 18 months or more, respectively, and 57, 36, or 14% of patients who responded to crizotinib had durable responses of 6, 12, or 18 months or more, respectively.1 Median overall survival had not been reached at the time of analysis.1 In the subgroup of 43 patients with measurable brain metastases at baseline, CNS overall response rate was 81 or 50% in patients receiving alectinib or crizotinib, respectively; complete response was achieved in 38 or 5% of patients receiving these respective treatments.1 At the time of analysis, durable responses of 12 months or more were observed in 59 or 36% of alectinib- or crizotinib-treated patients, respectively, with measurable brain metastases at baseline.1
In the NP28761 and NP28673 studies, 225 adults (87 patients in the NP28761 study and 138 in the NP28673 study) with locally advanced or metastatic ALK-positive NSCLC (as detected by an FDA-approved diagnostic test) who had experienced disease progression during crizotinib therapy received alectinib (600 mg orally twice daily).1, 2, 3 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.2, 3 Most patients enrolled in both studies had received systemic chemotherapy prior to crizotinib therapy for NSCLC, and, among those with CNS metastases, most had received CNS radiation therapy.1, 2, 3 The primary efficacy end point in both studies was the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by an IRC.1, 2, 3 The objective response rate and duration of response in the CNS in patients with CNS metastases were key secondary end points.1, 2, 3 IRC-assessed objective response rates with alectinib therapy were 38 and 44% in the NP28761 and NP28673 studies, respectively, and investigator-assessed objective response rates were 46 and 48%, respectively; all responses were partial responses.1 The median IRC-assessed duration of response was 7.5 and 11.2 months in the NP28761 and NP28673 studies, respectively.1
In the subgroup of 51 patients in both studies with baseline measurable CNS metastases according to RECIST 1.1 criteria, the CNS objective response rate with alectinib therapy was 61% (18% complete responses and 43% partial responses) and the median duration of CNS response was 9.1 months.1 CNS responses were observed irrespective of prior CNS irradiation.1
Alectinib also was compared with chemotherapy in a randomized, multicenter, open-label, phase 3 (ALUR) study.39 In the ALUR study, 107 patients with advanced or metastatic ALK -positive NSCLC previously treated with 2 prior lines of systemic therapy (including a platinum-based doublet chemotherapy and crizotinib therapy) were randomized in a 2:1 ratio to receive either alectinib 600 mg orally twice daily or chemotherapy (pemetrexed 500 mg/m2 IV every 3 weeks or docetaxel 75 mg/m2 IV every 3 weeks).39 Treatment was continued until disease progression, death, or withdrawal.39 The median age of patients was approximately 56 years in the alectinib-treated group and 59 years in the chemotherapy-treated group; approximately 82% of patients were white, 47% were females, and 100% had adenocarcinoma histology.39 In the alectinib-treated group, 6.9% of patients were Asian and 48.6% had never smoked.39 In the chemotherapy-treated group, 20% of patients were Asian and 45.7% had never smoked.39 At baseline, CNS metastases were present in 65.3 or 74.3% of patients randomized to alectinib or chemotherapy, respectively; 59.6 or 57.7% of these patients, respectively, had received treatment for CNS metastases.39
The primary end point in the ALUR study (investigator-assessed progression-free survival) was substantially greater in patients receiving alectinib compared with those receiving chemotherapy (9.6 versus 1.4 months; hazard ratio, 0.15; 95% confidence interval, 0.08-0.29).39 CNS objective response rate in patients with measurable baseline CNS disease also was substantially improved in patients receiving alectinib (54.2%) compared with those receiving chemotherapy (0%).39
Adjuvant Treatment of Resected ALK-Positive NSCLC
The indication for alectinib in the adjuvant treatment of resected ALK -positive NSCLC is based principally on the results of an open-label, randomized, phase 3 study (ALINA) in patients who had completely resected, histologically confirmed stage IB (tumors ≥4 cm), II, or IIIA NSCLC with documented ALK -positive disease.1, 42 Additionally, enrolled patients had to be eligible for platinum-based chemotherapy, an ECOG performance status of 0 or 1, and no prior systemic anticancer therapy.42 In ALINA, 257 patients were randomly assigned to alectinib 600 mg orally twice daily or IV platinum-based chemotherapy for 4 cycles, with each cycle lasting 21 days.1, 42 Treatment with alectinib continued for 24 months or until disease recurrence, unacceptable toxicity, or withdrawal of consent, whichever first.1, 42 The primary end point was disease-free survival, defined as time from randomization to the first documented disease recurrence, new primary NSCLC, or death from any cause.1, 42 Overall survival was a secondary end point.1, 42
The median age of patients enrolled in the study was 56 years (range, 26-87 years); 42% of patients were white, 56% were Asian, 0.4% were Black or African American, 0.4% were Hispanic or Latino, 52% were female, 60% had never smoked, and 53% had an ECOG performance status of 0.1 In the ALINA study, alectinib therapy was associated with a significant improvement in disease-free survival as compared to chemotherapy1, 42 The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63% in the chemotherapy group among patients with stage II or IIIA NSCLC.42 Overall survival data were not mature at the time of study publication.1, 42
Approximately 60% of patients with lung cancer have driver alterations (e.g., mutations in EGFR , ALK , or BRAF ; ROS-1 fusions, RET fusions, MET exon 14 skipping mutations, and NTRK fusions).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, lorlatinib).8, 9, 10, 40 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.8, 9, 10, 11
First-line Therapy for Metastatic 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 In a recent update, ASCO states that alectinib, brigatinib, or lorlatinib should be offered in the first-line setting in patients with stage IV NSCLC and driver alterations in ALK .43 ASCO also states that if alectinib, brigatinib, or lorlatinib are not available, ceritinib or crizotinib should be offered in the first-line setting.43
In the second-line setting, ASCO states that alectinib, brigatinib, or ceritinib should be offered in patients who received initial therapy with crizotinib.43 ASCO also states that for patients who previously received other ALK inhibitors including alectinib or brigatinib, clinicians may offer lorlatinib.43
The International Association for the Study of Lung Cancer recommends that, at a minimum, determination of EGFR and ALK alteration status is required for patients under consideration for neoadjuvant or adjuvant systemic therapy.44 The Association recommends adjuvant alectinib for patients with stage IB (tumors ≥4 cm) to IIIA disease with ALK alterations.44 Adjuvant chemotherapy prior to alectinib may be considered at provider discretion.44
Alectinib hydrochloride is administered orally twice daily with food.1 The capsules should be swallowed whole and should not be dissolved or opened.1
If a dose of alectinib is missed or vomiting occurs after administration of a dose, take the next dose at the regularly scheduled time.1
Do not store the capsules at temperatures above 30°C.1 Store in the original container to protect the drug from light and moisture.1
Dosage of alectinib hydrochloride is expressed in terms of alectinib.1
The recommended adult dosage of alectinib for the treatment of ALK -positive metastatic non-small cell lung cancer (NSCLC) is 600 mg orally twice daily.1 Alectinib therapy should be continued until disease progression or unacceptable toxicity occurs.1
The recommended adult dosage of alectinib for the adjuvant treatment of ALK -positive resected NSCLC is 600 mg orally twice daily.1 Alectinib therapy should be continued for a total of 2 years or until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
When dosage reduction is necessary, an initial dosage reduction to 450 mg twice daily is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 300 mg twice daily.1 If a dosage of 300 mg twice daily is not tolerated, alectinib should be discontinued.1
If an elevation in serum ALT or AST concentrations exceeding 5 times the upper limit of normal (ULN) occurs with a total bilirubin concentration of no more than 2 times the ULN, alectinib therapy should be withheld until liver function test results return to baseline values or decrease to no more than 3 times the ULN.1 Alectinib therapy may then be resumed at a reduced dosage.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 alectinib should be permanently discontinued.1
If an elevation in total bilirubin concentrations exceeding 3 times the ULN occurs, alectinib therapy should be withheld until total bilirubin concentrations return to baseline values or decrease to no more than 1.5 times the ULN.1 Alectinib therapy may then be resumed at a reduced dosage.1
Interstitial Lung Disease/Pneumonitis
If treatment-related interstitial lung disease/pneumonitis of any grade occurs, alectinib therapy should be permanently discontinued.1
If grade 3 renal impairment occurs, alectinib therapy should be withheld until serum creatinine improves to 1.5 times the ULN or less.1 Alectinib therapy may then be resumed at a reduced dosage.1
If grade 4 renal impairment occurs, alectinib therapy should be permanently discontinued.1
If symptomatic, but non-life-threatening, bradycardia occurs, therapy with alectinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of at least 60 beats/minute.1 If concomitant drugs known to cause bradycardia or hypotension are identified and the dosage of the concomitant drug can be adjusted or the drug can be discontinued, alectinib therapy can be resumed at the previous dosage upon recovery to asymptomatic bradycardia or to a heart rate of at least 60 beats/minute.1 If dosage adjustment or discontinuance of such concomitant drugs is not possible, or if no concomitant contributory drugs are identified, alectinib should be resumed at a reduced dosage upon recovery to asymptomatic bradycardia or to a heart rate of at least 60 beats/minute.1
If life-threatening bradycardia or bradycardia requiring urgent intervention occurs in patients receiving concomitant drugs known to cause bradycardia or hypotension, therapy with alectinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of at least 60 beats/minute.1 If the dosage of the concomitant drug can be adjusted or the drug can be discontinued, alectinib therapy may then be resumed at a reduced dosage with frequent monitoring; alectinib therapy should be permanently discontinued in case of recurrence.1
If life-threatening bradycardia or bradycardia requiring urgent intervention occurs in patients not receiving concomitant therapy with drugs known to cause bradycardia or hypotension, alectinib therapy should be permanently discontinued.1
If an elevation in serum CK concentrations exceeding 5 times the ULN occurs, alectinib therapy should be withheld until serum CK concentrations return to baseline values or decrease to no more than 2.5 times the ULN.1 Alectinib therapy may then be resumed at the previous dosage.1 If an elevation in serum CK concentrations exceeding 5 times the ULN recurs , alectinib therapy should be withheld until serum CK concentrations return to baseline values or decrease to no more than 2.5 times the ULN; alectinib therapy may then be resumed at a reduced dosage.1
If an elevation in serum CK concentrations exceeding 10 times the ULN occurs, alectinib therapy should be withheld until serum CK concentrations return to baseline values or decrease to no more than 2.5 times the ULN.1 Alectinib therapy may then be resumed at a reduced dosage.1
Withhold alectinib if hemolytic anemia is suspected and initiate appropriate testing.1 If hemolytic anemia is confirmed, consider resuming alectinib at a reduced dosage upon resolution or permanently discontinue the drug.1
No initial dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. 1 For patients with severe hepatic impairment (Child-Pugh class C), the manufacturer recommends an alectinib dosage of 450 mg twice daily.1
No initial dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 Pharmacokinetics and safety of alectinib have not been established in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) or end-stage renal disease.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe hepatotoxicity, including drug-induced liver injury, has been reported in patients receiving alectinib.1 In a pooled safety analysis, hepatotoxicity occurred in 41% of patients, with grade ≥3 hepatotoxicity reported in 8%.1 In the adjuvant therapy clinical trial (ALINA), hepatotoxicity was seen in 61% of patients administered alectinib, with grade ≥3 hepatotoxicity occurring in 4.7%.1 Most patients experienced elevated transaminases during the initial 3 months of treatment.1 Discontinuation of alectinib due to hepatotoxicity occurred in 3.6% of patients in the pooled analysis and 1.6% of patients in the ALINA study.1
In the pooled safety analysis, elevations in ALT or AST concentrations of 3 or more times the ULN with total bilirubin concentrations of 2 or more times the ULN and alkaline phosphatase concentrations within normal limits were reported in less than 1% of alectinib-treated patients.1 Drug-induced liver injury with grade 3-4 AST/ALT elevations was reported in 3 patients.1
The manufacturer states that liver function tests, including ALT, AST, and total bilirubin concentrations, should be monitored every 2 weeks for the first 3 months of alectinib therapy, then once every month, and as clinically indicated, with more frequent testing in patients who develop aminotransferase or bilirubin elevations during therapy.1 Temporary interruption followed by dosage reduction or permanent discontinuance of alectinib may be necessary depending on the severity of the hepatic toxicity.1
Interstitial Lung Disease/Pneumonitis
Interstitial lung disease (ILD)/pneumonitis may occur in patients receiving alectinib.1 In a pooled safety analysis, ILD/pneumonitis occurred in 1.3% of alectinib-treated patients; grade 3 ILD/pneumonitis occurred in 0.4% of patients.1 Discontinuation of therapy due to ILD/pneumonitis occurred in 5 patients.1 The median time to onset of grade ≥3 ILD/pneumonitis was 2.1 months (range, 0.6-3.6 months).1
Patients receiving alectinib should be monitored for pulmonary symptoms indicative of ILD or pneumonitis, and other potential causes of ILD or pneumonitis should be excluded.1 Alectinib should be permanently discontinued in patients who are diagnosed with treatment-related ILD or pneumonitis of any grade.1
Renal impairment, sometimes with fatal outcome, has occurred in patients receiving alectinib.1 In a pooled safety analysis, renal impairment was reported in 12% of alectinib-treated patients; 1.7% of patients receiving the drug experienced grade 3 or greater renal impairment (0.4% of these events resulted in death).1 The median time to grade 3 or 4 renal impairment was 3.7 months (range, 0.5-31.8 months).1 Dosage modification of alectinib was necessary because of renal impairment in 2.4% of patients.1
Temporary interruption followed by dosage reduction or permanent discontinuance of alectinib may be necessary depending on the severity of renal impairment.1
Alectinib may cause symptomatic bradycardia.1 In a pooled safety population, bradycardia (defined as a heart rate of less than 60 beats/minute) was reported in 11% of alectinib-treated patients; a heart rate of less than 50 beats/minute was reported in 20% of patients in whom serial ECGs were obtained.1
Heart rate and blood pressure should be monitored regularly in all patients receiving alectinib.1 For asymptomatic bradycardia, dose modification is not required.1 If symptomatic bradycardia occurs, temporary interruption of alectinib therapy, subsequent dosage reduction, or permanent discontinuance of the drug may be necessary depending on the severity of the bradycardia, the concomitant use of drugs known to cause bradycardia or hypotension, and the feasibility of modifying such concomitant therapy.1 Any concomitantly used drugs that may cause bradycardia or hypotension should be identified and the dosage should be adjusted or the drug should be discontinued if possible.1
Severe Myalgia and Creatine Kinase Elevation
Severe myalgia and creatine kinase (CK) elevation have been reported with alectinib therapy.1 In a pooled safety analysis, myalgia events were reported in 31% of alectinib-treated patients; 0.8% of patients receiving the drug experienced grade 3 or greater myalgia events.1 Elevated serum CK (creatine phosphokinase, CPK) concentrations were reported in 56% of patients receiving alectinib; 6% of patients receiving the drug had grade 3 or greater elevations in CK concentrations.1 Median time to grade 3 or greater CK elevations was 15 days (interquartile range, 15-337 days).1 Dosage modification because of myalgia events or elevated serum CK concentrations was required in 2.1 or 5%, respectively, of patients.1 In ALINA, elevated CK levels were reported in 77% of patients, with grade 3 or greater elevations occurring in 6%.1
The manufacturer states that serum CK concentrations should be monitored every 2 weeks for the first month of alectinib therapy and as clinically indicated in patients reporting muscle symptoms (e.g., unexplained or persistent muscle pain, tenderness, or weakness).1 Temporary interruption followed by dosage reduction or permanent discontinuance of alectinib may be necessary depending on the severity of the CK elevation.1
Hemolytic anemia, including cases associated with a negative direct antiglobulin test result, have been reported in patients receiving alectinib.1 In the ALINA study, hemolytic anemia was reported in 3.1% of patients administered alectinib.1
Withhold alectinib if hemolytic anemia is suspected and initiate appropriate testing.1 If hemolytic anemia is confirmed, consider resuming alectinib at a reduced dosage upon resolution or permanently discontinue the drug.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, alectinib may cause fetal harm.1 There are no adequate and well-controlled studies in humans; developmental toxicity, abortion, and embryolethality were observed when alectinib was administered to pregnant animals at maternally toxic dosages.1 Pregnancy should be avoided during therapy.1 If alectinib 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
Based on findings from animal studies and its mechanism of action, alectinib may cause fetal harm if administered to pregnant females.1
It is not known whether alectinib or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to alectinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 1 week after the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiation of alectinib therapy.1 Females of reproductive potential should use effective methods of contraception while receiving the drug and for 5 weeks after the last dose.1
Males with female partners of reproductive potential should use effective methods of contraception while receiving the drug and for 3 months after the last dose.1
Safety and efficacy of alectinib have not been established in pediatric patients.1 In animal toxicology studies, alectinib has been associated with changes in growing teeth (discoloration, changes in tooth size, histopathologic disarrangement of ameloblast and odontoblast layers) and bones (decreases in trabecular bone, increased osteoclast activity).1
In clinical studies, 19% of 533 patients were 65 years of age and older and 3.2% were 75 years of age and older.1 No overall differences in effectiveness based on age were observed.1 Exploratory analysis suggests that patients 65 years of age or older experience an increased incidence of serious adverse events (38% versus 25%), more adverse events leading to treatment discontinuation (18% versus 6%), and more adverse events leading to dose modifications (48% versus 35%) as compared to patients younger than 65 years of age.1
Mild hepatic impairment (Child-Pugh class A) did not have clinically important effects on systemic exposure to alectinib and its M4 metabolite.1 Following administration of a single 300-mg dose of alectinib, moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment increased the area under the concentration-time curve (AUC) of the total active forms of alectinib (i.e., alectinib plus M4) by 36 or 76%, respectively, compared with individuals with normal hepatic function; peak plasma concentration of the total active forms of alectinib was similar to that reported in individuals with normal hepatic function.1 Dosage adjustment is required in patients with severe hepatic impairment.1
Mild to moderate renal impairment (creatinine clearance of 30-89 mL/minute) did not have clinically important effects on systemic exposure to alectinib and its M4 metabolite.1 Pharmacokinetics and safety of alectinib have not been established in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) or end-stage renal disease.1
Hemodialysis is not expected to enhance clearance of alectinib because the drug and its M4 metabolite are extensively bound to plasma proteins.1
Adverse effects reported in 20% or more of patients receiving alectinib in clinical trials include hepatotoxicity, constipation, fatigue, myalgia, edema, rash, and cough.1
Clinically important drug interactions with alectinib have not been identified to date.1
Alectinib is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 to its major active metabolite, M4.1 In vitro studies suggest that M4, but not alectinib, is a substrate of P-glycoprotein (P-gp); neither alectinib nor M4 is a substrate of breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, or OATP1B3.1
In vitro studies indicate that alectinib and M4 do not inhibit CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 2D6.1 Alectinib also does not inhibit OATP1B1 or OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2 in vitro.1
In vitro studies suggest that alectinib and M4 inhibit P-gp and BCRP.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Clinically important drug interactions with alectinib have not been identified to date.1 Concomitant administration of alectinib and posaconazole (a potent CYP3A inhibitor) or rifampin (a potent CYP3A inducer) did not have a clinically important effect on the combined systemic exposure to alectinib and its M4 metabolite.1 Clinically important pharmacokinetic interactions between alectinib and midazolam (a CYP3A substrate) or repaglinide (a CYP2C8 substrate) are unlikely.1
Drugs Associated with Bradycardia
Alectinib has been associated with bradycardia.1 If clinically important bradycardia occurs with concomitant use of alectinib and other drugs known to cause bradycardia (including hypotensive agents), the dosage of the concomitant drug should be adjusted or the concomitant drug should be discontinued, if possible.1
Drugs Affecting Gastric Acidity
Concomitant administration of alectinib and esomeprazole did not have a clinically important effect on the combined systemic exposure to alectinib and its M4 metabolite.1
Alectinib hydrochloride, an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK) and ret proto-oncogene (RET), is an antineoplastic agent.1, 6, 8, 9, 11, 13 The drug inhibits ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins signal transducer and activator of transcription 3 (STAT3) and AKT serine/threonine kinase.1 The drug also inhibits leukocyte tyrosine kinase receptor (LTK) and cyclin-G-associated kinase (GAK).6, 8, 9
Activating mutations or translocations of the ALK gene have been identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).6, 7, 8, 9, 10, 11 Such ALK gene rearrangements have been identified in approximately 3-7% of patients with non-small cell lung cancer (NSCLC).8, 9, 10, 36 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.9, 10, 11
Although the ALK inhibitor 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.7, 8, 9, 11, 36 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.7, 8, 9, 11, 36, 37 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.7, 11, 12
In vitro, alectinib is approximately fivefold more potent than crizotinib in its activity against ALK.3 Alectinib demonstrated dose-dependent antitumor activity and increased survival in mice bearing NSCLC tumor xenografts that expressed EML4-ALK, including several cell lines with demonstrated resistance to crizotinib.1, 6, 7 In preclinical studies in vitro and in vivo, alectinib was active against several crizotinib-resistant ALK mutations (e.g., L1196M, C1156Y, F1174L, G1269A).1, 6, 8, 9
The CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of crizotinib into CSF;2, 6, 8, 9, 11, 12, 13, 36, 37 development and/or progression of brain metastases occurs in approximately one-half of patients during crizotinib treatment.3, 8 Alectinib crosses the blood-brain barrier, distributing into CSF at concentrations similar to estimated alectinib free plasma concentrations;1 the drug demonstrated antitumor activity and increased survival in mice bearing intracranial ALK -positive NSCLC tumor xenografts.1, 6, 13 In clinical studies, alectinib demonstrated antitumor activity in patients with crizotinib-resistant disease and baseline CNS metastases.1, 8, 12, 13
Exposure to alectinib is dose proportional over the oral dose range of 460-900 mg in the fed state.1 Following oral administration under fed conditions, peak plasma concentrations of alectinib are achieved within 4 hours.1 Steady-state concentrations of alectinib and its major active metabolite (M4) are achieved within 7 days.1 The absolute oral bioavailability of alectinib under fed conditions is 37%.1 Oral administration of a single 600-mg dose of the drug with a high-calorie, high-fat meal increases total systemic exposure to alectinib and M4 by 3.1-fold compared with administration in the fasting state.1 Alectinib and M4 are more than 99% bound to plasma proteins; the drug distributes into CSF at concentrations similar to estimated alectinib free plasma concentrations.1 Alectinib is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 to its major active metabolite, M4, which also is metabolized by CYP3A4.1 M4 exhibits in vitro potency and activity similar to those of alectinib.1 Following oral administration of radiolabeled alectinib, 98% of the dose is eliminated in feces, mainly as unchanged drug (84%) and, to a lesser extent, as M4 (6%); less than 0.5% of the dose is eliminated in urine.1 The mean elimination half-lives of alectinib and M4 in patients with ALK -positive NSCLC are 33 and 31 hours, respectively.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.
Alectinib is available only from designated specialty distributors and pharmacies.5 The manufacturer should be contacted for additional information.5
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions November 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech USA, Inc. Alecensa® (alectinib hydrochloride) capsules prescribing information. South San Francisco, CA; 2024 Apr. [Web]
2. Shaw AT, Gandhi L, Gadgeel S et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol . 2016; 17:234-42. [PubMed 26708155]
3. Ou SH, Ahn JS, De Petris L et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol . 2016; 34:661-8. [PubMed 26598747]
4. US Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Rockville, MD. From FDA website. [Web]
5. Genentech USA, Inc. Authorized Specialty Distributors. Accessed 2024 Sept 30. From Genentech Access Solutions® website. [Web]
6. McKeage K. Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer. Drugs . 2015; 75:75-82. [PubMed 25428710]
7. Song Z, Wang M, Zhang A. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance. Acta Pharm Sin B . 2015; 5:34-7. [PubMedCentral][PubMed 26579422]
8. 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. [PubMedCentral][PubMed 26753004]
9. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol . 2014; 12:429-39. [PubMedCentral][PubMed 25322323]
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