Small Molecule Antineoplastic Anaplastic Lymphoma Kinase (ALK) Inhibitors
Administer prn antiemetics as necessary.
Administer alectinib with food.
Do not open or dissolve the contents of the capsule.
If a dose is missed, or if vomiting occurs after taking a dose, take the dose at the next scheduled time. Do not repeat doses or make up missed doses.
bradycardia / Rapid / 8.6-18.0
visual impairment / Early / 4.6-10.0
anemia / Delayed / 2.0-7.0
elevated hepatic enzymes / Delayed / 0.7-6.0
hyponatremia / Delayed / 2.0-6.0
hyperbilirubinemia / Delayed / 2.4-5.0
lymphopenia / Delayed / 1.4-4.6
renal failure (unspecified) / Delayed / 1.7-4.1
hypokalemia / Delayed / 2.0-4.0
dyspnea / Early / 0-3.6
hypophosphatemia / Delayed / 1.4-2.8
hyperglycemia / Delayed / 2.0-2.2
hyperkalemia / Delayed / 0-1.4
pneumonitis / Delayed / 0.7-1.3
myalgia / Early / 0.7-1.2
musculoskeletal pain / Early / 0.7-1.2
diarrhea / Early / 0-1.2
asthenia / Delayed / 1.2-1.2
fatigue / Early / 1.2-1.2
pulmonary embolism / Delayed / 1.2-1.2
headache / Early / 0.8-0.8
edema / Delayed / 0.7-0.8
rash / Early / 0.4-0.7
nausea / Early / 0-0.7
dysgeusia / Early / 0-0.7
hypocalcemia / Delayed / 0-0.4
vomiting / Early / 0-0.4
weight gain / Delayed / 0-0.4
GI perforation / Delayed / 0-0.4
hemolytic anemia / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
infection / Delayed / Incidence not known
constipation / Delayed / 34.0-34.0
hypoalbuminemia / Delayed / 0-14.0
neutropenia / Delayed / 0-14.0
stomatitis / Delayed / 0-3.3
QT prolongation / Rapid / 0-1.0
bleeding / Early / 0.8-0.8
erythema / Early / Incidence not known
blurred vision / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
cough / Delayed / 0-19.0
back pain / Delayed / 12.0-12.0
photosensitivity / Delayed / 5.3-9.9
pruritus / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
acneiform rash / Delayed / Incidence not known
diplopia / Early / Incidence not known
Common Brand Names
Tyrosine kinase inhibitor that targets ALK and RET
Used for the treatment of patients with ALK-positive, metastatic NSCLC
Common adverse effects include fatigue, constipation, edema, myalgia, and anemia; serious adverse reactions include hepatotoxicity, pneumonitis, bradycardia, and elevated creatine phosphokinase (CPK)
Dosage And Indications
NOTE: The FDA has designated alectinib as an orphan drug for the treatment of ALK-positive NSCLC.
NOTE: Patients should be selected based on the presence of ALK positivity in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at www.fda.gov/CompanionDiagnostics. Oral dosage Adults
600 mg orally twice daily, with food, until disease progression or unacceptable toxicity. First-line treatment with alectinib significantly improved progression-free survival (PFS) compared with crizotinib in a multicenter, open-label clinical trial of patients with ALK-positive NSCLC (34.8 months vs. 10.9 months) (the ALEX study). After 37% of events being reported, the median overall survival (OS) was not reached with alectinib versus 57.4 months with crizotinib; the 5-year OS rate was 62.5% compared with 45.5%, respectively. The overall response rate was 79% (complete response [CR] 13%) for those who received alectinib compared with 72% (CR, 6%) for patients treated with crizotinib; the CNS objective response rate was 81% (CR, 38%) versus 50% (CR, 5%), respectively. Patients with locally advanced or metastatic ALK-positive NSCLC who were treated with alectinib after progression on crizotinib had objective response rates of 38% to 48% in two multicenter, single-arm clinical trials (n = 225). In a multicenter, randomized, open-label phase 3 study, treatment with alectinib (n = 72) also significantly improved median progression-free survival compared with chemotherapy (n = 35) (9.6 months vs. 1.4 months) in patients with advanced ALK-positive NSCLC who progressed on, or were intolerant to, crizotinib. The CNS objective response rate was also significantly higher with alectinib versus chemotherapy in patients with measurable baseline CNS disease (54.2% vs. 0%).
Baseline Hepatic Impairment
Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment necessary.
Severe hepatic impairment (Child-Pugh C): Reduce the dose of alectinib to 450 mg PO twice daily.
AST/ALT more than 5 times the upper limit of normal (ULN) AND total bilirubin 2 times ULN or less: Hold alectinib. When AST/ALT recovers to less than or equal to 3 times ULN or baseline, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
AST/ALT greater than 3 times ULN AND total bilirubin greater than 2 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue alectinib.
Total bilirubin greater than 3 times ULN: Hold alectinib. When total bilirubin recovers to less than or equal to 1.5 times ULN or baseline, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
Baseline Renal Impairment
A dosage adjustment is not recommended for patients with mild to moderate renal impairment. The safety of alectinib in patients with severe renal impairment (CrCL less than 30 mL/min) or end-stage renal disease has not been studied. Alectinib is not likely to be removed by hemodialysis.
Grade 3 renal impairment: Hold alectinib. When serum creatinine (SCr) recovers to less than or equal to 1.5 times ULN, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
Grade 4 renal impairment: Permanently discontinue alectinib.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Porfimer: (Major) Avoid coadministration of porfimer with alectinib due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like alectinib may increase the risk of a photosensitivity reaction.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with alectinib is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like alectinib may increase the risk of a photosensitivity reaction.
Alecensa Oral Cap: 150mg
600 mg by mouth twice daily.Geriatric
600 mg by mouth twice daily.Adolescents
Safety and efficacy have not been established.Children
Safety and efficacy have not been established.Infants
Safety and efficacy have not been established.Neonates
Safety and efficacy have not been established.
Mechanism Of Action
Alectinib is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and RET. Alectinib, a CNS-active and highly selective ALK inhibitor, inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT in nonclinical studies. It also decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite is M4, which has shown similar in vitro potency and activity. Alectinib and M4 have demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations in NSCLC tumors in patients who have progressed on crizotonib. Administration of alectinib resulted in antitumor activity and prolonged survival in mouse models implanted with tumors carrying ALK fusions, including mouse models implanted intracranially with ALK-driven tumor cell lines.
Alectinib is administered orally. Alectinib and its major metabolite, M4, are greater than 99% bound to plasma proteins, independent of drug concentration. The apparent volume of distribution (Vd) is 4,016 liters for alectinib and 10,093 liters for M4; alectinib concentrations in the cerebrospinal fluid of patients with ALK-positive NSCLC approximate the estimated alectinib free concentrations in the plasma. The apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4; the geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4. Steady-state concentrations are reached by day 7 of administration. The geometric mean accumulation was approximately 6-fold for both alectinib and M4. Ninety-eight percent of radioactivity was excreted in feces after oral administration of a single radiolabeled dose of alectinib under fed conditions; 84% of the dose was unchanged alectinib and 6% was M4. Excretion in the urine was less than 0.5% of the radiolabeled dose.
Affected cytochrome (CYP) 450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), and BCRP
Alectinib is metabolized by CYP3A4 to its major active metabolite, M4; M4 is subsequently also metabolized by CYP3A4. The mean metabolite/parent exposure ratio is 0.4 at steady state; alectinib and M4 account for 76% of the total radioactivity after a dose. In vitro studies suggest that alectinib is not a substrate of P-gp, but M4 is. Additionally, both alectinib and M4 inhibit P-gp and BCRP in vitro. Pharmacokinetic drug interactions with alectinib requiring dosage adjustments have not been identified. Alectinib and M4 are not substrates of BCRP, OATP1B1, or OATP1B3, and do not inhibit CYP1A2, 2B6, 2C9, 2C19, or 2D6. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 in vitro.
The maximal concentration (Cmax) for alectinib at steady-state was 665 ng/mL (CV, 44%) and was 246 ng/mL (CV, 45%) for M4, with a peak to trough concentration ratio of 1.2; the time to maximal concentration (Tmax) was was 4 hours. The geometric mean AUC at steady-state from 0 to 12 hours was 7,430 ng x h/mL (CV, 46%) for alectinib and 2,810 ng x h/mL (CV, 46%) for M4. Alectinib exposure is dose proportional between 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dose) under fed conditions. The absolute bioavailability (F) of alectinib was 37% (90% CI, 34% to 40%) under fed conditions; a high fat, high-calorie meal increased the AUC of alectinib plus M4 by 3.1-fold (90% CI, 2.7 to 3.6-fold) after oral administration of a single 600-mg dose.
Pregnancy And Lactation
Although there are no adequate and well-controlled studies in pregnant women, alectinib may cause fetal harm when administered during pregnancy. When administered to pregnant rabbits during organogenesis, abortion or complete embryo-fetal mortality occurred in 3 of 6 rabbits exposed to 2.9-fold the estimated AUC in humans treated with the recommended dose of 600 mg twice daily; the remaining 3 rabbits had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In pregnant rats, administration of alectinib during organogenesis at approximately 4.5-fold the AUC in humans at the recommended dose resulted in complete litter loss. Exposures of approximately 2.7-fold the estimated human AUC in humans at the recommended dose resulted in maternal toxicity in addition to decreased fetal weight, dilated ureter, thymic cord, small ventricle, and thin ventricle wall, and reduced number of sacral and caudal vertebrae.
It is not known whether alectinib is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from alectinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose.