Alectinib

Alectinib is used for: Non-small Cell Lung Cancer, Indicated for anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) ALK-positive, locally advanced or metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Non-small Cell Lung Cancer (NSCLC) Metastatic NSCLC Indicated for anaplastic lymphoma kinase (ALK)-positive, metastatic NSCLC 600 mg PO BID with food Continue until disease progression or unacceptable toxicity Adjuvant treatment Indicated as adjuvant treatment in adults following tumor resection of ALK-positive NSCLC (tumors ?4 cm or node positive) 600 mg PO BID with food Continue for a total of 2 years or until disease progression or unacceptable toxicity

Renal impairment Mild-to-moderate: No dose adjustment required Severe (CrCl <30 mL/min) or ESRD: Not studied

Should be taken with food: Swallow whole, do not open/dissolve the cap.

Hypersensitivity.

Based on findings from animal studies and its mechanism of action, alectinib can cause fetal harm when administered to pregnant women Renal impairment has occurred; the incidence of Grade >3 renal impairment was 1.7%, of which 0.5% were fatal events Hepatoxicity Severe hepatotoxicity, including drug-induced liver injury, reported Monitor liver function tests including ALT, AST, and total bilirubin every 2 weeks during the first 3 months of treatment, then once monthly and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations Modify dose as recommended Interstitial lung disease Interstitial lung disease (ILD) and pneumonitis reported Promptly investigate any patient who presents with worsening respiratory symptoms (eg, dyspnea, cough, fever) Immediately withhold treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified Severe myalgia and elevated CPK Severe myalgia and creatine phosphokinase (CPK) elevation reported Advise patients to report any unexplained muscle pain, tenderness, or weakness; assess CPK levels q2weeks for the first month of treatment and as clinically indicated in patients reporting symptoms Hemolytic anemia Hemolytic anemia was reported, including cases associated with a negative direct antiglobulin test (DAT) result If hemolytic anemia is suspected, withhold therapy and initiate appropriate laboratory testing If hemolytic anemia is confirmed, consider resuming at a reduced dose upon resolution or permanently discontinue therapy Bradycardia Symptomatic bradycardia can occur; monitor heart rate and blood pressure regularly; dose modification is not required in cases of asymptomatic bradycardia In cases of symptomatic bradycardia that is not life-threatening, withhold therapy until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications If attributable to a concomitant medication, resume therapy at a reduced dose; upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated Permanently discontinue drug in case of recurrence; permanently discontinue drug in cases of life-threatening bradycardia if no contributing concomitant medication is identified Monitoring Parameters Monitor creatine phosphokinase every 2 weeks for the first month and as clinically indicated thereafter in patients reporting symptoms of myalgia. Monitor heart rate and blood pressure as clinically indicated. Monitor liver function at baseline then every 2 weeks during the first 3 months of treatment and periodically thereafter as clinically indicated; more frequent monitoring should be performed in patients who develop aminotransferase and bilirubin elevations. Monitor for symptoms of interstitial lung disease and pneumonitis.

Pregnancy Based on animal studies and its mechanism of action, can cause fetal harm when administered to a pregnant woman There are no available data on use in humans during pregnancy Animal data Administration to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-times those observed in humans treated with alectinib at 600 mg BID Contraception Females: Use effective contraception during treatment and for 1 week after the final dose Males: Use effective contraception during treatment and for 3 months following the final dose Lactation Unknown if distributed in human breast milk Because of the potential for serious adverse reactions in breastfed infants from alectinib, advise a lactating woman not to breastfeed during treatment and for 1 week after the final dose

May increase plasma conc of co-administered substrates of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporters (eg, digoxin, dabigatran, methotrexate).

Side effects of Alectinib : >10% (All Grades) Anemia (56%) Increased AST (51%) Increased alkaline phosphatase (47%) Increased CPK (43%) Fatigue (26-41%) Hyperbilirubinemia (39%) Hyperglycemia (36%) Increased ALT (34%) Constipation (34%) Hypocalcemia (32%) Edema (22-30%) Hypokalemia (29%) Myalgia (23-29%) Increased creatinine (28%) Lymphopenia (22%) Hypophosphatemia (21%) Hyponatremia (20%) Cough (19%) Rash (15-18%) Nausea (14-18%) Headache (17%) Diarrhea (12-16%) Dyspnea (16%) Back pain (12%) Vomiting (7-12%) Bradycardia (11%) Increased weight (11%) 1-10% (All Grades Vision disorder (10%) 1-10% (Grade 3 or 4) Increased ALT (4.8%) Increased CPK (4.6%) Lymphopenia (4.6%) Vision disorders (4.6%) Hypokalemia (4%) Renal impairment (3.9%) Dyspnea (3.6%) Increased AST (3.6%) Dysgeusia (3.3%) Hypophosphatemia (2.8%) Hyperbilirubinemia (2.4%) Hyperglycemia (2%) Hyponatremia (2%) Anemia (2%) Fatigue (1.2%) Myalgia (1.2%) Diarrhea (1.2%) Increased alkaline phosphatase (1.2%) <1% (Grade 3 or 4) Edema (0.7-0.8%) Headache (0.8%) Rash (0.4-0.7%) Dysgeusia (0.7%) Nausea (0.7%) Vomiting (0.4%) Increased weight (0.4%) Hypocalcemia (0.4%)

Tyrosine kinase inhibitor that targets ALK and RET In nonclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations The major active metabolite of alectinib, M4, showed similar in vitro potency and activity Alectinib and M4 demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations identified in NSCLC tumors in patients who have progressed on crizotinib