Alecinix 150

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.

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

Non-small Cell Lung Cancer 600 mg PO BID until disease progression or unacceptable toxicity Dose reduction schedule Starting dose: 600 mg PO BID First dose reduction: 450 mg PO BID Second dose reduction: 300 mg PO BID Discontinue if patients are unable to tolerate 300 mg PO BID Nephrotoxicity Grade 3: Temporarily withhold until serum creatinine recovers to ?1.5x ULN, then resume at reduced dose Grade 4: Permanently discontinue Hepatotoxicity ALT or AST elevation >5x ULN with total bilirubin (TB) ?2x ULN: Temporarily withhold until recovery to baseline or to ?3 times ULN, then resume at reduced dose ALT or AST elevation >3x ULN with TB elevation >2x ULN in absence of cholestasis or hemolysis: Permanently discontinue TB elevation >3x ULN: Temporarily withhold until recovery to baseline or to ?1.5x ULN, then resume at reduced dose Hepatic impairment Mild (TB ?ULN and AST >ULN or TB >1-1.5x ULN and any AST): No dose adjustment required Moderate-to-severe: Not studied

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

Hypersensitivity.

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

Elevated liver enzymes reported; monitor liver function tests, including ALT, AST, and total bilirubin, q2weeks during the first 2 months of treatment, then periodically during treatment, with more frequent testing in patients who develop transaminase and bilirubin elevations Interstitial lung disease (ILD) and pneumonitis reported; promptly investigate any patient who presents with worsening respiratory symptoms (eg, dyspnea, cough, fever) and immediately withhold treatment in patients diagnosed with ILD/pneumonitis Symptomatic bradycardia may occur; monitor heart rate and blood pressure regularly Severe myalgia and elevated CPK 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 Based on findings from animal studies and its mechanism of action, alectinib can cause fetal harm when administered to pregnant women Renal impairment occurred; incidence of Grade ≥3 renal impairment was 1.7%, of which 0.5% were fatal events 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

>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%)

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).