Lorbrexen 100

Non-small Cell Lung Cancer

Non-small Cell Lung Cancer Indications Indicated for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on the following Crizotinib and at least 1 other ALK inhibitor, OR Alectinib or ceritinib as first ALK inhibitor therapy 100 mg PO qDay with or without food Continue until disease progression or unacceptable toxicity Hepatic impairment Mild (total bilirubin ?ULN with AST >ULN or total bilirubin >1-1.5x ULN with any AST): No dose adjustment necessary Moderate or severe: Recommended dose not established

Renal impairment Mild or moderate (CrCl 30-89 mL/min): No dosage adjustment necessary Severe (CrCl <30 mL/min): Recommended dose not established

Coadministration with strong CYP3A inducers

ALK/ROS1 tyrosine kinase inhibitor ALK and ROS1 kinases promote tumor progression in ALK/ROS1 positive lung cancer; lorlatinib binds to and inhibits both kinases, which leads to a disruption of the ALK- and ROS1-mediated signaling; this disruption can subsequently inhibit tumor cell growth in ALK- and ROS1-overexpressing tumor cells

Severe hepatotoxicity occurred in healthy subjects receiving lorlatinib with rifampin, a strong CYP3A inducer; consider discontinuing lorlatinib or CYP3A inducer for persistent Grade ≥2 hepatotoxicity (see Contraindications) CNS effects (eg, seizures, hallucinations, changes in cognitive function, mood [including suicidal ideation]) may occur Increased serum cholesterol and triglycerides may occur; initiate or increase dose of lipid-lowering agents in patients with hyperlipidemia; monitor serum cholesterol and triglycerides PR interval prolongation and AV block reported; monitor ECG before initiating treatment and periodically thereafter Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur

>10% Hypercholesterolemia (96%) Hypertriglyceridemia (90%) Edema (57%) Hyperglycemia (52%) Anemia (52%) Peripheral neuropathy (47%) Increased AST (37%) Hypoalbuminemia (33%) Increased ALT (28%) Cognitive effects (27%) Dyspnea (27%) Fatigue (26%) Weight gain (24%) Increased lipase (24%) Increased alkaline phosphatase (24%) Thrombocytopenia (23%) Arthralgia (23%) Mood effects (23%) Diarrhea (22%) Increased amylase (22%) Lymphopenia (22%) Hyperkalemia (21%) Hypomagnesemia (21%) Headache (18%) Cough (18%) Nausea (18%) Myalgia (17%) Dizziness (16%) Vision disorder (15%) Constipation (15%) Rash (14%) Back pain (13%) Pain in extremity (13%) Vomiting (12%) Speech effects (12%) Pyrexia (12%) Upper respiratory tract infection (12%) Grades 3 or 4 Hypercholesterolemia (18%) Hypertriglyceridemia (18%)

Pregnancy Based on findings from animal studies and its mechanism of action, embryo-fetal harm may occur when administered to a pregnant woman No available data on use in pregnant women Advise pregnant women of the potential risk to fetus Verify pregnancy status in females of reproductive potential before initiating treatment Animal data Administration of lorlatinib to pregnant rats and rabbits by oral gavage during organogenesis resulted in malformations, increased postimplantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at 100 mg qDay Contraception Female patients of reproductive potential: Use effective nonhormonal contraception during treatment and for at least 6 months after final dose, because lorlatinib can render hormonal contraceptives ineffective Males: Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after final dose Infertility Based on animal studies, male fertility may transiently be impaired Lactation No data on presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production Because of potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment and for 7 days after final dose

CYP3A4 inducers Coadministration with strong CYP3A inducers decrease lorlatinib plasma concentrations Effect of moderate CYP3A inducer on lorlatinib plasma concentrations not studied; if coadministration unavoidable, monitor ALT, AST, and bilirubin CYP3A4 inhibitors Coadministration with strong CYP3A inhibitors increased lorlatinib plasma concentrations CYP3A substrates Coadministration with CYP3A substrates decreases concentration of CYP3A substrates, which may reduce the efficacy of these substrates Avoid use with CYP3A substrates with narrow therapeutic index; if coadministration unavoidable, increase dose of CYP3A substrate in accordance to prescribing information