1 INDICATIONS AND USAGE
1.1 Adjuvant Treatment of Resected ALK-Positive Non-Small Cell Lung Cancer (NSCLC)
ALECENSA is indicated as adjuvant treatment in adult patients following tumor resection of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) (tumors ≥ 4 cm or node positive), as detected by an FDA-approved test [see Dosage & Administration (2.1)].
1.2 Treatment of Metastatic ALK-Positive NSCLC
ALECENSA is indicated for the treatment of adult patients with ALK-positive metastatic NSCLC as detected by an FDA-approved test [see Dosage & Administration (2.1)].
2. DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients with resectable tumors for the adjuvant treatment of NSCLC with ALECENSA based on the presence of ALK positivity in tumor tissue [see Indications and Usage (1.1) and Clinical Studies (14.1)].
Select patients for the treatment of metastatic NSCLC with ALECENSA based on the presence of ALK positivity in tumor tissue or plasma specimens [see Indications and Usage (1.2) and Clinical Studies (14.2)].
If ALK rearrangements are not detected in a plasma specimen, test tumor tissue if feasible.
Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Alectinib is a 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. In mouse models implanted with tumors carrying ALK fusions, administration of alectinib resulted in antitumor activity and prolonged survival, including in mouse models implanted intracranially with ALK-driven tumor cell lines.
12.3 Pharmacokinetics
Elimination
Metabolism: Alectinib is metabolized by CYP3A4 to its major active metabolite M4. The geometric mean metabolite/parent exposure ratio at steady-state is 0.40. M4 is subsequently metabolized by CYP3A4. Alectinib and M4 were the main circulating moieties in plasma, constituting 76% of the total radioactivity.