Alectinib (AF802, AF-802, CH 5424802, RG7853, RO5424802, ALECENSA®)

Agent Description

Alectinib is a kinase inhibitor for oral administration. The molecular formula for alectinib is C₃₀H₃₄N₄O₂ • HCl. The molecular weight is 482.62 g/mol (free base form) and 519.08 g/mol (hydrochloride salt). Alectinib is described chemically as 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. Alectinib HCl is a white to yellow white powder or powder with lumps with a pKa of 7.05 (base). Alectinib is supplied as hard capsules containing 150 mg of alectinib (equivalent to 161.33 mg alectinib HCl) and the following inactive ingredients: lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium. The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, corn starch, and carnauba wax. The printing ink contains red iron oxide (E172), yellow iron oxide (E172), FD&C Blue No. 2 aluminum lake (E132), carnauba wax, white shellac, and glyceryl monooleate.

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.

Classification

Anaplastic Lymphoma Kinase (ALK) inhibitor, ALK inhibitor, tyrosine kinase inhibitor, antineoplastic agent.

Molecular Targets

ALK and RET

Monograph

Alectinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Current approval is based on data from two Phase 2 studies.

Ongoing Phase 3 studies: J-ALEX, a Japanese P3 study demonstrated alectinib superiority over crizotinib in ALK-naive, ALK+ NSCLC patients. Alectinib received breakthrough designation by the FDA based on J-ALEX data. P3 study ALEX, comparing alectinib vs crizotinib in treatment-naive, ALK+ NSCLC completed recruitment. P3 study ALUR comparing alectinib vs chemotherapy (docetaxel or pemetrexed) in ALK+ NSCLC patients previously treated with crizotinib and platinum based chemo.

Ongoing combination studies: Alectinib + Atezolizumab, Phase 1b in ALK+ NSCLC; Alectinib + Bevacizumab, Phase 1/2 in ALK+ NSCLC

Package insert: https://www.gene.com/download/pdf/alecensa_prescribing.pdf

Studies of Interest

General areas of interest:

Trials further evaluating the CNS activity of alectinib
Understanding and treating resistance mechanisms that are occurring with alectinib
Combination with other agents
Indications beyond ALK+ NSCLC

Information collaborator would like included in investigator proposals

N/A

Genentech supports non-clinical research proposals through a separate mechanism. Please visit https://www.gene.com/gene/reagents-program/reagents-program.jsp if you wish to submit a request for a Genentech agent for non-clinical work.