Alectinib — Drug Monograph

Brand names: Alecensa

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Second-generation, highly selective ALK (anaplastic lymphoma kinase) and RET inhibitor. Potently inhibits ALK tyrosine kinase activity and the downstream signaling pathways (RAS/MEK/ERK and PI3K/AKT). Designed to overcome several crizotinib (first-generation ALK inhibitor) resistance mutations (particularly L1196M, C1156Y, F1174L); however, alectinib has limited activity against the G1202R solvent-front mutation, which is better addressed by third-generation lorlatinib. Critically, alectinib has excellent CNS penetration (P-gp efflux substrate but lower substrate affinity than crizotinib),…

FDA Indications

• ALK-positive NSCLC — first-line, metastatic (ALEX trial — superior PFS to crizotinib; HR 0.47; superior CNS activity)
• ALK-positive NSCLC — previously treated with crizotinib

Common Side Effects

• Fatigue
• Myalgia/musculoskeletal pain
• Edema (peripheral)
• Constipation
• Nausea
• Bradycardia
• Anemia
• Weight gain
• Photosensitivity (rash with sun exposure)

Clinical Pearl

Alectinib is the preferred first-line agent for ALK+ NSCLC (ALEX trial: 5-year PFS 62.5% vs. 32.5% for crizotinib; CNS response rate 81% vs. 50%). The CNS penetration of alectinib is clinically superior to crizotinib — this is paramount because ~40% of ALK+ NSCLC patients develop brain metastases. Photosensitivity is unique to alectinib in the ALK inhibitor class; patients should use SPF 50+ sunscreen daily and avoid prolonged sun exposure. Myalgia with elevated CPK is common — reassure…

Related Therapies & Mechanisms

• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor · NSCLC
• Capmatinib (Tabrecta) — Tyrosine Kinase Inhibitor · NSCLC
• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC
• Erlotinib (Tarceva) — Tyrosine Kinase Inhibitor · NSCLC