Alectinib (Alecensa®) is a potent, highly selective, active inhibitor of anaplastic lymphoma kinase (ALK) which is taken orally. Alectinib is licensed by the European Medicines Agency (EMA) since 2017 for the first-line treatment of adult patients with ALK-positive advanced non-small cell cancer (NSCLC). The EMA-approval is based on a randomised, open-label, phase III trial comparing alectinib (600mg twice daily) with crizotinib (250mg twice daily) in patients with previously untreated, advanced ALK-positive NSCLC (the ALEX trial).

Overall, 303 patients were randomised in the ALEX trial: 152 in the alectinib group and 151 in the crizotinib group. The trial met its primary endpoint at the primary analysis, demonstrating a statistically significant increase in progression-free survival (PFS) as ascertained by both the investigator assessment and the independent review committee assessment. At the data cut-off point, 23% of patients in the alectinib arm and 27% of patients in the crizotinib arm had died, with a 1-year survival rate of 84.3% and 82.5% respectively, with a hazard ratio (HR) of 0.76 (95% confidence interval [CI], 0.48-1.20, p=0.2). Median overall survival (OS) was not reached in either treatment arm. The time to CNS progression was significantly longer with alectinib than with crizotinib in the intention-to-treat population (cause-specific HR 0.16, (95% CI, 0.10, 0.28), p<0.001); 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group. A trend favouring alectinib over crizotinib was observed for patient-reported global health status/health-related quality of life (HRQoL) (HR 0.72, 95% CI, 0.38–1.39). Overall, patients in the alectinib arm reported clinically meaningful improvement in HRQoL and improvement in multiple lung cancer symptoms for a longer duration of time than patients in the crizotinib arm, but the differences were not statistically significant. The most common (≥20%) adverse event (AEs) for alectinib were constipation (35%), oedema (30%; including peripheral oedema, oedema, generalised oedema, eyelid oedema, periorbital oedema, face oedema and localised oedema) and myalgia (28%; including myalgia and musculoskeletal pain).

In a direct comparison, based on high quality of evidence, alectinib demonstrated a substantial and statistically significant increase in PFS. It is also associated with a statistically significant longer time to CNS progression compared to crizotinib. This is of high clinical relevance as CNS metastases and progression affect both the symptoms and the quality of life, as well as the prognosis of the patients. The OS data are immature and therefore preclude firm conclusions.