FDA Approves Alectinib for ALK Positive Metastatic NSCLC

ALK-rearrangement to be detected by an FDA-approved test

On 6 November 2017, the US Food and Drug Administration granted regular approval to alectinib (ALECENSA, Hoffmann-La Roche, Inc./Genentech, Inc.) for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.

In December 2015, alectinib received accelerated approval for treatment of patients with ALK-positive metastatic NSCLC whose disease progressed on or who were intolerant of crizotinib based on an independent review committee (IRC)-assessed overall response rate (ORR) of 38% and 44% among 87 and 138 patients, respectively, in two single arm trials.

This current approval is based on data from ALEX (NCT02075840), a randomised, multicentre, open-label, active-controlled trial conducted in 303 patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) CDx Assay performed through central laboratory testing. Patients were randomised 1:1 to receive alectinib 600 mg orally twice daily (n=152) or crizotinib 250 mg orally twice daily (n=151).

ALEX demonstrated an improvement in progression-free survival (PFS) as assessed by blinded IRC (BIRC), with a hazard ratio (HR) of 0.53 (95% CI: 0.38, 0.73; p < 0.0001). The estimated median PFS for patients randomised to alectinib was 25.7 months (95% CI: 19.9, not estimable [NE]) compared with 10.4 months (95% CI: 7.7, 14.6) for those randomised to crizotinib. The time to cause-specific central nervous system (CNS) progression as assessed by IRC was also significantly improved; there was a lower incidence of progression in the CNS as first site of disease progression, alone or concurrent with systemic progression, in the alectinib arm (12%) compared to the crizotinib arm (45%). Confirmed ORR was 79% (95% CI: 72, 85) and 72% (95% CI: 64, 79) in the alectinib and crizotinib arms, respectively. Among the 120 responders in the alectinib arm and the 109 responders in the crizotinib arm, the proportion of patients with response duration of ≥12 months was 64% and 36%, respectively.

CNS involvement was assessed in all patients. Among the 43 patients with measurable CNS lesions on baseline brain scans, the CNS ORR, assessed by BIRC neuro-radiologist, was 81% (95% CI: 58, 95) in the alectinib arm and 50% (95% CI: 28, 72) in the crizotinib arm. Among patients with measurable CNS lesions and a CNS response, the proportion of patients with a CNS response duration of ≥12 months was 59% in the alectinib arm and 36% in the crizotinib arm.

The most common adverse reactions (occurring in ≥20% of patients taking alectinib in ALEX) were fatigue, constipation, oedema, myalgia, and anaemia. Serious adverse reactions occurred in 28% of patients treated with alectinib. Adverse reactions leading to alectinib discontinuation occurred in 11%. Adverse reactions that led to alectinib discontinuation in 1% or more of patients were renal impairment, hyperbilirubinemia, increased alanine aminotransferase, and increased aspartate aminotransferase. Dose interruption due to adverse reactions occurred in 19% of alectinib-treated patients, while dose reductions were required in 16%.

The recommended dose of alectinib is 600 mg orally twice daily with food.

Full prescribing information is available here

FDA granted breakthrough therapy designation to alectinib for this indication in September 2016.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.