Takeda Announces EU Approval of Alunbrig (Brigatinib) as First-Line Monotherapy for ALK-Positive NSCLC

On April 6, Takeda announced that the European Commission had approved a new indication for Alunbrig (brigatinib) for the first-line treatment of ALK-positive non-small cell lung cancer (NSCLC) in patients who have not previously received an ALK inhibitor.

The European Union’s approval was primarily based on the results of the Phase III ALTA-1L study. The ALTA-1L study employed a multicenter, randomized, open-label, active-controlled design and enrolled 275 adult patients with ALK-positive locally advanced or metastatic disease who had not previously received ALK inhibitors, to evaluate the efficacy and safety differences between brigatinib and crizotinib. In the brigatinib group (n=137), 29% of patients had brain metastases at baseline, and 26% had previously received chemotherapy; in the crizotinib group (n=138), 30% had brain metastases at baseline, and 27% had previously received chemotherapy. Patients in the brigatinib group received a 7-day lead-in period at 90 mg once daily, followed by 180 mg once daily; patients in the crizotinib group received 250 mg twice daily. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee (BIRC). Secondary endpoints included overall response rate (ORR), intracranial ORR, intracranial PFS, overall survival (OS), safety, and tolerability.

The results showed that brigatinib demonstrated significantly superior efficacy compared with crizotinib in patients with brain metastases. With a follow-up of more than 2 years, BIRC assessment revealed that brigatinib reduced the risk of intracranial progression or death by 69% compared with crizotinib in patients with baseline brain metastases (HR = 0.31, 95% CI: 0.17–0.56); investigator assessment revealed that brigatinib reduced the risk of disease progression or death by 76% compared with crizotinib in patients with baseline brain metastases (HR = 0.24, 95% CI: 0.12–0.45).

The efficacy of brigatinib in the ITT population was consistent with that in the brain metastasis subgroup, with the median PFS more than doubling at 2 years of follow-up. The median PFS assessed by BIRC for the two treatment groups was 24.0 months (95% CI: 18.5–NE) and 11.0 months (95% CI: 9.2–12.9), respectively; the median PFS assessed by investigators was 29.4 months (95% CI: 21.2–NE) and 9.2 months (95% CI: 7.4–12.9), respectively.

Regarding safety, in the ALTA-1L study, the safety profile of brigatinib was generally consistent with the existing European Summary of Product Characteristics (SmPC). The most common treatment-related adverse events of Grade ≥3 included increased creatine phosphokinase (CPK) (24.3%), increased lipase (14.0%), and hypertension (11.8%). In the crizotinib group, the predominant events were increased alanine aminotransferase (ALT) (10.2%), increased aspartate aminotransferase (AST) (6.6%), and increased lipase (6.6%).

Globally, 1.8 million new cases of lung cancer are diagnosed annually, with non-small cell lung cancer (NSCLC) accounting for 85% of these cases. ALK gene rearrangements are among the more common driver oncogenic alterations in NSCLC, occurring in approximately 3% to 5% of patients with metastatic NSCLC. Brigatinib is a highly selective ALK inhibitor that was previously granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ALK-positive NSCLC who have developed resistance to crizotinib.