The European Commission ( EC ) has extended the marketing authorization of Alunbrig ( Brigatinib ) to include use as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase-positive ( ALK+ ) advanced non-small cell lung cancer ( NSCLC ) previously not treated with an ALK inhibitor.
The approval is based on results from the phase 3 ALTA-1L trial, which has evaluated the safety and efficacy of Brigatinib compared to Crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.
Results from the trial have shown Brigatinib demonstrated superiority compared to Crizotinib with significant anti-tumor activity observed in patients with baseline brain metastases.
After more than two years of follow-up, Brigatinib has reduced the risk of intracranial disease progression or death by 69% in patients with brain metastases at baseline ( hazard ratio [ HR ] = 0.31, 95% CI: 0.17–0.56 ), as assessed by a blinded independent review committee ( BIRC ), and has reduced the risk of disease progression or death by 76% in patients with brain metastases at baseline ( HR = 0.24, 95% CI: 0.12–0.45 ), as assessed by investigators.
Brigatinib has also demonstrated consistent overall efficacy ( intent to treat population ), with a median progression-free survival ( PFS ) more than two times longer than that with Crizotinib at 24.0 months ( 95% CI: 18.5–NE ) versus 11.0 months ( 95% CI: 9.2–12.9 ) for Crizotinib, as assessed by BIRC, and 29.4 months ( 95% CI: 21.2–NE ) versus 9.2 months ( 95% CI: 7.4–12.9 ), as assessed by investigators.
The safety profile of Brigatinib in the ALTA-1L trial was generally consistent with the existing European summary of product characteristics ( SmPC ).
The most common treatment-emergent adverse events ( TEAEs ) grade greater than or equal to 3 in the Brigatinib arm were increased CPK ( 24.3% ), increased lipase ( 14.0% ) and hypertension ( 11.8% ); and for Crizotinib were increased ALT ( 10.2% ), AST ( 6.6% ) and lipase ( 6.6% ).
The phase 3 ALTA-1L ( ALK in Lung Cancer Trial of BrigAtinib in 1st Line ) trial of Brigatinib in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients ( Brigatinib, n=137, Crizotinib, n=138 ) with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.
Patients received either Brigatinib, 180 mg once daily with seven-day lead-in at 90 mg once daily, or Crizotinib, 250 mg twice daily.
The median age was 58 years in the Brigatinib arm and 60 years in the Crizotinib arm.
Twenty-nine percent of patients had brain metastases at baseline in the Brigatinib arm versus 30% in the Crizotinib arm.
Twenty-six percent of patients received prior chemotherapy for advanced or metastatic disease in the Brigatinib arm versus 27% in the Crizotinib arm.
BIRC-assessed progression-free survival was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, intracranial ORR, intracranial progression-free survival, overall survival ( OS ), safety and tolerability.
Non-small cell lung cancer is the most common form of lung cancer, accounting for approximately 85% of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization ( WHO ).
Genetic studies have indicated that chromosomal rearrangements in ALK are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene. ( Xagena )
Source: Takeda, 2020