The FDA ( U.S. Food and Drug Administration ) has approved Alunbrig ( Brigatinib ) for adult patients with anaplastic lymphoma kinase-positive ( ALK+ ) metastatic non-small cell lung cancer ( NSCLC ) as detected by an FDA-approved test.
This approval expands Alunbrig’s indication to include the first-line setting.
Brigatinib is a potent and selective next-generation tyrosine kinase inhibitor ( TKI ) designed to target ALK molecular alterations.
The approval is based on results from the phase 3 ALTA 1L trial, which is evaluating the safety and efficacy of Alunbrig compared to Crizotinib in adult patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.
After more than two years of follow-up, results from the ALTA 1L trial have shown demonstrated Brigatinib superiority over Crizotinib, with significant anti-tumor activity observed, especially in patients with baseline brain metastases.
Brigatinib has reduced the risk of disease progression or death twofold compared with Crizotinib ( PFS hazard ratio = 0.49 ), with a 24-month median progression-free survival ( PFS ) as assessed by a blinded independent review committee ( BIRC ) versus 11 months for Crizotinib.
Brigatinib has demonstrated a confirmed overall response rate ( ORR ) of 74% ( 95% CI: 66–81 ) for Brigatinib and 62% ( 95% CI: 53–70 ) for Crizotinib as assessed by a BIRC.
Brigatinib has demonstrated a confirmed intracranial ORR for patients with measurable brain metastases at baseline of 78% ( 95% CI: 52–94 ) for patients treated with Brigatinib and 26% ( 95% CI: 10–48 ) for patients treated with Crizotinib.
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 orally once daily with seven-day lead-in at 90 mg once daily, or Crizotinib, 250 mg orally twice daily.
The median age was 58 years in the Brigatinib arm and 60 years in the Crizotinib arm.
29% of patients had brain metastases at baseline in the Brigatinib arm versus 30% in the Crizotinib arm.
26% 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 major efficacy outcome measure. Additional efficacy outcome measures included confirmed overall response rate per RECIST v1.1 and intracranial ORR.
The warnings and precautions for Brigatinib are: interstitial lung disease ( ILD ) / pneumonitis, hypertension, bradycardia, visual disturbance, creatine phosphokinase ( CPK ) elevation, pancreatic enzyme elevation, hyperglycemia and embryo-fetal toxicity.
In the ALTA 1L trial, serious adverse reactions occurred in 33% of patients receiving Brigatinib. The most common serious adverse reactions other than disease progression were pneumonia ( 4.4% ), ILD / pneumonitis ( 3.7% ), pyrexia ( 2.9% ), dyspnea ( 2.2% ), pulmonary embolism ( 2.2% ), and asthenia ( 2.2% ).
Fatal adverse reactions other than disease progression occurred in 2.9% of patients and included pneumonia ( 1.5% ), cerebrovascular accident ( 0.7% ), and multiple organ dysfunction syndrome ( 0.7% ).
The most common adverse reactions in the ALTA 1L trial ( greater than or equal to 10% ) with Brigatinib were diarrhea ( 53% ), rash ( 40% ), cough ( 35% ), hypertension ( 32% ), fatigue ( 32% ), nausea ( 30% ), myalgia ( 28% ), dyspnea ( 25% ), abdominal pain ( 24% ), and headache ( 22% ).
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 anaplastic lymphoma kinase are key drivers in a subset of NSCLC patients.
Approximately 3-5% of patients with metastatic NSCLC have a rearrangement in the ALK gene. ( Xagena )
Source: Takeda, 2020