Takeda Pharmaceutical Co. Ltd. said FDA has approved the supplemental new drug application for Alunbrig (brigatinib) 180 mg tablets.
Alunbrig received an accelerated approval from the FDA in April 2017 for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib.
This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
The recommended dosing regimen for ALUNBRIG is 90 mg orally once daily for the first seven days and if tolerated, the dose is then increased to 180 mg orally once daily.
The recommended dosing regimen was supported by the results of the pivotal phase II ALTA (ALK in Lung Cancer Trial of AP26113) trial. This two-arm, open-label, multicenter trial of 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib found that, of the patients who received the recommended dosing regimen (90→180 mg), 53 percent achieved a confirmed objective response as assessed by an independent review committee.
Additionally, 67 percent of patients with measurable brain metastases who received this dosing regimen achieved a confirmed intracranial OR by IRC assessment.
In ALTA, serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. Overall, the most common serious adverse reactions were pneumonia and interstitial lung disease/pneumonitis.
Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).
At the recommended dosing regimen, the most common adverse reactions (≥25%) with Alunbrig were nausea, diarrhea, fatigue, cough, and headache. The ALTA trial is ongoing and updated data will be presented at the 18th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, Oct. 15-18, in Yokohama, Japan.
Alunbrig was discovered by ARIAD Pharmaceuticals Inc., which was acquired by Takeda in February 2017.
| APHINITY Study Results Median follow-up for intent-to-treat (ITT) population 45.4 months (381 events) | ||
| Primary endpoint: invasive disease-free survival (iDFS) HR=0.81; 95% CI 0.66-1.00, p=0.045 | ||
| Perjeta + Herceptin + chemotherapy n=2,400 | Placebo + Herceptin + chemotherapy n=2,404 | |
| iDFS at 3 years | ||
| ITT population n=4,804 | 94.1% 171 events | 93.2% 210 events |
| HR=0.81; 95% CI 0.66-1.00, p=0.045 | ||
Node-positive subgroup n=3,005 | 92.0% 139 events | 90.2% 181 events |
| HR=0.77; 95% CI 0.62-0.96, p=0.019 | ||
Node-negative subgroup n=1,799 | 97.5% 32 events | 98.4% 29 events |
| HR=1.13; 95% CI 0.68-1.86, p=0.644 | ||
| Hormone receptor-positive subgroup n=3,082 | 94.8% 100 events | 94.4% 119 events |
| HR=0.86; 95% CI 0.66-1.13, p=0.277 | ||
| Hormone receptor-negative subgroup n=1,722 | 92.8% 71 events | 91.2% 91 events |
| HR=0.76; 95% CI 0.56-1.04, p=0.085 | ||
| Estimate of iDFS at 4 years* | ||
| ITT population n=4,804 | 92.3% | 90.6% |
| Node-positive subgroup n=3,005 | 89.9% | 86.7% |
| Node-negative subgroup n=1,799 | 96.2% | 96.7% |
| Hormone receptor-positive subgroup n=3,082 | 93.0% | 91.6% |
| Hormone receptor-negative subgroup n=1,722 | 91.0% | 88.7% |
| Safety | ||
| Grade 3 or higher adverse event (AE) | 64.2% | 57.3% |
| Fatal AE | 0.8% | 0.8% |
| Primary cardiac event** | 0.7% | 0.3% |
| Difference 0.4%; 95% CI 0.0-0.8% | ||
| Most common (≥5%) severe (Grade 3 or higher) AEs | ||
| Neutropenia Decrease in a certain type of white blood cell | 16.3% | 15.7% |
| Febrile neutropenia Fever associated with decrease in a certain type of white blood cell | 12.1% | 11.1% |
| Diarrhea | 9.8% | 3.7% |
| Diarrhea Onset after chemotherapy, during targeted therapy | 0.5% | 0.2% |
| Neutrophil count decreased Decrease in a certain type of white blood cell | 9.6% | 9.6% |
| Anemia Decrease in red blood cells or hemoglobin | 6.9% | 4.7% |
* iDFS at four years was calculated based on data available at the time of primary analysis with median follow-up of 45.4 months
** Primary cardiac events included heart failure New York Heart Association (NYHA) class III or IV with left ventricular ejection fraction (LVEF) drop ≥10 points from baseline and to below 50 percent; and cardiac death
