FDA approves Takeda's Alunbrig (brigatinib) for the treatment of crizotinib-resistant ALK-positive metastatic non-small cell lung cancer_Canghule

Takeda Pharmaceutical Co., Ltd. announced today that the U.S. Food and Drug Administration has granted accelerated approval to brigatinib 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 received accelerated approval based on tumor response rate and duration of response, and continued approval for this indication may be contingent on confirmation of clinical benefit in confirmatory trials.

Expert opinion

Clinical expert evaluation

D. Ross, director of thoracic oncology at the University of Colorado Dr. Camidge said: "In recent years, small molecule ALK inhibitors have brought revolutionary treatment options to patients with advanced ALK-positive non-small cell lung cancer. However, we still need more ALK inhibitors like brigatinib that have a manageable safety profile and can address the clinical resistance mechanisms of crizotinib, including central nervous system progression. The ALTA trial showed that Brigatinib showed excellent efficacy after treatment with crizotinib, with most patients treated with 180 mg once daily achieving overall response, with a median duration of response of more than one year. Of particular note, significant activity was also observed in patients with brain metastases."

Patient Organization Voice

Bonnie, founder of the Addario Lung Cancer Foundation. Addario said: "For patients with ALK-positive metastatic non-small cell lung cancer who have progressed or are intolerant to crizotinib, they are facing uncertainty about disease progression and the potential serious impact of brain metastases. The approval of brigatinib brings new hope."

Takeda leadership statement

R&D head's perspective

Takeda chief medical and scientific officer Andy Dr. Plump said: "The rapid development of brigatinib is due to the dedication of many scientific researchers and clinicians, who carefully designed and developed this new drug to meet the unmet medical needs of patients with ALK-positive non-small cell lung cancer. Most importantly, we would like to thank the patients and families who participated in the clinical trials."

Oncology Division President Statement

Christophe, President of Takeda Oncology Division Dr. Bianchi said: "Today's FDA approval of brigatinib is an important milestone for the treatment of ALK-positive metastatic non-small cell lung cancer, especially for those patients whose disease has progressed or are intolerant to crizotinib. Takeda is committed to continuing to develop brigatinib globally to benefit more patients in need of this therapy."

ALTA trial key data

The FDA approval is mainly based on the results of the pivotal Phase II ALTA trial. This study included 222 patients with ALK-positive advanced non-small cell lung cancer whose disease progressed after treatment with crizotinib. The primary efficacy endpoint was confirmed objective response rate as assessed by an independent review committee.

Recommended dosing regimen

The recommended dosing regimen of brigatinib is 90 mg orally once a day for the first 7 days, and then increased to 180 mg orally once a day if well tolerated.

Efficacy results

Data with a median follow-up of 8 months showed that among patients who received the recommended dosing regimen, the confirmed objective response rate was 53% as assessed by the independent review committee and 54% as assessed by the investigators. The median duration of response, as assessed by an independent review committee, was 13.8 months. Among patients with measurable brain metastases, 67% achieved confirmed intracranial objective response.

Safety Features

Important warnings and precautions for brigatinib include: interstitial lung disease/pneumonitis, hypertension, bradycardia, visual impairment, elevated creatine phosphokinase, elevated pancreatic enzymes, hyperglycemia, and embryo-fetal toxicity.

Adverse reaction data

The incidence rates of serious adverse reactions in the 90mg group and the 90→180mg group were 38% and 40% respectively. The most common serious adverse reactions were pneumonia and interstitial lung disease/pneumonitis. Fatal adverse reactions occurred in 3.7% of patients. The most common adverse reactions under the recommended dosing regimen include nausea, diarrhea, fatigue, cough and headache.

Disease background information

Non-small cell lung cancer is the most common type of lung cancer, accounting for approximately 85% of new lung cancer cases diagnosed in the United States each year. Approximately 2-8% of patients with non-small cell lung cancer have ALK gene rearrangements. The central nervous system is a common site of progression for ALK-positive non-small cell lung cancer, and up to 70% of patients treated with first-line ALK inhibitors are at risk of brain metastasis.

Drug R&D History

Brigatinib is a targeted anti-cancer drug discovered by ARIAD Pharmaceuticals. Takeda completed the acquisition of the company in February 2017. The drug has received FDA breakthrough therapy designation and orphan drug designation. In February 2017, the marketing authorization application for brigatinib was submitted to the European Medicines Agency.

Details of important safety information

Interstitial lung disease/pneumonitis

In the ALTA trial, the incidence of interstitial lung disease/pneumonitis was 3.7% in the 90mg group and 9.1% in the 90→180mg group. It is recommended to closely monitor respiratory symptoms in the early stages of treatment. If new or worsening symptoms occur, medication should be suspended and promptly evaluated.

Hypertension and bradycardia

The incidence rates of hypertension in the 90mg group and the 90→180mg group were 11% and 21% respectively. Bradycardia occurred in both groups, and regular monitoring of heart rate and blood pressure is recommended, with special attention to the risks when combined with antihypertensive drugs that can cause bradycardia.

Other important safety considerations

The incidence of visual impairment in the two groups was 7.3% and 10% respectively. Elevated creatine phosphokinase, elevated pancreatic enzymes, and hyperglycemia are also important parameters to monitor. Based on the mechanism of action and animal studies, brigatinib may cause harm to the fetus, and patients of childbearing age need to take effective non-hormonal contraceptive measures.

Drug Interaction Tips

Concomitant use with strong CYP3A inhibitors or inducers should be avoided. Coadministration with CYP3A substrates, including hormonal contraceptives, may result in decreased substrate concentrations and loss of efficacy.

Usage in Special Populations

No dose adjustment is required for patients with mild liver impairment or mild to moderate renal impairment. Safety has not been studied in patients with moderate to severe hepatic impairment or severe renal impairment. No clinically relevant safety or efficacy differences were observed between patients 65 years of age and older and younger patients.

The above information is professional medical content based on clinical data. Please follow your doctor’s instructions for specific medication.