A tyrosine kinase inhibitor approved for patients with ALK-positive non-small cell lung cancer resistant to prior crizotinib.

Trade name Alunbrig.

90-180 mg daily tablets.

An anaplastic lymphoma kinase (ALK) inhibitor, is the fourth approved drug in this class.

The anaplastic lymphoma kinase (ALK) protein is a receptor tyrosine kinase of the insulin receptor family.

Has activity against ROS 1 and T790 M positive disease.

A potent inhibitor of multiple tyrosine kinases, including ALK, ROS1, IGF1R, and FLT3 but, more importantly, the broadest inhibition of ALK resistance mutations to date, including the G1202R and L1196M mutations, as well as EGFR point mutations and deletions, ROS1 mutants, and FLT3 mutants.

Oncogenic ALK fusion proteins are formed when a chromosomal translocation leads to part of the ALK gene breaking off and fusing to another gene, resulting in inappropriate activation of ALK’s kinase activity, which promotes cancer cell proliferation and survival.

ALK-positive disease is found in 3%-7% of patients with NSCLC, the number of cases of ALK-positive disease is estimated to exceed 8,000 a year in the United States.

An option for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) whose disease is no longer responding to the first-line ALK inhibitor crizotinib.

Phase 2 ALTA trial, demonstrated a significant proportion of patients experience tumor shrinkage.

The recommended dose is 90 mg orally once daily for the first seven days followed by 180 mg orally once daily.

Overall response rate for the 90-mg and 180-mg doses were 48% and 53%, respectively.

Median duration of response was 13.8 months for both doses.

Among the patients with brain metastases, the intracranial response rates for the two doses were 42% and 67%, respectively.

Progression free survival for the 90-mg and 180-mg doses were 9.2 months and 12.9 months, respectively, and estimated 1-year overall survival was 71% and 80%, respectively, the latter representing a nonstatistically significant 43% reduction in the risk of death with the 180 mg dose.

There were 4 confirmed CRs in the 180-mg arm and 1 in the 90-mg arm.

Treatment was discontinued in 8% of patients in the 180-mg arm and 3% in the 90-mg arm because of adverse events.

In treatment naïve ALK positive NSCLC patients, progression free survival was significantly longer in patients who receive brigatinib than among those who receive Crizotinib.

It is superior to crizotinib in treatment naïve patients.

It is a broad range of activity against crizotinib resistant mutations compared with alectinib.

Associated with a lower rate of intracranial disease progression compared with crizotinib -19% versus 9%, respectively.

Most common adverse effects are nausea, diarrhea, fatigue, cough, and headache, and visual disturbances.

Most common serious adverse effects are pneumonia and interstitial lung disease/pneumonitis.

Other potential toxicities include: hypertension, bradycardia, creatine phosphokinase (CPK) and pancreatic enzyme elevation, and hyperglycemia.

Drug should be withheld with new or worsening respiratory symptoms, for grade 3 hypertension, for symptomatic bradycardia, for patients with new or worsening visual symptoms, for grade 3 or 4 CPK or pancreatic enzyme elevation, or if adequate hyperglycemia control cannot be achieved.

Can cause fetal harm.

Phase 2 ALTA trial, in which a significant proportion of patients experienced tumor shrinkage: 222 patients were randomized to receive either 90 mg daily or 180 mg daily, following a 7-day lead-in at 90 mg to mitigate previously observed pulmonary adverse events. ORRs were 48% and 53% for the 90-mg and 180-mg doses, respectively.

The most common adverse events were nausea, diarrhea, fatigue, cough and headache, and visual disturbances.

Pneumonia and interstitial lung disease/pneumonitis are noted as the most serious adverse events.

The drug carries warnings about hypertension, bradycardia, creatine phosphokinase and pancreatic enzyme elevation, and hyperglycemia.

Patients should be monitored for respiratory symptoms, blood pressure and heart rate, new visual symptoms, and muscle pain.

Next-generation ALK inhibitor blocks broadest range of resistance mechanisms to date.

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