FDA grants accelerated approval to brigantinib for ALK NSCLC

2 May 2017
FDA grants accelerated approval to brigantinib for ALK NSCLC

The U.S. Food and Drug Administration has granted accelerated approval to brigatinib  for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

Approval was based on a non-comparative, two-arm, open-label, multicenter clinical trial demonstrating a clinically meaningful and durable overall response rate (ORR) in patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib (the ALTA Trial; NCT02094573).

All patients had tumours with a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis® ALK Break-Apart fluorescence in situ hybridization Probe Kit test.

A total of 222 patients were randomised to brigatinib orally either 90 mg once daily (n=112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (n=110).

ORR was assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. ORR was 48% (95% CI: 39%, 58%) in the 90 mg arm and 53% (95% CI: 43%, 62%) in the 180 mg arm.

After a median duration of follow-up of 8 months, median duration of response (DOR) was 13.8 months in both arms.

In patients with measurable brain metastases at baseline, intracranial ORR was 42% (95% CI: 23%, 63%) in the 90 mg arm (n=26) and 67% (95% CI: 41%, 87%) in the 180 mg arm (n=18).

Median intracranial DOR was not estimable in the 90 mg arm and was 5.6 months in the 180 mg arm.

Among patients who exhibited an intracranial response, 78% of patients in the 90 mg arm and 68% of patients in the 180 mg arm maintained an intracranial response for at least 4 months.

Safety was evaluated in 219 patients who received at least one dose of brigatinib in the ALTA trial.

“In recent years, small molecule ALK inhibitors have revolutionised the treatment options for those with advanced ALK non-small cell lung cancer. Nevertheless, there is still a need for additional ALK inhibitors like brigatinib, which have a manageable safety profile and may address mechanisms of clinical resistance to crizotinib, including progression in the central nervous system,” said D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the University of Colorado. “The ALTA trial showed that brigatinib was highly effective post-crizotinib with the majority of patients who received 180 mg once daily with a seven-day lead in at 90 mg once daily achieving an overall response and a median duration of response greater than one year. Importantly, the extent of activity among those with brain metastases was also notable.”

The most common adverse reactions, occurring in at least 25% of patients taking brigatinib, were nausea, diarrhoea, fatigue, cough, and headache.

The most common serious adverse reactions were pneumonia and ILD/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).

Visual disturbances also occurred in patients receiving brigatinib.

Adverse reactions leading to permanent discontinuation of brigatinib occurred in 2.8% and 8.2% of patients receiving 90 mg and 180 mg, respectively.

Patients receiving brigatinib should be monitored for new or worsening respiratory symptoms, hypertension, bradycardia, visual symptoms, and elevations in amylase, lipase, blood glucose, and creatine phosphokinase.

The recommended dosing regimen of brigatinib is 90 mg orally once daily for the first 7 days then, if tolerated, increase to 180 mg orally once daily.

Source: FDA