FDA Grants Accelerated Approval to Brigatinib and Breakthrough Therapy Designation to Lorlatinib

Brigatinib is indicated in patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib and lorlatinib in patients who were previously treated with one or more ALK inhibitors

On 28 April, 2017, the US Food and Drug Administration (FDA) granted accelerated approval to brigatinib (ALUNBRIG tablets, Takeda Pharmaceutical Company Limited, through its wholly owned subsidiary ARIAD Pharmaceuticals, Inc.) 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, multicentre 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 (112 patients) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (110 patients).

The ORR was assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The 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 (26 patients) and 67% (95% CI: 41%, 87%) in the 180 mg arm (18 patients).

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. 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 interstitial lung disease/pneumonitis. Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnoea, 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.

Full prescribing information is available here.   

FDA previously granted brigatinib Breakthrough Therapy Designation for the treatment of patients with ALK-positive NSCLC whose tumours are resistant to crizotinib, as well as Orphan Drug Designation for the treatment of ALK-positive NSCLC. FDA granted this application priority review. As a condition of the accelerated approval, the company is required to verify the clinical benefit of brigatinib in a confirmatory trial.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

FDA grants Breakthrough Therapy designation to lorlatinib, a next-generation ALK/ROS1 inhibitor

Pfizer Inc. announced on 27 April 2017 that its investigational next-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), lorlatinib, was granted Breakthrough Therapy designation from the US FDA for the treatment of patients with ALK-positive metastatic NSCLC, previously treated with one or more ALK inhibitors.

Enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA), Breakthrough Therapy designation is intended to expedite the development and review of a potential new medicine if it is intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies. The Breakthrough Therapy designation is distinct from the FDA’s other mechanisms to expedite drug development and review.

ALK gene rearrangement is a genetic alteration that drives the development of lung cancer in some patients. Due to additional mutations that the tumour may acquire during treatment, disease progression remains a challenge in patients with ALK-positive metastatic NSCLC.

Lorlatinib is next-generation ALK/ROS1 TKI that has been shown to be highly active in preclinical lung cancer models harbouring chromosomal rearrangements of both ALK and ROS1. Lorlatinib was specifically designed to inhibit tumour mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier. Lorlatinib is an investigational agent and has not received regulatory approval for any indication anywhere in the world.

The FDA Breakthrough Therapy designation is supported by the efficacy and safety data of an ongoing phase I/II clinical trial of lorlatinib, which includes patients with ALK-positive NSCLC who were previously treated with one or more ALK inhibitors.

Additionally, the phase III CROWN study (NCT03052608) recently began enrolling patients. The CROWN is an ongoing, open label, randomised, two-arm study comparing lorlatinib to crizotinib in the first-line treatment of patients with metastatic ALK-positive NSCLC.

Pfizer assumes no obligation to update forward-looking statements contained in their press release as the result of new information or future events or developments.