Alectinib, a next-generation ALK inhibitor, was called a new standard of care for ALK-positive non–small cell lung cancer (NSCLC) based on results from the phase 3 ALEX clinical trial presented at the 2017 ASCO Annual Meeting. In the study, alectinib prevented cancer progression for a median of 15 months or longer and delayed time to brain metastases compared with crizotinib, the current standard of care, with fewer side effects.
“This is the first head-to-head trial to compare a next-generation ALK inhibitor with the standard of care, crizotinib,” said lead author Alice T. Shaw, MD, Director of Thoracic Oncology at Massachusetts General Cancer Center, Boston. “This global study establishes alectinib as the new standard of care for initial treatment in this setting. Alectinib was especially beneficial in controlling and preventing brain metastases, which can have a major impact on patients’ quality of life.”
Most patients with ALK-positive NSCLC treated with crizotinib will develop resistance and disease progression, and the brain is the most common site of disease progression.
Alectinib is a more potent ALK inhibitor than crizotinib and is better able to penetrate the central nervous system (CNS). Alectinib is approved by the FDA for the treatment of ALK-positive NSCLC patients in whom prior crizotinib treatment failed. Dr Shaw and colleagues wanted to study the new drug in the first-line setting.
First-Line Treatment
The ALEX study randomized 303 ALK-positive patients with advanced or metastatic NSCLC who had not received prior therapy for metastatic disease. Patients were randomized in a 1:1 ratio to first-line treatment with 1 of 2 oral drugs: alectinib 600 mg twice daily versus crizotinib 250 mg twice daily. Patients with CNS metastasis were allowed in the trial.
The study met its primary end point of prolonged progression-free survival (PFS). Median PFS was not yet reached with alectinib versus 11.1 months for crizotinib, representing a 53% reduction in risk of disease progression (P <.0001). Results were similar in an independent review, with a median progression-free survival of 25.4 months with alectinib versus 10.4 months with crizotinib.
“This represents more than a doubling of progression-free survival,” she said. “Nobody expected it would be possible to delay advanced lung cancer progression by this much. Most targeted therapies for lung cancer are associated with a median progression-free survival of roughly 12 months.”
Alectinib achieved an 84% reduction in risk of CNS progression compared with crizotinib. Brain metastases developed in 9% of the alectinib group versus 41% of the crizotinib group.
Importantly, alectinib was associated with fewer side effects compared with crizotinib. The rate of grade 3/4 adverse events was 41% in the alectinib group compared with 50% in the crizotinib group. Patients treated with alectinib had fewer treatment interruptions, dose reductions, or discontinuations compared with crizotinib.
At a press conference, results from the ALEX trial were greeted with enthusiasm. “This is a watershed moment in the treatment of ALK-positive NSCLC. Often studies show only incremental improvements with a new treatment. This is different. Alectinib shows a dramatic increase in efficacy that is also accompanied by better tolerability,” stated ASCO Expert John Heymach, MD, Professor and Chairman of the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.
“I firmly agree with Dr Shaw. This is a new standard of care for first-line ALK-positive lung cancer,” Dr Heymach stated.
