The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib should be the new standard of care for first-line treatment of ALK-positive non–small-cell lung cancer (NSCLC), according to a new study (abstract LBA9008) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.
The newer ALK inhibitor halted cancer growth for a median of 15 months longer and caused fewer severe side effects than the current standard of care, crizotinib.
“This is the first global study to compare alectinib with crizotinib in ALK-positive lung cancer. The efficacy and safety results establish alectinib as the new standard of care for patients with advanced, previously untreated ALK-positive NSCLC,” said lead author Alice T. Shaw, MD, PhD, director of thoracic oncology at Massachusetts General Hospital Cancer Center in Boston, in a press briefing.
Alectinib is a more potent, next-generation inhibitor of ALK that has shown robust activity in early trials, and penetrates the brain better than crizotinib. It was initially approved in 2015 for use in patients with advanced NSCLC that worsens despite crizotinib.
In an open-label, multicenter, phase III trial, the researchers randomly assigned 303 patients with stage IIIB or IV, ALK-positive NSCLC to receive alectinib 600 mg twice daily orally or crizotinib 250 mg twice daily orally. The patients had not received prior systemic therapy for advanced NSCLC.
At 1 year of treatment, alectinib met the primary endpoint—“it reduced the risk of progression by 53% compared with crizotinib and more than doubled the median progression-free survival (PFS),” said Shaw. Based on independent review, the PFS was 25.7 months with alectinib and 10.4 months with crizotinib.
Most targeted therapies for lung cancer are associated with a median PFS of about 12 months, she noted.
The 12-month cumulative incidence of CNS progression was 9.4% with alectinib and 41.4% with crizotinib, an 84% reduction. “Alectinib significantly delayed disease progression in the brain,” she said.
Severe side effects were less common with alectinib (41% of patients) than with crizotinib (50% of patients). “Alectinib led to fewer severe side effects than crizotinib, and fewer dose reductions, dose interruptions, and discontinuations,” said Shaw.
The most common side effects of alectinib were fatigue, constipation, muscle aches, and swelling. Crizotinib primarily caused gastrointestinal problems and liver enzyme abnormalities.
The researchers plan to follow these patients to determine whether alectinib leads to better overall survival. Several ongoing clinical trials are comparing other next-generation ALK inhibitors to crizotinib in the first-line setting.
ASCO Expert John Heymach, MD, PhD, of the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston, commented: “This is a watershed moment for treatment of ALK-positive NSCLC. This second-generation targeted treatment halted advanced lung cancer growth for more than 2 years while preventing brain metastases.”
He noted that the brain is the most common site of progression. “The dramatic reduction in brain metastases is a striking result. I agree that this should be the new standard of care for first-line treatment of ALK-positive NSCLC.”