Alectinib stops lung cancer progression more than a year longer than crizotinib

Data from a phase III clinical trial reveal a more effective initial treatment for patients with ALK-positive non-small cell lung cancer (NSCLC). Compared with the current standard of care, crizotinib, the newer ALK inhibitor alectinib halted cancer growth for a median of 15 months longer and resulted in fewer severe side effects, according to findings presented in Chicago in early June at the American Society of Clinical Oncology 2017 Annual Meeting.

“This is the first global study to compare alectinib with crizotinib in ALK-positive lung cancer and establishes alectinib as the new standard of care for initial treatment in this setting,” stated lead study author Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at Massachusetts General Hospital Cancer Center in Boston, MA. “Alectinib was especially beneficial in controlling and preventing brain metastases, which can have a major impact on patients’ quality of life.”

Research has shown that about 5% of NSCLCs are ALK-positive, meaning they have a genetic rearrangement where the ALK gene is fused with another gene. In the United States, about 12,500 people are diagnosed with ALK-positive NSCLC every year.

Crizotinib, which was approved by the Food and Drug Administration in 2011, is the first medicine to specifically target ALK. Although the majority of patients initially benefit from therapy with crizotinib, this cancer typically starts growing again within a year. Alectinib is a more potent, next-generation inhibitor of ALK. It was initially approved in 2015 for use in patients with advanced NSCLC that worsens despite crizotinib.

This is an open label clinical trial (ALEX), in which researchers randomly assigned 303 patients with stage IIIB or IV, ALK-positive NSCLC to receive either alectinib or crizotinib. These patients had not received prior systemic therapy for advanced NSCLC.

Researchers found that alectinib reduced the risk of cancer progression or death by 53% compared with crizotinib. Based on an independent review, use of alectinib extended the median time to progression by about 15 months (median progression-free survival was 25.7 months with alectinib and 10.4 months with crizotinib).

“Nobody imagined it would be possible to delay advanced lung cancer progression by this much,” Dr. Shaw pointed out. “Most targeted therapies for lung cancer are associated with a median progression-free survival of roughly 12 months.”

While both treatments have been found to cross the blood-brain barrier, alectinib was more effective in preventing brain metastases than crizotinib, because it can better penetrate into the brain. At 12 months, the incidence of brain metastases was much lower with alectinib than with crizotinib (9% vs 41%).

Overall, study authors noted that severe side effects were less common with alectinib than with crizotinib, occurring in 41% vs 50% of patients. The most common side effects of alectinib were fatigue, constipation, muscle aches, and swelling, whereas crizotinib caused gastrointestinal problems and liver enzyme abnormalities.

The researchers next step will be to continue to follow patients in this study to see if those treated with alectinib live longer than those treated with crizotinib. Meanwhile, they noted, several ongoing clinical trials are comparing other next-generation ALK inhibitors with crizotinib in the first-line setting.

ASCO Perspective:

“The fact that this second-generation targeted treatment halted advanced lung cancer growth for more than two years while preventing brain metastases is a remarkable result in this difficult disease,” said ASCO Expert John Heymach, MD, PhD. “Thanks to this advance, we are on the road to helping these patients live longer and better.”

This study was funded by F. Hoffmann-La Roche.