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CHICAGO -- Progression-free survival (PFS) in advanced ALK-positive non-small cell lung cancer (NSCLC) more than doubled in patients who received the ALK inhibitor alectinib (Alecensa), a randomized trial showed.

Patients treated initially with crizotinib (Xalkori) had a median PFS of 11.1 months as determined by trial investigators, whereas the median had yet to be reached in the group of patients randomized to alectinib (Alecensa). Review of the data by an independent committee yielded an even greater difference, as the median PFS increased from 10.4 months with crizotinib to 25.7 months with alectinib.

Analysis of the key secondary endpoint of time to development of brain metastasis showed that alectinib dramatically slowed central nervous system (CNS) progression, as 9.4% of patients had developed brain metastases at the 12-month follow-up compared with 41.4% in the crizotinib arm.

in December 2015 for treating ALK-positive NSCLC in patients intolerant of or progressing with crizotinib. The new study was intended to support an expanded indication for first-line treatment.

"The is the first global, head-to-head trial comparing two ALK inhibitors in the first-line treatment setting," Alice Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, said at a press briefing at the American Society of Clinical Oncology annual meeting. "The efficacy and safety results establish alectinib as the new standard of care for patients with advanced, previously untreated ALK-positive non-small cell lung cancer."

The results represent a "watershed moment" for the treatment of ALK-mutant NSCLC, said John Heymach, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"Often, studies comparing similar-type agents will show incremental improvements. This one is different," said Heymach. "There is a dramatic difference in efficacy, more than doubling the time to progression or death. It's also accompanied by improved tolerability. Finally, one of the most debilitating things that can occur in these patients with ALK-mutant disease is brain metastasis. What's really impressive about this study is the dramatic reduction in the risk of brain metastasis, an 84% reduction in the likelihood, which is an absolutely striking result."

Putting the results into context, Heymach noted that crizotinib ascended to the top of first-line options for ALK-positive NSCLC on the basis of a randomized trial that demonstrated a 4- to 5-month difference in PFS versus chemotherapy.

"I firmly agree with Dr. Shaw's conclusion that this is a new standard for first-line ALK-fusion lung cancer," he added.

The ALK-mutant subset accounts for about 5% of all NSCLC, or about 60,000 new cases a year worldwide. Although many patients respond initially to crizotinib, treatment failure occurs frequently within the first 12 months. The brain and other components of the CNS are common sites of distant failure.

The new-generation ALK inhibitor alectinib has greater potency and better CNS penetration, as compared with crizotinib. Preliminary clinical studies suggested alectinib has considerable activity in ALK-positive NSCLC, including patients with .

Shaw reported findings from an international, randomized phase III trial designed to test the hypothesis that alectinib would outperform crizotinib as first-line treatment for patients with ALK-positive NSCLC. Eligible patients had newly diagnosed, untreated, advanced or metastatic NSCLC with ALK mutations confirmed by central immunohistochemical testing. Patients with asymptomatic brain metastases were eligible.

Patients were randomized to alectinib or crizotinib, and treatment continued until disease progression or development of unacceptable toxicity. The protocol did not permit crossover to the opposite treatment arm. The trial had a primary endpoint of PFS, and secondary endpoints included time to CNS progression, objective response, duration of response, overall survival (OS), and safety and tolerability.

Data analysis included 303 randomized patients and showed a 53% reduction in the hazard for progression of death in patients treated with alectinib versus crizotinib (HR 0.47, 95% CI 0.34-0.65, P=0.0001). Independent review of PFS found a 50% reduction in the hazard ratio in favor of alectinib. The analysis of time to CNS progression showed an 84% reduction in the hazard for patients in the alectinib group (HR 0.16, 95% CI 0.10-0.28, P<0.0001).

Grade 3/4 adverse events occurred about 20% less often with alectinib than with crizotinib (41% versus 50%), and the incidence of fatal adverse events was 3% with alectinib and 5% with crizotinib. Adverse events leading to discontinuation, dose reduction, or dose interruption all occurred less frequently in the alectinib arm.

A preliminary analysis of OS showed no difference between groups, but follow-up for that endpoint will continue.

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