Alectinib vs Crizotinib in First-Line Treatment of ALK-Positive NSCLC

Second-Generation ALK Inhibitor Shows Increased Efficacy, Better Tolerability


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In 2011, crizotinib (Xalkori) became the first effective targeted therapy for anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC). Now data from a phase III trial show that alectinib (Alecensa), a second-generation ALK inhibitor, outperformed crizotinib, the current standard of care.

Alectinib prevented cancer progression for a median of 15 months longer than crizotinib, and delayed the time to brain metastases compared with crizotinib as well, according to the results of the phase III ALEX trial presented at the 2017 ASCO Annual Meeting.1 Moreover, this new treatment had fewer severe side effects compared with crizotinib.


Nobody expected it would be possible to delay advanced lung cancer progression by this much.
— Alice T. Shaw, MD, PhD

“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, PhD, Director of Thoracic Oncology at Massachusetts General Hospital 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.”

ALK is found in about 5% of cases of NSCLC, which accounts for about 50,000 new cases worldwide each year. “The current standard of care—first-generation ALK inhibitor crizotinib—is effective initially, but most patients will develop resistance, and the central nervous system [CNS] is a common site of progression. This likely reflects the drug’s poor penetrance into the CNS,” Dr. Shaw explained.

Alectinib is more potent and CNS-penetrant than crizotinib. The next-generation drug is already approved by the U.S. Food and Drug Administration for the treatment of patients with ALK-positive NSCLC who failed to respond to prior crizotinib.

Key Findings

The open-label, randomized ALEX study enrolled 303 patients with ALK-positive advanced or metastatic NSCLC who received no prior therapy for metastatic disease. Patients were randomized in a 1:1 ratio to first-line oral treatment with alectinib at 600 mg twice daily vs crizotinib at 250 mg twice daily. Treated or untreated CNS metastasis was allowed for enrollment in the trial. The primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included independent review committee–assessed progression-free survival, time to CNS disease progression, and safety.

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The study met its primary endpoint of prolonged progression-free survival. Median progression-free survival was not yet reached with alectinib vs 11.1 months for crizotinib, representing a 53% reduction in the risk of disease progression (P < .0001). Results were similar according to independent review, with a median progression-free survival of 25.7 months with alectinib vs 10.4 months with crizotinib, “representing more than a doubling in progression-free survival,” Dr. Shaw emphasized.

“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,” Dr. Shaw commented.

Benefits of Alectinib in ALEX Trial

  • In the phase III ALEX trial, alectinib extended progression-free survival by a median of 15 months compared with crizotinib for the treatment of advanced ALK-positive NSCLC.
  • The time to brain metastases was delayed with alectinib.
  • Alectinib had fewer severe adverse events than did crizotinib.
  • Alectinib represents a new standard of care for first-line treatment of ALK-positive NSCLC.

Significantly slower time to CNS progression was observed in the alectinib-treated group, for an 84% reduction in the risk of CNS progression favoring alectinib over crizotinib. At 12 months, CNS progression was observed in 9% of the alectinib group vs 41% of the crizotinib group.

A striking finding was that fewer severe side effects were observed with alectinib compared with crizotinib, which is unusual when a treatment is more effective than its comparator. Patients treated with alectinib had fewer grades 3–5 adverse events (41% vs 50%, respectively) and required fewer treatment interruptions, dose reductions, or treatment discontinuations than did crizotinib.

Patients in the study will be followed for survival. ■

DISCLOSURE: The study was funded by F. Hoffmann-La Roche. Dr. Shaw has received honoraria and institutional research funding from Roche, Genentech, Novartis, and Pfizer; and has served as a consultant or advisor to Roche/Genentech, ARIAD, Blueprint Medicines, Daiichi Sankyo, EMD Serono, Ignyta, KSQ Therapeutics, Loxo Oncology, Novartis, Pfizer, Foundation Medicine, and Taiho Pharmaceutical.

REFERENCE

1. Shaw AT, Peters S, Mok T, et al: Alectinib versus crizotinib in treatment-naive advanced ALK-positive non-small cell lung cancer: Primary results of the global phase III ALEX study. 2017 ASCO Annual Meeting. Abstract LBA9008. Presented June 6, 2017.


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“This is a watershed moment in the treatment of anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC). Often studies show only incremental improvements with a new treatment. This is different. Alectinib [Alecensa] shows a dramatic increase in efficacy that is also accompanied ...


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