Crizotinib Provides Benefit for ALK-Rearranged NSCLC with Brain Metastases

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A retrospective analysis of crizotinib data demonstrates control in advanced, metastatic disease, although brain metastases continued to progress.
A retrospective analysis of crizotinib data demonstrates control in advanced, metastatic disease, although brain metastases continued to progress.

Crizotinib therapy provides systemic and intracranial disease control in patients with ALK-rearranged non-small cell lung cancer (NSCLC) who have brain metastases, according to a study published in the Journal of Clinical Oncology (JCO).1

Crizotinib is a tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in August 2011 for treatment of NSCLC with ALK rearrangements. These mutations are found in approximately 5% of patients with NSCLC.

The study, a retrospective analysis of data from two trials of crizotinib in patients with advanced ALK-rearranged NSCLC, found benefit in patients with either untreated or previously treated brain metastases. Nevertheless, progression of pre-existing brain lesions and development of new lesions continued during crizotinib therapy.

As new therapies extend survival of NSCLC patients, brain metastases are likely to become a common clinical challenge. In a JCO podcast, Rafael Rosell, MD, of the Catalan Institute of Oncology in Barcelona, Spain, who was not involved in the study, said, “A potential limitation of crizotinib could be its less than optimal activity in the central nervous system due to limited blood-brain barrier penetration.”

Disease Control Found in Treated and Untreated Brain Metastases

In this analysis, researchers examined data from 888 patients with ALK-rearranged NSCLC who had been treated with crizotinib: 109 with previously untreated brain metastases; 166 with previously treated brain metastases; and 613 with no detected brain metastases. From the data they determined the disease control rate (DCR), defined as the percentage of patients with complete response, partial response, or stable disease at 12 weeks.

Results were similar whether the patient's brain metastases had been previously treated or not.

In patients with untreated brain metastases, at 12 weeks the systemic DCR was 63% (95% CI, 54% to 72%) and the intracranial DCR was 56% (95% CI, 46% to 66%). Systemic objective response rate (ORR) was 53% (95% CI, 43% to 63%), and intracranial ORR was 18% (95% CI, 5% to 40%).

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In patients with previously treated brain metastases, at 12 weeks the systemic DCR was 65% (95% CI, 57% to 72%) and the intracranial DCR was 62% (95% CI, 54% to 70%). Systemic ORR was 46% (95% CI, 39% to 54%), and intracranial ORR was 33% (95% CI, 13% to 59%).

In patients with no detectable brain metastases, 12 week systemic DCR was 71% and systemic ORR was 55%.

Despite these favorable results, patients with brain metastases did not fare as well as patients without them. Median progression-free survival was 5.9 months in patients with previously untreated brain metastases, 6 months in patients with previously treated brain metastases, and 8.8 months in patients with no detectable brain metastases at baseline.

Progression occurred during crizotinib therapy in 43% of patients with untreated brain metastases and 32% of those with previously treated brain metastases. In both groups, the central nervous system was the most common site of progression. New brain metastases were detected in 20% of patients who had no brain metastases on entry into the study.

These results “suggest that crizotinib may delay the natural history of brain metastasis progression or development when compared to first-line systemic chemotherapy,” said Dr. Rosell.

Reference

  1. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. January 26, 2015. [Epub ahead of print] doi: 10.1200/JCO.2014.59.0539

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