Newest Drug for ALK-Positive NSCLC Approved in Japan

Zosia Chustecka


July 07, 2014

The newest drug to target specifically non-small-cell lung cancer (NSCLC) that has tested positive for anaplastic lymphoma kinase (ALK) fusion gene has been granted its first approval worldwide in Japan.

The drug is alectinib, and will be marketed in Japan by Chugai, a part of the Roche group. It will be available later this year, the company said.

The Japan Ministry of Health, Labour and Welfare based the approval on a phase 1/2 clinical study (AF-001JP) conducted in Japan for which the primary end point was response rate (and was shown to be >90%).

Roche noted that ongoing clinical trials will be used for regulatory submissions elsewhere in the world. The global phase 3 studies of alectinib include a companion test codeveloped with Ventana Medical Systems, Inc., a member of the Roche Group.

In the United States, alectinib was recently granted breakthrough therapy designation by the US Food and Drug Administration (FDA) for patients with ALK-positive NSCLC who have progressed on crizotinib (Xalkori, Pfizer).

Crizotinib was the first drug to target ALK-positive NSCLC, and was approved in the United States in August 2011.

Since then another drug that targets this specific patient population has been approved in the United States. In April, the FDA granted an accelerated approval for ceritinib (Zykadia, Novartis) for use in patients with ALK-positive NSCLC who have previously been treated with crizotinib.

Details of Japanese Study

The Japanese study was conducted in patients with advanced, recurrent, or unresectable ALK-positive NSCLC who had already received treatment with 1 or more chemotherapy regimens.

The trial was conducted in 2 parts. Phase 1 involved 24 patients and evaluated safety, tolerability, and pharmacokinetic parameters, and established a recommended dose (300 mg orally twice daily).

Phase 2 involved 46 patients and evaluated the efficacy and safety of the recommended dose. In this study, alectinib demonstrated a response rate of 93.5% (43 of 46 patients; 95% confidence interval [CI], 82.1% - 98.6%).

In addition, progression-free survival at 12 months was measured as 83% (95% CI, 68% - 92%).

Of the 70 patients who were involved in the studies, 14 had brain metastases, and 9 of these remained in the study without central nervous system or systemic progression for more than 12 months. Roche noted that these are patients who are difficult to treat with other drugs, and that it will continue to research this issue. "Early studies with alectinib have shown activity on brain metastases, indicating that the drug may be taken up in the brain.... One of the ways the blood–brain barrier prevents molecules from affecting the brain is to actively eject them from the barrier through a process known as 'active efflux.' The active efflux system does not recognize alectinib, which means that it may travel into and throughout brain tissue," the company noted.

There were no treatment-related deaths and/or grade 4 or higher serious adverse reactions assessed according to Common Terminology Criteria for Adverse Events, as defined by the Japan Clinical Oncology Group. The most frequently observed grade 3 or higher adverse reaction was neutropenia, and the incidence of the adverse event was 4 out of 58 patients (6.9%) who were treated with 300 mg twice daily, the approved dose.


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