The investigational compound ceritinib (LDK378) was highly active in patients with advanced ALK-positive non-small cell lung cancer, according to the results of a study published in the New England Journal of Medicine.

Lung cancer is the leading cause of cancer death in the U.S. and around the world. Up to 7 percent of non-small cell lung cancers (NSCLC) have an abnormal version of the anaplastic lymphoma kinase (ALK) gene. Lung cancers with this abnormality typically occur in non-smokers. The abnormal gene contributes to the growth and development of cancer cells.

Xalkori® (crizotinib) is a targeted oral medication that blocks the protein produced by the ALK gene. It works by works by binding with and inhibiting the action of the enzyme that is produced by the mutated gene. Xalkori has become a standard treatment for advanced ALK-positive NSCLC—but most patients will become resistant to it and are left with limited treatment options.

Ceritinib is a highly selective ALK-inhibitor that has shown promise in early trials—and in fact, has shown greater anti-tumor activity than Xalkori. The investigational drug has not yet been FDA-approved for treatment outside of clinical trials.

Researchers conducted a phase I trial that consisted of two stages. The first phase, a dose-escalation phase, included 59 patients with NSCLC who received daily doses of ceritinib ranging from 50 milligrams to 750 milligrams in order to determine the maximum tolerated dose.

The expansion phase of the study included an additional 71 patients (total 130). Most patients (122) had ALK-positive NSCLC; some were Xalkori-resistant and Xalkori-naïve. Patients received the maximum tolerated dose in order to determine safety and efficacy.

The majority of patients in the study experienced a clinical response to ceritinib. The overall response rate among patients with ALK-positive NSCLC was 58 percent and the median progression-free survival was seven months. Patients were treated with a doses ranging from 400 mg to the maximum tolerated dose of 750 mg.

The most frequent adverse events were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%) and increased alanine aminotransferase levels (35%). The most common grade 3 or 4 study drug-related adverse events were increased alanine aminotransferase levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%) and increased lipase levels (7%), all of which were reversible upon treatment discontinuation. Preliminary data from this study were first presented at the 2013 American Society of Clinical Oncology annual meeting. The study is ongoing with more data to become available.

The data from this study will serve as the basis for regulatory application to the U.S. Food and Drug Administration (FDA), with action expected this year. The FDA designated ceritinib as a Breakthrough Therapy, which is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint.


Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. New England Journal of Medicine. 2014; 370: 1189-1197.


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