ALK-Positive NSCLC Responds to Ceritinib Treatment

Non–small-cell lung cancer (NSC LC) harboring anaplastic lymphoma kinase (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib (Xalkori). Despite initial responses to crizotinib, resistance ultimately occurs. In preclinical studies, ceritinib (Zykadia), a novel, oral adenosine triphosphate–competitive inhibitor of the ALK tyrosine kinase, has shown greater antitumor potency than crizotinib. In a phase 1 study, researchers sought to determine the safety, maximum tolerated dose, and antitumor activity of ceritinib in patients with advanced ALK-rearranged NSCLC. The results demonstrated that ceritinib produced a highly active response rate in this patient population, including patients with previous crizotinib treatment and irrespective of the presence of ALK resistance mutations (Shaw AT, et al. N Engl J Med. 2014;370:1189-1197).

The trial consisted of 2 phases and included 130 patients. In the dose-escalation phase, 59 patients with tumors harboring ALK alterations were treated with ceritinib at doses of 50 mg to 750 mg once daily in 21-day cycles. In an expansion phase, 71 patients were treated at the maximum tolerated dose of 750 mg daily. Among the 130 patients enrolled, 122 had advanced NSCLC and had previously received cytotoxic chemotherapy. Of the 122 patients with advanced NSCLC, 68% had previously received crizotinib.

The most common adverse events (AEs) were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%), and elevated alanine aminotransferase (ALT; 35%) levels. The most common grade 3 or 4 drug-related AEs were increased ALT levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%), and increased lipid lipase levels (7%), all of which were reversible on discontinuation of treatment. Of 130 patients, 66 (51%) required at least 1 dose reduction. In 8 (6%) of the 130 patients, ceritinib was permanently discontinued. No treatment-related deaths occurred.

Among the 114 patients with NSCLC who received ?400 mg of ceritinib daily, the overall response rate was 58%, which included 1 (1%) confirmed complete response and 65 (57%) partial responses. The overall response rate was 56% among 80 patients previously receiving crizotinib, and 62% among the 34 crizotinib-naïve patients. Among 114 patients receiving ?400 mg daily, the median progression-free survival was 7 months, which was similar at 6.9 months in the crizotinib relapse group and was 10.4 months in crizotinib-naïve patients.

Because ceritinib has been shown to induce substantial and durable responses in a majority of cases, these findings suggest that ceritinib can be an alternative treatment to crizotinib.

On April 29, 2014, the US Food and Drug Administration granted accelerated approval for ceritinib for patients with metastatic ALK-positive NSCLC.

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