What is the role of ceritinib (Zykadia) in the treatment of non-small cell lung cancer (NSCLC)?

Updated: Aug 21, 2019
  • Author: Maurie Markman, MD, MS; Chief Editor: Keith K Vaux, MD  more...
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A second ALK tyrosine kinase inhibitor, ceritinib (Zykadia), gained accelerated approval from the FDA in 2014 for patients with ALK-positive metastatic NSCLC whose disease had progressed or who were intolerant to crizotinib, which was based on a blinded independent review committee (BIRC)–assessed ORR of 44% of 163 patients in a single-arm trial. Early-stage results showed that ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who experienced disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. [13]

Ceritinib was shown to overcome crizotinib resistance mutations in a preclinical trial. In vitro and in vivo models of acquired resistance to crizotinib were evaluated, including cell lines established from biopsies of crizotinib-resistant NSCLC patients. Results revealed that ceritinib overcame crizotinib resistance mutations, in particular, ALK-harboring L1196M, G1269A, I1171T, and S1206Y mutations. [34]

In May 2017, ceritinib was granted approval for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)–positive as detected by an FDA-approved test. This approval also included use as first-line treatment. Approval was based on data from ASCEND-4, a randomized, multicenter, open-label, active-controlled trial conducted in patients with untreated ALK-positive NSCLC. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) test performed through central laboratory testing.

ASCEND-4 randomized 376 patients (1:1) to receive either ceritinib (N=189) 750 mg orally once daily until disease progression or platinum-pemetrexed doublet chemotherapy (N=187). Patients in the chemotherapy arm received pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC 5-6) on day 1 of every 21-day cycle for up to 4 cycles, followed by pemetrexed maintenance therapy. Results demonstrated improved PFS as assessed by BIRC, with a hazard ratio (HR) of 0.55 (P< 0.0001). The estimated median PFS was 16.6 months in the ceritinib arm and 8.1 months in the chemotherapy arm. Confirmed ORR was 73% and 27% in the ceritinib and chemotherapy arms, respectively. Estimated median response durations were 23.9 months and 11.1 months in the ceritinib and chemotherapy arms, respectively. Overall survival data are immature. [35]

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