The US Food and Drug Administration (FDA) granted Priority Review for the expanded use of Zykadia® (ceritinib) as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The FDA also granted Breakthrough Therapy designation to Zykadia for the first-line treatment of patients with ALK+ metastatic NSCLC with metastases to the brain.
Zykadia is an oral, selective inhibitor of anaplastic lymphoma kinase (ALK), a gene that can fuse with others to form an abnormal “fusion protein” that promotes the development and growth of certain tumors in cancers including non-small cell lung cancer (NSCLC).
The FDA’s decision on Zykadia is based on the primary analysis of ASCEND-4, a global clinical trial which evaluated Zykadia compared to platinum-based chemotherapy in adult patients with Stage IIIB or IV ALK+ NSCLC.
ASCEND-4 was a Phase III randomized, open-label, multicenter, global clinical trial to evaluate the safety and efficacy of Zykadia compared to standard chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK+ advanced NSCLC who received no prior therapy for their advanced disease. Patients received Zykadia orally at 750 mg/daily or standard pemetrexed-based platinum doublet chemotherapy per label (pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5-6) for 4 cycles followed by pemetrexed maintenance.
Of 376 patients, 189 (59 with brain metastases) were randomized to Zykadia and 187 (62 with brain metastases) to chemotherapy. Approximately 60% of patients with baseline brain metastases treated with Zykadia did not have prior radiation therapy, the current standard of treatment for baseline brain metastases. Among patients randomized to the chemotherapy arm, 105 (72%) of 145 received an ALK inhibitor as their first treatment after discontinuation of chemotherapy.
In the ASCEND-4 trial patients treated with first-line Zykadia had a median progression-free survival (PFS) of 16.6 months compared to 8.1 months for patients treated with standard first-line platinum chemotherapy.
Patients receiving Zykadia without brain metastases experienced a median PFS of 26.3 months compared with 8.3 months among patients treated with chemotherapy1.
In a pre-specified analysis of patients receiving Zykadia with brain metastases at baseline, the median PFS was 10.7 months (95% CI: 8.1, 16.4) in the Zykadia group versus 6.7 months (95% CI: 4.1, 10.6) in the chemotherapy group (HR = 0.70 [95% CI: 0.44, 1.12]). Intracranial overall response rate (ORR) (72.7%, [95% CI: 49.8, 89.3]) is consistent with whole body ORR (72.5% [95% CI: 65.5, 78.7]).
 Soria JC, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomized, open-label Phase 3 study. The Lancet. 2017.
 US Food and Drug Administration. Priority Review. Available at http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm. Accessed February 2, 2017.
 US Food and Drug Administration. Fact Sheet: Breakthrough Therapies. Available at http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm. Accessed February 6, 2017.
 World Health Organization. Estimated number of deaths, both sexes, worldwide in 2012. World Health Organization. http://gco.iarc.fr/today/online-analysis-pie?mode=cancer&mode_population=continents&population=900&sex=0&cancer=11&type=1&statistic=0&prevalence=0&color_palette=default. Accessed on January 19, 2017.
 World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Lung Cancer. Available at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=lung. Accessed February 2, 2017.
 Lovly, C., L. Horn, W. Pao. 2016. Molecular Profiling of Lung Cancer. My Cancer Genome. Available at https://www.mycancergenome.org/content/disease/lung-cancer/. Accessed February 7, 2017.
 Riess JW, Wakelee, HA. Metastatic Non-Small Cell Lung Cancer Management: Novel Targets and Recent Clinical Advances. Clinical Advances in Hematology & Oncology. 2012; 10: 226-224.
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