Date: 2014-09-27
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 2014 Congress of the European Society for Medical Oncology (ESMO)
Company: Novartis (Switzerland)
Product: Zykadia® (ceritinib) - LDK378
Action
mechanism: tyrosine kinase inhibitor. LDK378 (ceritinib) is a selective inhibitor of anaplastic lymphoma kinase or ALK.
Disease: anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The 246 patients with ALK+ NSCLC in this Phase I single-arm study received ceritinib 750 mg daily and were observed over time for a median duration of 11.1 months. Of these, 166 (67%) had received at least two prior treatment regimens and 163 (66%) had been previously treated with an ALK inhibitor. This study is part of the ongoing Novartis clinical trial program in this patient population. Several major studies evaluating treatment with ceritinib are being conducted in more than 300 study centers across more than 30 countries. Two Phase II single-arm clinical trials in previously treated and treatment-naïve ALK+ NSCLC patients, (NCT01685060 and NCT01685138), are fully enrolled and ongoing. In addition, two Phase III clinical trials comparing ceritinib with chemotherapy in treatment-naïve and in previously-treated patients, (NCT01828099 and NCT01828112), are ongoing and actively recruiting patients worldwide.
Latest
news: * On September 27, 2014, Novartis announced new data showing patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) lived an average of more than 18 months without their cancer progressing when taking Zykadia® (ceritinib) as their first ALK inhibitor. Overall, data from the pivotal study confirmed ceritinib continues to demonstrate efficacy in ALK+ NSCLC patients regardless of whether or not they received previous treatment with an ALK inhibitor. In addition, patients who entered the study with brain metastases experienced similar results following treatment with ceritinib. These data have been presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid. Among the combined study population of 246 NSCLC patients, including patients who had received previous treatment with an ALK inhibitor as well as those receiving one for the first time, ceritinib achieved an overall response rate (ORR) of 61.8% and a median progression-free survival (PFS) of 9.0 months. In the subset of 83 patients who had not received prior treatment with an ALK inhibitor, ceritinib achieved an ORR of 72.3% and a median PFS of 18.4 months. Among the subset of 163 patients who were previously treated with the commonly prescribed ALK inhibitor crizotinib, the ORR was 56.4% and the median PFS was 6.9 months. In 124 patients who entered the trial with brain metastases, those treated with ceritinib achieved an ORR of 55.6%. Of note, ceritinib also demonstrated activity in the brain, known as intracranial responses, suggesting that ceritinib may be an effective therapy for brain metastases, one of the most common and difficult-to-treat sites of disease progression for patients with ALK+ NSCLC. Specifically, ceritinib shrank brain metastases in about one-third of the 29 patients who entered the study with measurable brain lesions. No unexpected side effects were observed and the most common adverse events, occurring in more than half of patients, were diarrhea, nausea and vomiting. Approximately 2-7% of patients with NSCLC harbor the ALK gene rearrangement, which causes cancer growth. These patients are candidates for treatment with a targeted ALK inhibitor. Patients with ALK+ NSCLC are often younger than the average NSCLC patient and in many cases have never smoked. In the subset of 83 patients who had not received prior treatment with an ALK inhibitor, the ORR was 72.3% [95% CI, 61.4-81.6%] and the median PFS was 18.4 months [95% CI, 11.1-NE (not estimable) months]. Among the subset of 163 patients receiving 750 mg of ceritinib daily and who were previously treated with the commonly prescribed ALK inhibitor crizotinib, the ORR was 56.4% [95% CI, 48.5-64.2%] and the median PFS was 6.9 months [95% CI, 5.6-8.7 months].
In the 124 patients who started the study with brain metastases, ceritinib achieved an ORR, including partial responses (PR) and complete responses (CR), of 55.6% [95% CI, 46.5-64.6%]. Confirmed responses (PR/CR) were seen in 51.0% of patients [50 of 98 patients; 95% CI, 40.7-61.3%] with brain metastases who had received previous ALK inhibitor therapy, while 73.1% of patients [19 of 26 patients; 95% CI, 52.2-88.4%] with brain metastases who were not previously treated with an ALK inhibitor achieved confirmed responses following treatment with ceritinib. The median PFS was 6.9 months [95% CI, 4.9-8.4 months] among patients with brain metastases who were previously treated with an ALK inhibitor and 9.7 months [95% CI, 4.6-NE months] in those with brain metastases who were receiving ALK inhibitor therapy for the first time.
Seventy-four out of the 124 ALK+ NSCLC patients with brain metastases had MRI scans available for evaluation, of whom 29 were identified as having measurable brain lesions at baseline according to standard clinical criteria (RECIST v1.1). Ceritinib achieved confirmed responses in the brain in 34.5% of those patients with measurable brain lesions [10 of 29 patients, 95% CI, 17.9-54.3%].
Discontinuation of treatment due to adverse events occurred in 9.8% of ALK+ NSCLC patients in the study.
Among 255 patients treated with ceritinib at a dose of 750 mg once daily, including 246 patients with NSCLC and nine patients with other types of cancer, 156 (61.2%) required at least one dose reduction. The most frequent adverse events (incidence >50%) among 255 patients were diarrhea (86.7%), nausea (82.7%) and vomiting (61.6%). Most adverse events were of low grade and treated with dose interruption and/or dose reductions[1].
The study presented at ESMO 2014 served as the basis for the FDA approval of Zykadia® in April 2014, which followed the FDA\'s Breakthrough Therapy designation. Additional ongoing regulatory reviews for Zykadia® are currently underway in the European Union and several countries within North America, South America, Central America and Asia.
