Ranee Mehra, MD
The next-generation ALK inhibitor ceritinib (Zykadia) showed clinically significant antitumor activity in patients with ALK-rearranged non-small cell lung cancer (NSCLC), including those with brain metastases, said Ranee Mehra, MD, attending physician, Fox Chase Cancer Center, Philadelphia, who reported study results at the 2014 Society for Neuro-Oncology’s (SNO) Annual Meeting in Miami Beach, Florida.
Crizotinib was the first ALK inhibitor to gain approval for patients with NSCLC; however, this treatment has limited efficacy in the central nervous system (CNS). In studies exploring crizotinib, approximately 46% of patients progressed in the CNS, reported Mehra.
Ceritinib, which recently received FDA approval for patients with ALK-rearranged advanced NSCLC, demonstrated efficacy in patients with brain metastases regardless of prior ALK inhibitor treatment. This efficacy could be related to ceritinib’s potency, which appears to be 20-fold greater than crizotinib, Mehra said.
In the phase I ASCEND-1 study, which was instrumental in the approval of ceritinib, ALK-inhibitor naÃ¯ve patients treated with ceritinib experienced an overall response rate (ORR) of 72.3% and a median progression-free survival (PFS) of 18.4 months. In ALK inhibitor treated patients, the ORR was 56.4% and the median PFS was 6.9 months.1
Results presented at the SNO meeting were from a subset of patients with brain metastases who were part of the ASCEND-1 study.2
In this subset, researchers analyzed the response of patients with ALK-positive advanced NSCLC and clinically and neurologically stable brain metastases at baseline and who had received 750 mg/day of ceritinib. The response was based on investigator assessment.
In total, 124 patients in the ASCEND-1 study had brain metastases at baseline, including 98 with prior ALK inhibitor treatment and 26 who were ALK inhibitor-naÃ¯ve. The subset of patients with brain metastases had a median age of 51; the median time from the diagnosis of NSCLC to the first dose of ceritinib was 20.5 months. The median duration of exposure was 27 weeks.
For the full cohort, the ORR was 54%. The ORR was 50% and 69.2%, in patients who were ALK-inhibitor treated and naÃ¯ve, respectively. The median duration of response was 7 months for the full subset of patients with brain metastases, 6.9 months for the ALK inhibitor-treated cohort, and not estimable in the ALK inhibitor naÃ¯ve cohort. There was a median 6.9- and 8.3-month PFS in the ALK inhibitor-treated and ALK inhibitor naÃ¯ve groups.
Fourteen patients had measurable target lesions at baseline, with 50% achieving a response in the brain (4 ALK inhibitor-treated, 3 ALK inhibitor-naÃ¯ve) and 21.4% having stable disease. Patients with stable disease had all been treated with a prior ALK inhibitor.
In terms of safety, the most common all-grade adverse events experienced by the larger cohort versus patients with brain metastases were diarrhea (86% vs 79%), nausea (80% vs 82%), and vomiting (60% vs 63%). “All patients had at least one adverse event,” Mehra said.
Ceritinib is a novel, orally active small-molecule tyrosine kinase inhibitor of ALK. Inhibition of ALK causes the disruption of ALK-mediated signaling and cell growth. ALK alterations and gene rearrangements are associated with a variety of tumors. “Approximately 2% to 7% of patients with non-small cell lung cancer have an ALK gene rearrangement,” Mehra said.
Both patients who were ALK inhibitor naÃ¯ve and those who had used ALK inhibitors before showed durable intracranial responses, Mehra said. Due to limited data available, researchers could not evaluate the effect of prior intracranial radiation. A phase II study will be underway soon to evaluate ceritinib specifically for brain metastases, Dr. Mehra said.
Two phase III studies are enrolling patients to further explore the efficacy and safety of ceritinib in patients with ALK-positive NSCLC. In the first, ceritinib will be compared with chemotherapy in untreated patients with ALK-rearranged NSCLC (NCT01828099). The second will compare ceritinib to chemotherapy in ALK-positive patients with NSCLC following progression on chemotherapy and crizotinib (NCT01828112).
Felip E, Kim D, Mehra R, et al. Efficacy and Safety of Ceritinib in Patients (pts) with Advanced Anaplastic Lymphoma Kinase (ALK)-rearranged (ALK+) Non-small Cell Lung Cancer (NSCLC): An Update of ASCEND-1. Presented at the: 2014 ESMO Annual Congress, Madrid, Spain. Abstract #1295P.
Shaw A, Mehra R, Tan DSW, et al. Ceritinib (LDK378) for treatment of patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases (BM) in the ASCEND-1 trial. Presented at the SNO Annual Meeting, Miami Beach, Florida. Abstract BM-32.Â
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