A phase I single-arm study of LDK378 (ceritinib) demonstrated an overall response rate of 58 percent in patients with ALK-positive non-small cell lung cancer. Patients who received 400 mg or higher of LDK378 per day had a median progression-free survival of seven months.
The study, published in The New England Journal of Medicine, served as the basis for a regulatory application to the FDA, which has designated LDK378 as a breakthrough therapy.
The study evaluated 114 advanced anaplastic ALK+ NSCLC patients treated with LDK378, including patients who had progressed during or following treatment with a commonly prescribed ALK inhibitor, crizotinib, and those who had not received prior treatment with an ALK inhibitor.
“The majority of patients in the study experienced a clinical response to LDK378. In addition, responses were seen in untreated lesions in the central nervous system in patients who previously received crizotinib,” said lead investigator Alice Shaw, of Massachusetts General Hospital Cancer Center. “These results are important because most patients experience a disease relapse less than a year after starting crizotinib and have limited treatment options.”
The study enrolled 130 patients, including 122 patients with ALK+ NSCLC. Of 114 ALK+ NSCLC patients treated with LDK378 at 400 mg or higher per day, 80 had progressed during or following treatment with crizotinib, and 34 patients with ALK+ NSCLC were crizotinib-naïve. The maximum tolerated dose observed in the study was 750 mg per day.
The median duration of response for the 66 responding patients treated at 400 mg or higher per day was 8.2 months [95% CI; 6.9-11.4 months]. In all 114 ALK+ NSCLC patients treated at 400 mg or higher per day, median PFS was 7.0 months [95% CI; 5.6-9.5 months].
In the 114 ALK+ NSCLC patients treated with LDK378 at 400 mg or higher per day, the ORR was 58 percent [95% CI; 48-67%] (1 CR and 65 PRs), which includes those patients who had progressed during or after crizotinib therapy (ORR 56 percent [95% CI; 45-67%]) and those who were crizotinib-naïve (ORR 62 percent [95% CI; 44-78%]).
In the 78 patients with ALK+ NSCLC who received LDK378 at the maximum tolerated dose of 750 mg per day, the ORR was 59 percent [95% CI; 47-70%] (46 PRs), which includes those who had progressed during or after crizotinib therapy (ORR 56 percent [95% CI; 41-70%]) and those who were crizotinib-naïve (ORR 64 percent [95% CI; 44-81%]).
Sixty-six of 130 patients (51 percent) required at least one dose reduction, and in 8 of 130 patients (6 percent), the study drug was permanently discontinued due to an adverse event. At the 750 mg dose level, 50 of 81 patients (62 percent) required at least one dose reduction, of which 32 occurred in cycle 3 or later. No treatment-related deaths occurred.
The most frequent adverse events were nausea, diarrhea, vomiting, fatigue and increased alanine aminotransferase levels. Preliminary data from this publication were first presented at the 2013 American Society of Clinical Oncology annual meeting. The study is ongoing with more data to become available.
Several major studies evaluating treatment with LDK378 are being conducted in more than 300 study centers across more than 30 countries. Currently, two phase II clinical trials (NCT01685060 and NCT01685138) are fully enrolled and ongoing. In addition, two phase III clinical trials (NCT01828099 and NCT01828112) are ongoing and are actively recruiting patients worldwide to further evaluate LDK378 in patients with ALK+ NSCLC.
