Updated results of the phase I ASCEND-1 trial, reported by Kim et al in The Lancet Oncology, indicate that the ALK inhibitor ceritinib (Zykadia) produced high response rates in advanced ALK-rearranged non–small cell lung cancer (NSCLC), including intracranial disease, in both patients with and without prior ALK inhibitor treatment.1
In the open-label trial, 246 patients enrolled from 20 sites in 11 countries in Europe, North America, and Asia-Pacific between January 2011 and July 2013 received oral ceritinib at 750 mg/d. Patients had ALK-rearranged locally advanced or metastatic disease that had progressed despite standard therapy or for which there was no effective standard therapy. A total of 83 patients had received no prior ALK inhibitor treatment, and 163 had received crizotinib (Xalkori), with 5 receiving alectinib (Alecensa) after crizotinib. In patients without and with prior ALK treatment, 53% and 54% of patients were female, 58% and 66% were white, and 42% and 29% were Asian.
At data cutoff in April 2014, median follow-up was 11.1 months. Response was observed in 60 (72%, 95% confidence interval [CI] = 61%–82%) of 83 ALK inhibitor–naive patients and 92 (56%, 95% CI = 49%–64%) of 163 ALK inhibitor–pretreated patients. Median duration of response was 17.0 months (95% CI = 11.3 months to not estimable) and 8.3 months (95% CI = 6.8–9.7 months).
Median progression-free survival was 18.4 months (95% CI = 11.1 months to not estimable) and 6.9 months (95% CI = 5.6–8.7 months). Median overall survival was not reached (95% CI = 19.6 months to not estimable) and 16.7 months (95% CI = 14.8 months to not estimable).
Among 94 patients with retrospectively confirmed brain metastases and at least one post-baseline imaging assessment, intracranial disease control was reported in 15 (79%, 95% CI = 54%–94%) of 19 ALK inhibitor–naive patients (complete or partial response in 42%) and in 49 (65%, 95% CI = 54%–76%) of 75 ALK inhibitor–pretreated patients (complete or partial response in 18%). Of 36 patients with measurable brain metastases at baseline, 25 had received radiotherapy to the brain. In these patients, response was achieved in 2 of 4 who were ALK inhibitor–naive and in 7 of 21 who had received ALK inhibitor treatment. Among the 11 who had not received brain radiotherapy, response was observed in three of four without and four of seven with prior ALK inhibitor treatment.
Serious adverse events were observed in 48% of patients. The most common grade 3 or 4 laboratory abnormalities were increased alanine transaminase (30%) and increased aspartate transaminase (10%). Gastrointestinal disorders occurred in 99% of patients, with the majority being grade 1 or 2. The most common grade 3 or 4 nonlaboratory adverse events were diarrhea (6%) and nausea (6%). Adverse events led to dose interruption in 74% of patients and dose reduction in 62%. Two patients died from adverse events considered related to study treatment: one from interstitial lung disease and one from multiorgan failure associated with infection and ischemic hepatitis.
The investigators concluded:
“The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases.”
Alice T. Shaw, MD, of Massachusetts General Hospital, is the corresponding author of The Lancet Oncology article. ■
Disclosure: The study was funded by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit www.thelancet.com.