Ceritinib in ALK-rearranged non-small-cell lung cancer

Abstract

Background: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.

Methods: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.

Results: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).

Conclusions: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Figure 1. Response to Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer (NSCLC)

Panel A shows the change in tumor size after patients received ceritinib at doses of 400 to 750 mg per day. The bars indicate the largest percentage change in target lesions from baseline. The dashed line indicates a 30% reduction from baseline. Dots below individual bars indicate patients with disease progression or death at the time of data cutoff. Panel B shows positron- emission tomographic scans taken at baseline (left) and after 3.5 weeks of ceritinib treatment (right) in a patient with crizotinib-resistant disease. Subsequent computed tomographic scans after 6 weeks of ceritinib treatment showed a 52% reduction in tumor burden in this patient.

Figure 2. Progression-free Survival

Shown are Kaplan–Meier estimates of progression-free survival among patients with advanced, ALK-rearranged non–small-cell lung cancer (NSCLC) who received ceritinib at doses of 400 to 750 mg daily. In these 114 patients, the median progression-free survival was 7.0 months (blue). In the subgroup of 80 patients who had received crizotinib previously, the median progression-free survival was 6.9 months (orange). In the subgroup of 34 patients who had not received crizotinib previously, the median progression-free survival was not reached (green). Vertical lines on the survival curves indicate censoring of data.

Figure 3. Correlation of Response to Ceritinib with ALK Gene Alteration among Patients with Crizotinib Resistance

A total of 19 patients with crizotinib-resistant, ALK-rearranged non–small-cell lung cancer underwent biopsy at one study site before the initiation of ceritinib. Shown here is the largest percentage decrease in target lesions in these 19 patients. All the tumors were positive for ALK rearrangement, on the basis of the standard fluorescence in situ hybridization (FISH) assay with the use of break-apart probes. ALK genotypes are shown above the bars. Amp denotes amplification of the ALK fusion gene as determined by means of FISH, and NM no ALK mutation or amplification. Data are shown for patients who had received crizotinib as the last therapy before ceritinib treatment (dark blue bars) and for patients who received any intervening systemic therapy between crizotinib and ceritinib (light blue bars). Dots below individual bars indicate patients with disease progression or death at the time of data cutoff.