1. There was a 58% response rate to ceritinib among non-small-cell lung cancer (NSCLC) patients.
2. Median progression-free survival among patients with NSCLC on ceritinib was 7.0 months.
3. Ceritinib was effective in patients who had previously failed treatment with the currently approved ALK inhibitor, crizotinib.
Evidence Rating Level: 2 (Good)
Study Rundown: In this phase I trial sponsored by Novartis, the anaplastic lymphoma kinase (ALK) inhibitor, ceritinib was tested on 140 patients with advanced cancers with ALK rearrangements to determine the maximum tolerated dose of ceritinib, as well as its safety profile and anti-tumor activity.
The majority of patients in the trial had non-small-cell lung cancers (NSCLC). ALK rearrangements occur in only about 5% of NSCLC, but the ALK inhibitor, crizotinib has been shown to produce response rates of about 60% and median progression-free survival of 8 to 10 months in patients with such tumors. Resistance to crizotinib typically develops within 12 months.
A total of 114 patients with NSCLC received ceritinib at a dose of at least 400 mg/day, which produced a response rate and median progression-free survival comparable to published figures for crizotinib: 58% response rate, median progression-free survival of 7.0 months. These results are strengthened by the relatively large size of this phase I trial.
The study also reports data which suggests that ceritinib has good activity against tumors that are resistant to crizotinib. First, they found that response rates to ceritinib were similar between patients who had previously received crizotinib and those who had not. Second, they found tumor response to ceritinib among 7 patients with documented resistance mutations to crizotinib. These results suggest that ceritinib could be useful as a second-line agent after crizotinib to extend progression-free survival in patients with advanced ALK-rearranged NSCLC.
Relevant Reading: Anaplastic lymphoma kinase in human cancer
In-Depth [phase 1 trial]: A maximum tolerated dose of 750 mg was established in 59 patients during a dose-escalation phase of the study. Subsequently, 71 additional patients were enrolled and treated, for a total of 130 patients in the trial. Eight patients enrolled had tumors with ALK rearrangements which were not NSCLC. The remaining 122 patients had advanced NSCLC and 83 of these patients had previously received crizotinib.
Of 114 patients with NSCLC who received at least 400 mg/day of ceritinib, the overall response rate was 58% (95% CI, 48 to 67). Among patients who received crizotinib previously, the overall response rate was 56% (95% CI, 45 to 67).
Dose-limiting toxic events included diarrhea, nausea, vomiting, elevated aminotransferase levels and hypophosphatemia. Ceritinib was permanently discontinued in 8 of 130 patients due to an adverse event.
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