The second-generation oral ALK inhibitor ceritinib (Zykadia; LDK378) demonstrated rapid and durable responses in patients with ALK-positive, metastatic, nonâ€“small cell lung cancer (NSCLC)-regardless of whether they had been previously treated with crizotinib-achieving overall response rates of 60% or more in each subgroup of patients who had received zero to three prior therapies for their advanced lung cancer.
Dong-Wan Kim, MD, PhD
The second-generation oral ALK inhibitor ceritinib (Zykadia; LDK378) demonstrated rapid and durable responses in patients with ALK-positive, metastatic, non—small cell lung cancer (NSCLC)—regardless of whether they had been previously treated with crizotinib—achieving overall response rates of 60% or more in each subgroup of patients who had received zero to three prior therapies for their advanced lung cancer.
These longer-term results from the international phase I ASCEND-1 clinical trial were presented at the 2014 ASCO Annual Meeting by Dong-Wan Kim, MD, PhD, Seoul National University Hospital in South Korea. Initial results from this trial had established a recommended 750-mg daily dose of ceritinib for use in the expansion cohorts.
Ceritinib received accelerated approval from the FDA on April 29, 2014, for the treatment of ALK-positive metastatic NSCLC after initial treatment with the first-generation ALK inhibitor crizotinib (Xalkori). The approval was based on a single-arm trial that showed a 54.6% overall response rate with a median duration of response of 7.4 months.
These more mature data are important to validate the initial activity seen with ceritinib in this patient population, said Ranee Mehra, MD, another of the trial investigators and a medical oncologist at the Fox Chase Cancer Center in Philadelphia. In preclinical studies, ceritinib has been shown to be about 20 times more potent than crizotinib. “The increased potency [of ceritinib] seems to overcome a lot of resistance to crizotinib,” said D. Ross Camidge, MD, PhD, associate professor of medical oncology at the University of Colorado in Denver, who was not part of the study. “Hence, prolonged responses after acquired resistance to crizotinib are common [with ceritinib].”
The international, multicenter study reported here involved 246 patients with ALK-positive NSCLC: 163 patients were previously treated with crizotinib, and 83 patients were ALK inhibitor naïve. The median age was 53 years (range, 22-80), and 62% were never-smokers. Kim noted that overall, 42.7% of patients in the study (n = 105) were heavily treated (≥3 prior therapies). Of the 144 evaluable patients, the median duration of response was 9.69 and 7.39 months for all patients and ALK inhibitor—treated patients, respectively, and the progressionfree survival (PFS) was 8.21 and 6.9 months for each respective group. Analysis of ALK inhibitor–naïve patients is ongoing. Ceritinib also was found to be active in patients with brain metastases. The overall response rate was 54% (67 of 124 patients), and the median PFS was 6.9 months.
As of the October 31, 2013, data cutoff, 52% (128 patients) were still on treatment, of whom 74 were previously treated with an ALK inhibitor and 54 were ALK inhibitor naïve. Of the patients who discontinued the trial, 9.4% did so due to adverse events (AEs), including 17 ALK inhibitor—treated patients and seven patients who were ALK inhibitor naïve. Dose reductions occurred in 52.2% of patients (n = 133), and all were due to an AE, the researchers noted.
The most common all-grade AEs across all patients were gastrointestinal: diarrhea (86%), nausea (80%), vomiting (60%), and abdominal pain (54%), though only a small percentage of each were grade 3 or 4—6%, 4%, 4%, and 2%, respectively. High-grade laboratory abnormalities (grade 3/4) were elevated ALT, AST, and glucose, at 27%, 13%, and 13%, respectively. Ten patients developed pneumonitis. Two patients discontinued treatment, and there was one patient death, attributed to pneumonitis.
Camidge noted that the 50% dose-reduction rate indicates that although the adverse events are manageable by supportive measures or dose reductions, ceritinib is a more difficult drug to administer compared with crizotinib in many patients. “Developing a standardized algorithm based on good data to manage the side effects will be key.” “Ceritinib showed significant activity in a preclinical [mouse model] even in crizotinib-resistant models,” said Mehra. “This suggests that a subset of these tumors remain driven by the ALK kinase, even after [exposure to] an ALK inhibitor.”
According to Camidge, early rebiopsy analysis after progression of patients on crizontinib showed that the tumors had an ALK-dominant mechanism of resistance in 30% to 40% of the cases, resulting in either a mutation or gene copy number change. “But we are seeing about a 60% response rate which is a good problem to have,” he added. Nevertheless, further research will be required to understand the biology of the ALKdominant mechanism in these ALK inhibitor—exposed tumors.
Phase III trials of ceritinib that are currently recruiting patients include NCT01828112, which is comparing the drug to chemotherapy in ALK-positive NSCLC patients who have received prior chemotherapy and crizotinib, and NCT01828099, which is evaluating ceritinib in those who are both chemotherapy- and crizotinib-naïve.
Kim DW, Mehra R, Tan SW, et al. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial. J Clin Oncol. 2014;32:5s (suppl; abstr 8003).