Byoung Chul Cho, MD, PhD
A lower dose of ceritinib (Zykadia) taken with a low-fat meal showed similar efficacy with fewer dose reductions and less severe gastrointestinal (GI) adverse events (AEs) versus a 750-mg dose taken without food for patients with untreated ALK
-positive metastatic non–small cell lung cancer (NSCLC), according to findings from the ASCEND-8 trial presented at the 18th World Conference on Lung Cancer (WCLC).
The median progression-free survival (PFS) was 17.6 months in those treated with the 450-mg dose (95% CI, 8.5-NE) and was 10.9 months (95% CI, 6.3-NE) for those treated with ceritinib at 750 mg after fasting. There were also significant improvements with the 450-mg versus 750-mg doses for grade 3/4 diarrhea (1.1% vs 7.8%, respectively), nausea (0% vs 5.6%), and vomiting (0% vs 4.4%).
"Overall, these data suggest that ceritinib at a dose of 450 mg with food could be a potential new treatment regimen for managing GI AEs with similar efficacy as 750 mg fasted dose in treatment-naive patients with ALK-rearranged advanced NSCLC," said investigator Byoung Chul Cho, MD, PhD, an associate professor at Yonsei Cancer Center in Seoul, the Republic of Korea. "This study is ongoing and enrolling treatment-naive NSCLC patients with ALK rearrangements."
Ceritinib received an accelerated approval from the FDA in April 2014 for patients with ALK-positive NSCLC following progression or intolerance to crizotinib (Xalkori). In May 2017, based on findings from the ASCEND-4 trial, a full regulatory approval was granted, and the indication was expanded to include the frontline setting. The current FDA recommended dose of ceritinib is 750 mg taken at least 1 hour before or at least 2 hours after a meal.
In the randomized phase I ASCEND-8 study, 267 patients were enrolled across 3 cohorts. All patients had stage IIIB/IV ALK
-positive NSCLC. Approximately half of patients in each group were treatment-naive (TN). In the first group, 89 patients (TN = 41) received ceritinib at 450 mg with a low-fat meal; in the second group, 87 patients (TN = 40) got ceritinib at 600 mg with a low-fat meal; and, in the final group, 91 patients (TN = 40) received 750-mg ceritinib after fasting.
Findings presented at WCLC were from a planned interim analysis for TN patients detected by IHC (N = 121). Safety findings were from all enrolled patients who received ≥1 dose of ceritinib (N = 265). The median ages were 59, 52, and 51 years in the 450 mg, 600 mg, and 750 mg arms, respectively. Most patients were never smokers (range, 55%-67.5%) and the ECOG performance status was most commonly 1 (56.1% to 62.5%). A third of patients had brain metastases and the most common prior therapy was radiotherapy (22% of patients).
By blinded independent review committee, the objective response rate (ORR), which consisted primarily of partial responses, was similar across groups. The highest ORR was seen in the 450-mg group, at 78%. In the 600-mg arm, the ORR was 75% and in the 750-mg group the ORR was 70%. When considering stable disease, the disease control rates were 92.7%, 92.5%, and 90% in the 450 mg, 600 mg, and 750 mg arms, respectively.
The median time to response was the same in all 3 groups (6.3 weeks). The median duration of response was 16.4 months in the 450-mg group and was not evaluable (NE) for those in the 600-mg arm. In the 750-mg arm, the median duration of response was 10.4 months.
In the 450-mg arm, the 15-month PFS rate was 66.4%. For the 600-mg group, the median PFS was not yet evaluable (95% CI, 8.3-NE) and the 15-month PFS rate was 58%. In the 750-mg group, the 15-month PFS rate was 41%. "Of note, the 12-month duration of response and the 15-month PFS rates were highest in the 450-mg ceritinib arm," said Cho.
The median treatment exposure was 37.9 weeks in the 450-mg group versus 35.3 and 33.1 weeks in the 600 mg and 750 mg groups, respectively. The median relative dose intensity was 100% in the 450-mg arm compared with 85.8% and 90.2% in the 600 mg and 750 mg groups, respectively. Just 18% of patients required ≥1 dose reduction and 42.7% required a dose interruption in the 450-mg arm. In the 600 mg and 750 mg groups, respectively, the rates of dose reductions were nearly tripled (58.1% and 51.1%) and dose interruptions were more common (64% and 61.1%).
All-cause serious AEs were experienced by 22.5% of patients in the 450-mg group and by 29.1% and 22.2% of those in the 600 mg and 750 mg groups, respectively. AEs leading to treatment discontinuation were similar across groups and "there were no study-drug related on-treatment deaths among the 3 treatment arms," noted Cho.
Overall, outside of GI toxicity, the AE profiles were similar across the 3 groups, he noted. For the 450 mg, 600 mg, and 750 mg doses, respectively, all-grade AE differences were seen for diarrhea (56.2% vs 61.6% vs 75.6%), nausea (44.9% vs 55.8% vs 50%), and vomiting (34.8% vs 53.5% vs 55.6%).
"In the 450-mg fed arm, there were no GI AEs leading to study drug discontinuation, and lower GI AEs leading to dose adjustment or interruption. There were no GI AEs requiring dose reduction," said Cho. "This is probably because a majority of these patients had grade 1 toxicity, so all patients could resume the original dose of ceritinib after a short duration of interruption."
Cho BC, Obermannová R, Bearz A, et al. Efficacy and Updated Safety of Ceritinib (450 Mg or 600 Mg) with Low-Fat Meal vs 750 Mg Fasted in ALK+ Metastatic NSCLC. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract 9366.
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