What is the role of ceritinib in the treatment of non–small cell lung cancer (NSCLC)?

Updated: Jun 05, 2020
  • Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
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Answer

Ceritinib, an ALK inhibitor, received accelerated approval from the FDA in 2014 for patients with ALK-positive metastatic NSCLC whose disease had progressed or who were intolerant to crizotinib based on a blinded independent review committee (BIRC)-assessed ORR of 44% among 163 patients in a single-arm trial. A phase I study found that ceritinib at the dose of 400 mg daily provided a response rate of 58%, with a median progression-free survival of 7 months. Dose-limiting toxicity included diarrhea, vomiting, dehydration, elevated aminotransferase level, and hypophosphatemia. In this study, ceritinib was effective for both crizotinib-naive patients and those who had tumor progression with crizotinib. [185]

In May 2017, ceritinib was granted regular approval for patients with metastatic NSCLC whose tumors are ALK positive, as detected by an FDA-approved test. This approval also included use as first-line treatment. Approval was based on data from ASCEND-4, a randomized, multicenter, open-label, active-controlled trial conducted in patients with untreated ALK-positive NSCLC. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) test performed through central laboratory testing.

ASCEND-4 randomized 376 patients (1:1) to receive either ceritinib (n=189) 750 mg orally once daily until disease progression or platinum-pemetrexed doublet chemotherapy (n=187). Patients in the chemotherapy arm received pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC 5-6) on day 1 of every 21-day cycle for up to 4 cycles, followed by pemetrexed maintenance therapy. Results demonstrated improved PFS as assessed by BIRC, with a hazard ratio (HR) of 0.55 (P < 0.0001). The estimated median PFS was 16.6 months in the ceritinib arm and 8.1 months in the chemotherapy arm. Confirmed ORR, was 73% and 27% in the ceritinib and chemotherapy arms, respectively. Estimated median response durations were 23.9 months and 11.1 months in the ceritinib and chemotherapy arms, respectively. Overall survival data are immature. [186]

In the ASCEND-8 trial, 137 patients receiving ceritinib 450 mg or 600 mg daily with food (~100-500 calories and 1.5-15 grams of fat) or 750 mg daily under fasted conditions, there was no clinically meaningful difference in the systemic steady-state exposure of ceritinib (AUC) for the 450 mg with food arm compared to the 750 mg fasted arm. The steady-state AUC increased by 24% and the peak plasma concentration increased by 25% in the 600 mg with food arm compared to the 750 mg fasted arm. [187]

In the ASCEND-8 trial, 137 patients receiving ceritinib 450 mg or 600 mg daily with food (~100-500 calories and 1.5-15 grams of fat) or 750 mg daily under fasted conditions, there was no clinically meaningful difference in the systemic steady-state exposure of ceritinib (AUC) for the 450 mg with food arm compared to the 750 mg fasted arm. The steady-state AUC increased by 24% and the peak plasma concentration increased by 25% in the 600 mg with food arm compared to the 750 mg fasted arm. [187]


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