Authors: Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA
Study Type: Large prospective phase I trial with a dose-escalation phase evaluating 10 doses of ceritinib, and a three-arm expansion phase with efficacy endpoints
Study Treatment: Ceritinib (Zykadia, LDK378), an oral tyrosine kinase inhibitor of ALK. In the phase I dose escalation portion, ceritinib was administered orally once with a three-day PK evaluation period, and subsequently daily oral dosing for 21-day cycle. In the expansion portion, ceritinib was administered once orally daily at the MTD for each 21-day cycle, with treatment until progression, unacceptable toxicity, or withdrawal.
Eligibility: NSCLC patients with an ALK rearrangement or patients with other cancers with genetic aberrations in ALK were eligible. Patients with asymptomatic central nervous system metastases were eligible. Patients who had received prior treatment with ALK inhibitors were eligible.
Outcome Measures: In the phase I dose-escalation portion, the safety outcome endpoints were the maximum tolerated dose and dose-limiting toxicities. In the phase I expansion portion, the efficacy outcome endpoints included overall response rate and progression-free survival.
Results: 130 patients were treated as of October 2012. 59 patients were treated in the dose-escalation portion and 71 were treated in the expansion phase, with 114 NSCLC patients treated at at least the 400mg ceritinib dose level. The MTD was 750mg and dose-limiting toxicities included diarrhea, vomiting, nausea, dehydration, elevated aminotransferase level and hypophosphatemia. The response rate in 114 patients treated with 400mg ceritinib or higher was 58% and median progression free survival was 7 months. One patient with anaplastic large-cell lymphoma and one patient with inflammatory myofibroblastic tumor also demonstrated a response to ceritinib therapy.
Acquired resistance subgroup
: 19 patients with crizotinib-resistant ALK-rearranged NSCLC had a repeat biopsy before treatment with ceritinib. Five patients had NSCLC harboring the resistance mutations
ALK L1196M (3 patients), S1206Y (1 patient) and G1269A+1151Tins (1 patient). Two patients had NSCLC with ALK amplification. The response rate in the crizotinib-resistant NSCLC patients treated with ceritinib was 68%.