Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of ALK-dependent cancer cells both in vitro and in vivo.
Ceritinib was evaluated in two single-arm studies in patients with ALK-positive NSCLC previously treated with an ALK inhibitor. Investigators used the overall response rate (ORR) as the primary efficacy endpoint.
In the first (phase I) study in patients who had previously received treatment with crizotinib (Xalkori) (n=80), the ORR was 56% (95% CI 45–67) and the median progression-free survival (PFS) was 6.9 months (95% CI 5.3–8.8).
The second (phase II) study evaluated the efficacy and safety of ceritinib in 140 patients who had been previously treated with 1-3 lines of cytotoxic chemotherapy followed by crizotinib, and who had then progressed on crizotinib. ORR with ceritinib was 37.1% (95% CI 29.1–45.7) and median PFS was 5.7 months (95% CI 5.3–7.4).
The most commonly reported adverse effects (≥10%) of ceritinib were GI upset, fatigue, abnormal LFT results, anorexia, raised blood creatinine, rash and anaemia.
Zykadia has been authorised under the 'conditional approval' scheme, meaning further evidence of clincial benefit from the ongoing second study, as well as a phase III study comparing ceritinib with other chemotherapy, is required.