ALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK signaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; this generates an EML4-ALK fusion protein containing the protein kinase domain of ALK fused to the N-terminal part of EML4. Ceritinib was demonstrated to be effective against EML4-ALK activity in a NSCLC cell line (H2228), resulting in inhibition of cell proliferation in vitro and regression of tumours in H2228-derived xenografts in mouse and rat.
Clinical efficacy and safety
Previously untreated ALK-positive advanced NSCLC - randomised phase 3 Study A2301 (ASCEND-4)
The efficacy and safety of Zykadia for the treatment of advanced ALK-positive NSCLC patients who have not received previous systemic treatment anti-cancer therapy (including ALK inhibitor) with the exception of neo-adjuvant or adjuvant therapy, was demonstrated in a global multicentre, randomised, open-label phase 3 Study A2301.
A total of 376 patients were randomised in a 1:1 ratio (stratified by WHO performance status, prior adjuvant/neoadjuvant chemotherapy and presence/absence of brain metastasis at screening) to receive either ceritinib (750 mg daily, fasted) or chemotherapy (based on investigator's choice - pemetrexed [500 mg/m2] plus cisplatin [75 mg/m2] or carboplatin [AUC 5-6], administered every 21 days). Patients who completed 4 cycles of chemotherapy (induction) without progressive disease subsequently received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days. One hundred and eighty-nine (189) patients were randomised to ceritinib and one hundred eighty-seven (187) were randomised to chemotherapy.
The median age was 54 years (range: 22 to 81 years); 78.5% of patients were younger than 65 years. A total of 57.4% of patients were female. 53.7% of the study population was Caucasian, 42.0% Asian, 1.6% Black and 2.6% other races The majority of patients had adenocarcinoma (96.5%) and had either never smoked or were former smokers (92.0%). The Eastern Cooperative Oncology Group (ECOG) performance status was 0/1/2 in 37.0%/56.4%/6.4% of patients, and 32.2% had brain metastasis at baseline. 59.5% of patients with brain metastasis at baseline received no prior radiotherapy to the brain. Patients with symptomatic CNS (central nervous system) metastases who were neurologically unstable or had required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms, were excluded from the study.
Patients were allowed to continue the assigned study treatment beyond initial progression in case of continued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapy arm could cross-over to receive cer