Ceritinib, a highly selective second-generation anaplastic lymphoma kinase (ALK) inhibitor, suppresses the phosphorylation of ALK and thereby inhibits the proliferation of ALK-positive cancer cells. Ceritinib is recommended as first-line treatment for adults with ALK-positive advanced NSCLC, based on its recent approval by the US Food and Drug Administration (FDA) and has received a positive statement by the European Committee for Medicinal Products for Human Use (CHMP) in Europe.

The approval was based on an open-label, randomised, multicentre trial, ASCEND-4 (phase III). ASCEND-4 evaluated the comparative efficacy and safety of ceritinib versus platinum-based chemotherapy in a total of 376 untreated patients with advanced ALK-positive non-squamous NSCLC.
Compared with chemotherapy, ceritinib increased median progression-free survival (PFS) by 8.5 months in the intent-to-treat population. The PFS benefit of ceritinib over chemotherapy was reported in patients regardless of the presence or absence of baseline brain metastases (BM). At the time of analysis, overall survival (OS) data were not mature. In addition, ceritinib significantly improved the general quality of life (QoL) and prolonged time to deterioration for cancer-specific symptoms compared with chemotherapy. The most common adverse events (AEs) were diarrhoea, nausea, vomiting and increased alanine aminotransferase in ceritinib recipients and nausea, vomiting and anaemia in chemotherapy recipients. AEs requiring dose adjustment or interruption were reported in 80% of ceritinib patients versus 45% of patients receiving chemotherapy.

Overall, ceritinib increased PFS and duration of response in untreated ALK-positive NSCLC, regardless of the presence or absence of baseline BM, relative to platinum-based chemotherapy. Ceritinib also improved general QoL and prolonged time to deterioration of cancer-specific symptoms compared to chemotherapy. However, results from ASCEND-4 hold limited external validity as crizotinib is now standard care over chemotherapy for ALK-positive NSCLC and it is unclear whether increased PFS actually confers a meaningful change in OS. Comparative studies of other second- and third-generation ALK inhibitors are ongoing which may offer further first-line options.