Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

Abstract

The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib’s efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse. Different mechanisms of acquired resistance have been identified, including secondary ALK mutations, ALK copy number alterations and activation of bypass tracks. Different highly potent and brain-penetrant next-generation ALK inhibitors have been developed and tested in NSCLC patients with ALK rearrangements. Ceritinib, a structurally distinct and selective ALK inhibitor, showed 20 times higher potency than crizotinib in inhibiting ALK and had activity against the most common crizotinib-resistant mutations, including L1196M and G1269A, in preclinical models. In Phase I and II studies, ceritinib demonstrated pronounced activity in both crizotinib-naïve and crizotinib-refractory patients, with responses observed regardless of the presence of ALK resistance mutations. Ceritinib was the first ALK inhibitor to be approved for the treatment of crizotinib-refractory, ALK-rearranged NSCLC, and recent results from a Phase III study have demonstrated superior efficacy compared to standard chemotherapy in the first- and second-line setting. We provide an extensive overview of ceritinib from the design of the compound through preclinical data until efficacy and toxicity results from Phase I–III clinical studies. We review the molecular alterations associated with resistance to ceritinib and highlight the importance of obtaining tumor biopsy at progression to tailor therapy based upon the underlying resistance mechanism. We finally provide an outlook on novel rational therapeutic combinations.

Partial Response to Ceritinib in a Patient With Abdominal Inflammatory Myofibroblastic Tumor Carrying a TFG-ROS1 Fusion

“…In enzymatic assays, ceritinib showed 20 times greater potency than crizotinib against ALK. 24 In addition, ceritinib has shown comparable activity to crizotinib against ROS1. 25,26 In an open-label multicenter phase II study, ceritinib showed potent clinical activity in patients with NSCLC harboring ROS1 rearrangement, with a 62% objective response rate and 9.3 and 19.3 months of median progression-free survival among all patients and those who were crizotinib-naïve, respectively.…”

Recent advances in targeted small‐molecule inhibitor therapy for non–small‐cell lung cancer—An update

“…The EML4–ALK fusion gene results in an oncogenic fusion protein that promotes cell proliferation, differentiation and inhibits apoptosis. This is mediated through activation of the tyrosine kinase function of ALK and its downstream signalling, namely the Ras/MAPK, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K)/protein kinase B (AKT) and Janus kinase (JAK)/signal transducer and transcription activation pathways . Alectinib and crizotinib are the earlier small‐molecule inhibitors of ALK kinase available for ALK translocation‐positive cancer.…”

“…In addition, secondary mutations, namely, L1196M and C1156Y emerged, contributing to tumour resistance. Whereas the gate keeper mutation L1196M hinders drug binding, G1269A mutation in the ATP binding pocket affects the ALK‐TKI interaction …”

“…Presence of neither the gatekeeper L1169M mutation nor G1269A inhibited ceritinib activity. In rodent models, it has shown penetration into the BBB with a brain‐to‐blood exposure (AUC INF ) of approximately 15% . However, with prolonged use, a new mutation like G1202R or F1174C/L emerges, rendering the tumour unresponsive.…”

Ceritinib in the treatment of ALK-positive patients with nonsmall-cell lung cancer

“…Церитиниб -высокоселективный мощный ингибитор киназы анапластической лимфомы второго поколения. В доклинических исследованиях было показано, что церитиниб ингибирует активность ALK-киназы приблизительно в 20 раз мощнее, чем кризотиниб, и обладает способностью проникать через гематоэнцефалический барьер [2]. В одном из первых клинических исследований I фазы ASCEND-1 была продемонстрирована высокая противоопухолевая активность церитиниба.…”