The accelerated path of ceritinib: Translating pre-clinical development into clinical efficacy

Abstract

The discovery of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved-ceritinib and alectinib-and others that are in development-brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor-pre-treated and -naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation-driven tumors.

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer

“…Ceritinib may also be used in the first or subsequent lines of therapy for ALK positive metastatic NSCLC. In preclinical models, it has been shown to be a more potent ALK inhibitor than Crizotinib [ 37 ]. However, it has not been directly compared to the first-in-class compound in the first-line or subsequent-line settings.…”

Ceritinib Aggravates Glycemic Control in Insulin-treated Patients with Diabetes and Metastatic ALK-positive Lung Cancer

“…Anaplastic lymphoma kinase (ALK) rearrangements that result from fusion with echinoderm microtubule-associated protein-like 4 define a distinct molecular subtype of non-small cell lung cancer (NSCLC) (1). Approximately 2-6% of patients with NSCLC exhibit ALK-positive NSCLC, with higher rates observed in a clinically enriched (younger, never-smokers) population of patients with adenocarcinoma (2). ALK-positive NSCLC depends on ALK for its growth and survival and shows marked sensitivity to selective ALK inhibitors (3).…”

Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

“…Several highly potent and selective ALK-targeted tyrosine kinase inhibitors (TKIs)-TAE684, crizotinib, LDK378 (ceritinib), and lorlatinib-effectively block ALK-driven cell growth in NB cell lines and tumor models (8,13,15,(17)(18)(19)(20). Whereas TAE684 did not advance beyond preclinical use, the U.S. Food and Drug Administration approved crizotinib as a first-in-line drug for ALK-positive non-small cell lung cancer (NSCLC) and designated LDK378 and lorlatinib as breakthrough therapies (21,22). These compounds are currently undergoing clinical evaluation for ALK-positive malignancies including NB (ClinicalTrials.gov: NCT01121588, NCT01742286, and NCT03107988) (23).…”