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.

Keywords: ALK tyrosine kinase inhibitors; acquired resistance; anaplastic lymphoma kinase gene; non-small cell lung cancer.

Figure 1

Chemical structure of ceritinib.

Figure 2

Ceritinib is a potent and selective ALK tyrosine kinase inhibitor, with activity against various crizotinib and alectinib resistance mutations (in green). Ceritinib-resistant ALK mutations (in red) include G1202R and F1174C/L. Abbreviations: AKT, protein kinase B; ALK, anaplastic lymphoma kinase; BAD, Bcl-2-associated death promoter; EML4, echinoderm microtubule-associated protein-like 4; ERK, extracellular signal-regulated kinase; HELP, hydrophobic EMAP-like protein; JAK, Janus kinase; MEK, MAPK/Erk kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; STAT3, signal transducer and activator of transcription; TM, transmembrane domain; WD, tryptophan–aspartic acid.