Spotlight on ceritinib in the treatment of ALK plus NSCLC: design, development and place in therapy
Por:
Santarpia, M, Daffina, MG, D'Aveni, A, Marabello, G, Liguori, A, Giovannetti, E, Karachaliou, N, Cao, MG, Rosell, R and Altavilla, G
Publicada:
1 ene 2017
Resumen:
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-naive 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.
Filiaciones:
Santarpia, M:
Univ Messina, Dept Human Pathol G Barresi, Med Oncol Unit, Via Consolare Valeria 1, Messina, Italy
Daffina, MG:
Univ Messina, Dept Human Pathol G Barresi, Med Oncol Unit, Via Consolare Valeria 1, Messina, Italy
D'Aveni, A:
Univ Messina, Dept Human Pathol G Barresi, Med Oncol Unit, Via Consolare Valeria 1, Messina, Italy
Marabello, G:
Univ Messina, Dept Human Pathol G Barresi, Med Oncol Unit, Via Consolare Valeria 1, Messina, Italy
Liguori, A:
Univ Messina, Dept Human Pathol G Barresi, Med Oncol Unit, Via Consolare Valeria 1, Messina, Italy
Giovannetti, E:
Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands
Univ Pisa, Inst Nanosci & Nanotechnol, Dept Nanosci & Nanotechnol, CNR Nano, Pisa, Italy
Univ Pisa, Canc Pharmacol Lab, AIRC Start Up Unit, Pisa, Italy
Karachaliou, N:
Univ Hosp Sagrat Cor, IOR, Barcelona, Spain
Cao, MG:
Quiron Dexeus Univ Inst, IOR, Oncol Dept, Barcelona, Spain
:
Germans Trias & Pujol Univ Hosp, Germans Trias & Pujol Res Inst, Canc Biol & Precis Med Program, Badalona, Spain
Germans Trias & Pujol Univ Hosp, Catalan Inst Oncol, Badalona, Spain
Altavilla, G:
Univ Messina, Dept Human Pathol G Barresi, Med Oncol Unit, Via Consolare Valeria 1, Messina, Italy
Green Published, gold, Green Submitted
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