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Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions.
Lavacchi, Daniele; Caliman, Enrico; Rossi, Gemma; Buttitta, Eleonora; Botteri, Cristina; Fancelli, Sara; Pellegrini, Elisa; Roviello, Giandomenico; Pillozzi, Serena; Antonuzzo, Lorenzo.
Afiliação
  • Lavacchi D; Clinical Oncology Unit, Careggi University Hospital, Florence, Italy.
  • Caliman E; Clinical Oncology Unit, Careggi University Hospital, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Rossi G; Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
  • Buttitta E; Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
  • Botteri C; Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
  • Fancelli S; Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
  • Pellegrini E; Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
  • Roviello G; Department of Health Science, University of Florence, Firenze, Italy.
  • Pillozzi S; Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
  • Antonuzzo L; Clinical Oncology Unit, Careggi University Hospital, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. Electronic address: lorenzo.antonuzzo@unifi.it.
Pharmacol Ther ; 237: 108170, 2022 09.
Article em En | MEDLINE | ID: mdl-35296436
ABSTRACT
To date, treatment options for patients with chemorefractory cholangiocarcinoma (CCA) are limited. However, the advancements in molecular techniques have recently increased the opportunity to offer molecularly targeted therapies to patients with several cancer types and some targetable oncogenic alterations have been identified also in CCA. Among these potentially actionable molecular alterations, isocitrate dehydrogenase-1 (IDH1) mutations have been detected in approximately 10-20% of intrahepatic CCA (iCCA). IDH1 is responsible for the accumulation of oncometabolites inducing epigenetic changes that are involved in various signaling pathways. Ivosidenib is the first IDH1 inhibitor which significantly improved progression-free survival (PFS) (2.7 vs 1.4 months) and overall survival (OS) (10.3 vs 5.1 months [adjusted median OS]) compared with placebo in chemorefractory IDH1-mutated CCA. The very low incidence of grade (G) 3-4 adverse events (AEs) and treatment discontinuation due to toxicity, associated with a significantly less marked decline in health-related quality of life for patients in the ivosidenib group than in placebo group, facilitates patient adherence and clinician confidence. Here, we review the development of ivosidenib in CCA patients and evaluate the clinical impact of the results of the phase III ClarIDHy trial which was responsible for the Food and Drug Administration (FDA) approval for patients with IDH1-mutated CCA whose disease progressed after standard chemotherapy (CT). We also discuss the known primary and secondary resistance mechanisms, including concomitant and acquired mutations in other genes (e.g. IDH2 mutations), second-site mutation in IDH1, and enhanced activation of other pathways (e.g. PI3K/AKT/mTOR pathway). Finally we examine the future directions, as the opportunity to combine ivosidenib with other synergistic agents, including standard chemotherapy (CT), immune checkpoint inhibitors (ICIs), and IDH2 inhibitors.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias dos Ductos Biliares / Colangiocarcinoma / Antineoplásicos Tipo de estudo: Clinical_trials Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias dos Ductos Biliares / Colangiocarcinoma / Antineoplásicos Tipo de estudo: Clinical_trials Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article