PMID- 35296436
OWN - NLM
STAT- MEDLINE
DCOM- 20220816
LR  - 20220823
IS  - 1879-016X (Electronic)
IS  - 0163-7258 (Linking)
VI  - 237
DP  - 2022 Sep
TI  - Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future 
      directions.
PG  - 108170
LID - S0163-7258(22)00064-X [pii]
LID - 10.1016/j.pharmthera.2022.108170 [doi]
AB  - 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.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Lavacchi, Daniele
AU  - Lavacchi D
AD  - Clinical Oncology Unit, Careggi University Hospital, Florence, Italy.
FAU - Caliman, Enrico
AU  - Caliman E
AD  - Clinical Oncology Unit, Careggi University Hospital, Florence, Italy; Department 
      of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
FAU - Rossi, Gemma
AU  - Rossi G
AD  - Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
FAU - Buttitta, Eleonora
AU  - Buttitta E
AD  - Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
FAU - Botteri, Cristina
AU  - Botteri C
AD  - Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
FAU - Fancelli, Sara
AU  - Fancelli S
AD  - Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
FAU - Pellegrini, Elisa
AU  - Pellegrini E
AD  - Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
FAU - Roviello, Giandomenico
AU  - Roviello G
AD  - Department of Health Science, University of Florence, Firenze, Italy.
FAU - Pillozzi, Serena
AU  - Pillozzi S
AD  - Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
FAU - Antonuzzo, Lorenzo
AU  - Antonuzzo L
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20220313
PL  - England
TA  - Pharmacol Ther
JT  - Pharmacology & therapeutics
JID - 7905840
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Pyridines)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - EC 1.1.1.42. (IDH1 protein, human)
RN  - Q2PCN8MAM6 (ivosidenib)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - *Antineoplastic Agents/adverse effects
MH  - *Bile Duct Neoplasms/chemically induced/drug therapy/genetics
MH  - Bile Ducts, Intrahepatic
MH  - *Cholangiocarcinoma/chemically induced/drug therapy/genetics
MH  - Glycine/analogs & derivatives
MH  - Humans
MH  - Isocitrate Dehydrogenase/genetics
MH  - Mutation
MH  - Phosphatidylinositol 3-Kinases/genetics/therapeutic use
MH  - Pyridines
MH  - Quality of Life
OTO - NOTNLM
OT  - Cholangiocarcinoma
OT  - ClarIDHy
OT  - D-2-hydroxyglutarate
OT  - IDH1
COIS- Declaration of Competing Interest The authors declare that they have no competing 
      interests.
EDAT- 2022/03/18 06:00
MHDA- 2022/08/17 06:00
CRDT- 2022/03/17 05:30
PHST- 2021/12/02 00:00 [received]
PHST- 2022/03/04 00:00 [revised]
PHST- 2022/03/08 00:00 [accepted]
PHST- 2022/03/18 06:00 [pubmed]
PHST- 2022/08/17 06:00 [medline]
PHST- 2022/03/17 05:30 [entrez]
AID - S0163-7258(22)00064-X [pii]
AID - 10.1016/j.pharmthera.2022.108170 [doi]
PST - ppublish
SO  - Pharmacol Ther. 2022 Sep;237:108170. doi: 10.1016/j.pharmthera.2022.108170. Epub 
      2022 Mar 13.