IDH-mutant cholangiocarcinoma is a molecularly defined subtype of intrahepatic cholangiocarcinoma characterized by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2). IDH mutations occur in approximately 15-20% of intrahepatic cholangiocarcinomas and cause production of the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits alpha-ketoglutarate-dependent dioxygenases and leads to widespread epigenetic dysregulation. IDH-mutant cholangiocarcinomas have distinct clinical features including younger age at onset and better prognosis compared to IDH wild-type tumors. Ivosidenib, a selective IDH1 inhibitor, demonstrated improved progression-free survival in the ClarIDHy trial, establishing it as standard therapy for IDH1-mutant cholangiocarcinoma.
Ask a research question about IDH-Mutant Cholangiocarcinoma. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: IDH-Mutant Cholangiocarcinoma
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
IDH-mutant cholangiocarcinoma is a molecularly defined subtype of intrahepatic cholangiocarcinoma
characterized by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2). IDH mutations
occur in
approximately 15-20% of intrahepatic cholangiocarcinomas and cause production of
the oncometabolite
2-hydroxyglutarate (2-HG), which inhibits alpha-ketoglutarate-dependent dioxygenases
and leads to
widespread epigenetic dysregulation. IDH-mutant cholangiocarcinomas have distinct
clinical features
including younger age at onset and better prognosis compared to IDH wild-type tumors.
Ivosidenib,
a selective IDH1 inhibitor, demonstrated improved progression-free survival in the
ClarIDHy trial,
establishing it as standard therapy for IDH1-mutant cholangiocarcinoma.
categories:
- Gastrointestinal Cancer
- Hepatobiliary Cancer
- Molecularly Defined Cancer
parents:
- intrahepatic cholangiocarcinoma
pathophysiology:
- name: IDH1/2 Neomorphic Mutation
description: >-
IDH1 R132 or IDH2 R140/R172 mutations are neomorphic, conferring a new enzymatic
function.
Instead of converting isocitrate to alpha-ketoglutarate (aKG), mutant IDH converts
aKG
to the oncometabolite D-2-hydroxyglutarate (2-HG). 2-HG accumulates to millimolar
concentrations in tumor cells.
evidence:
- reference: PMID:25536104
reference_title: "Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications."
supports: PARTIAL
snippet: "Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%)."
explanation: "Supports the presence of IDH1 mutations in intrahepatic cholangiocarcinoma."
cell_types:
- preferred_term: cholangiocyte
term:
id: CL:1000488
label: cholangiocyte
molecular_functions:
- preferred_term: isocitrate dehydrogenase (NADP+) activity
modifier: ABNORMAL
term:
id: GO:0004450
label: isocitrate dehydrogenase (NADP+) activity
locations:
- preferred_term: intrahepatic bile duct
term:
id: UBERON:0003704
label: intrahepatic bile duct
downstream:
- target: 2-HG Accumulation and Dioxygenase Inhibition
description: Oncometabolite production inhibits aKG-dependent enzymes
- name: 2-HG Accumulation and Dioxygenase Inhibition
description: >-
2-HG is structurally similar to alpha-ketoglutarate and competitively inhibits
aKG-dependent dioxygenases, including TET2 (DNA demethylation), JMJD histone
demethylases, and prolyl hydroxylases. This leads to widespread epigenetic and
metabolic dysregulation.
evidence:
- reference: PMID:24569570
reference_title: "Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma."
supports: SUPPORT
snippet: "These mutations result in elevated levels of an oncometabolite, 2-hydroxyglutarate, which is associated with higher DNA CpG methylation and altered histone methylation that accompany a block in cellular differentiation."
explanation: "Abstract links IDH mutations to elevated 2-hydroxyglutarate and epigenetic effects."
downstream:
- target: Epigenetic Dysregulation and DNA Hypermethylation
description: TET2 inhibition blocks DNA demethylation
- target: Histone Methylation Alterations
description: JMJD inhibition alters histone methylation landscape
- name: Epigenetic Dysregulation and DNA Hypermethylation
description: >-
2-HG inhibition of TET2 blocks conversion of 5-methylcytosine to 5-hydroxymethylcytosine,
causing DNA hypermethylation. This CpG island methylator phenotype (CIMP) silences
tumor suppressor genes and differentiation programs, contributing to the block
in
cellular differentiation characteristic of IDH-mutant tumors.
biological_processes:
- preferred_term: DNA methylation
modifier: INCREASED
term:
id: GO:0040029
label: epigenetic regulation of gene expression
downstream:
- target: Differentiation Block and Tumor Growth
description: Epigenetic silencing impairs normal differentiation programs
- name: Histone Methylation Alterations
description: >-
2-HG inhibits Jumonji domain-containing histone demethylases, leading to accumulation
of repressive histone methylation marks (H3K9me3, H3K27me3). This contributes
to
transcriptional silencing and the differentiation block.
- name: Differentiation Block and Tumor Growth
description: >-
Combined epigenetic alterations block normal cholangiocyte differentiation, maintaining
cells in a progenitor-like state with proliferative capacity. This promotes tumor
growth while the cells retain sensitivity to IDH inhibition, which can restore
differentiation programs.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
histopathology:
- name: Well Differentiated Cholangiocarcinoma
finding_term:
preferred_term: Cholangiocarcinoma
term:
id: NCIT:C4436
label: Cholangiocarcinoma
frequency: VERY_FREQUENT
description: Most cholangiocarcinomas are well differentiated.
evidence:
- reference: PMID:12901270
reference_title: "[Cholangiocarcinoma--bile ducts cancer]."
supports: PARTIAL
snippet: "Histologically, 90-95% of CC are well differentiated"
explanation: Abstract notes that the majority of cholangiocarcinomas are well differentiated.
phenotypes:
- category: Hepatic
name: Hepatomegaly
frequency: FREQUENT
description: >-
Liver enlargement from tumor mass. Intrahepatic cholangiocarcinoma typically presents
as a liver mass.
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
- category: Hepatic
name: Jaundice
frequency: FREQUENT
description: >-
Jaundice may result from biliary obstruction by tumor or diffuse hepatic involvement.
Less common in intrahepatic compared to hilar or distal cholangiocarcinoma.
phenotype_term:
preferred_term: Jaundice
term:
id: HP:0000952
label: Jaundice
- category: Gastrointestinal
name: Abdominal Pain
frequency: FREQUENT
description: >-
Right upper quadrant pain or discomfort from tumor mass effect or liver capsule
involvement.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Constitutional
name: Weight Loss
frequency: FREQUENT
description: >-
Unintentional weight loss from cancer cachexia and reduced oral intake.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
- category: Constitutional
name: Fatigue
frequency: FREQUENT
description: >-
Fatigue from hepatic dysfunction and advanced disease.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Gastrointestinal
name: Nausea
frequency: OCCASIONAL
description: >-
Nausea from hepatic dysfunction or disease-related effects.
phenotype_term:
preferred_term: Nausea
term:
id: HP:0002018
label: Nausea
biochemical:
- name: Serum 2-HG
notes: >-
D-2-hydroxyglutarate can be measured in serum and serves as a pharmacodynamic
biomarker
for IDH inhibitor activity. Levels decrease with effective IDH inhibition.
- name: CA 19-9
notes: >-
Carbohydrate antigen 19-9 is often elevated in cholangiocarcinoma but is not specific.
Useful for monitoring treatment response when elevated at baseline.
- name: Liver Function Tests
notes: >-
Elevated alkaline phosphatase, GGT, and bilirubin may indicate biliary obstruction.
Transaminases may be elevated with hepatic involvement.
genetic:
- name: IDH1
association: Somatic Neomorphic Mutation
notes: >-
IDH1 R132 mutations (R132C, R132H, R132G, R132S, R132L) occur in approximately
15%
of intrahepatic cholangiocarcinomas. The R132C substitution is most common in
cholangiocarcinoma (unlike R132H in glioma). Ivosidenib specifically targets IDH1
mutant protein.
evidence:
- reference: PMID:24569570
reference_title: "Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma."
supports: PARTIAL
snippet: "Hotspot mutations in IDH isoforms 1 or 2 occur in approximately 15% of intrahepatic cholangiocarcinomas."
explanation: "Abstract reports IDH1/2 hotspot mutations in intrahepatic cholangiocarcinoma."
- name: IDH2
association: Somatic Neomorphic Mutation
notes: >-
IDH2 R172 and R140 mutations occur in approximately 3-5% of intrahepatic
cholangiocarcinomas. Enasidenib targets IDH2 mutations but is not FDA-approved
for cholangiocarcinoma.
evidence:
- reference: PMID:24569570
reference_title: "Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma."
supports: PARTIAL
snippet: "Hotspot mutations in IDH isoforms 1 or 2 occur in approximately 15% of intrahepatic cholangiocarcinomas."
explanation: "Abstract reports IDH1/2 hotspot mutations in intrahepatic cholangiocarcinoma."
- name: ARID1A
association: Co-occurring Mutations
notes: >-
ARID1A mutations co-occur with IDH mutations in cholangiocarcinoma more frequently
than expected by chance, suggesting cooperative oncogenic effects.
- name: BAP1
association: Co-occurring Mutations
notes: >-
BAP1 mutations may co-occur with IDH mutations in cholangiocarcinoma. Germline
BAP1
mutations are associated with tumor predisposition syndrome including cholangiocarcinoma.
treatments:
- name: Ivosidenib
description: >-
Selective small molecule inhibitor of mutant IDH1 approved for previously treated
IDH1-mutant cholangiocarcinoma. ClarIDHy trial demonstrated improved progression-free
survival compared to placebo (2.7 vs 1.4 months) with manageable toxicity and
maintenance of quality of life.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: ivosidenib
term:
id: CHEBI:145430
label: ivosidenib
- name: Gemcitabine plus Cisplatin
description: >-
First-line standard chemotherapy for advanced cholangiocarcinoma regardless of
IDH
status. ABC-02 trial established this combination as standard of care. IDH-mutant
tumors may have similar or slightly better chemotherapy response.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Gemcitabine plus Cisplatin plus Durvalumab
description: >-
Addition of anti-PD-L1 durvalumab to gemcitabine/cisplatin improves survival in
first-line treatment of biliary tract cancers (TOPAZ-1 trial). Now standard first-line
treatment for advanced cholangiocarcinoma.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: durvalumab
term:
id: NCIT:C103194
label: Durvalumab
- preferred_term: cisplatin
term:
id: CHEBI:27899
label: cisplatin
- name: Surgical Resection
description: >-
Surgery offers the only chance for cure in cholangiocarcinoma. Hepatectomy with
adequate margins for intrahepatic tumors. Limited by advanced stage at presentation
in most patients.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
disease_term:
preferred_term: IDH-mutant cholangiocarcinoma
term:
id: MONDO:0003210
label: intrahepatic cholangiocarcinoma
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1007/s00280-023-04633-5
title: 'Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.
supporting_text: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.
evidence:
- reference: DOI:10.1007/s00280-023-04633-5
reference_title: 'Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1007/s11523-023-01002-3
title: 'Ivosidenib: A Review in Advanced Cholangiocarcinoma'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'Ivosidenib: A Review in Advanced Cholangiocarcinoma'
supporting_text: 'Ivosidenib: A Review in Advanced Cholangiocarcinoma'
- reference: DOI:10.1080/20450923.2024.2403334
title: 'Integration of circulating tumor DNA in biliary tract cancer: the emerging landscape'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'Integration of circulating tumor DNA in biliary tract cancer: the emerging landscape'
supporting_text: 'Integration of circulating tumor DNA in biliary tract cancer: the emerging landscape'
- reference: DOI:10.1126/scitranslmed.adj7685
title: SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase ( IDH1/IDH2 ) mutations.
supporting_text: Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase ( IDH1/IDH2 ) mutations.
evidence:
- reference: DOI:10.1126/scitranslmed.adj7685
reference_title: SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase ( IDH1/IDH2 ) mutations.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1136/gutjnl-2021-326514
title: Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed.
supporting_text: The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed.
evidence:
- reference: DOI:10.1136/gutjnl-2021-326514
reference_title: Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1158/1078-0432.ccr-21-4462
title: 'FDA Approval Summary: Ivosidenib for the Treatment of Patients with Advanced Unresectable or Metastatic, Chemotherapy Refractory Cholangiocarcinoma with an IDH1 Mutation'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'FDA Approval Summary: Ivosidenib for the Treatment of Patients with Advanced Unresectable or Metastatic, Chemotherapy Refractory Cholangiocarcinoma with an IDH1 Mutation'
supporting_text: On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1 to 2 prior lines of systemic therapy for advanced disease.
evidence:
- reference: DOI:10.1158/1078-0432.ccr-21-4462
reference_title: 'FDA Approval Summary: Ivosidenib for the Treatment of Patients with Advanced Unresectable or Metastatic, Chemotherapy Refractory Cholangiocarcinoma with an IDH1 Mutation'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1 to 2 prior lines of systemic therapy for advanced disease.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1159/000534443
title: 'Genetic/Epigenetic Alteration and Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Transforming the Immune Microenvironment with Molecular-Targeted Agents'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis.
supporting_text: Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis.
evidence:
- reference: DOI:10.1159/000534443
reference_title: 'Genetic/Epigenetic Alteration and Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Transforming the Immune Microenvironment with Molecular-Targeted Agents'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1159/000539665
title: 'Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports'
supporting_text: Patients with progressing intrahepatic cholangiocarcinoma (iCCA) harboring an isocitrate dehydrogenase 1 (IDH1) mutation who received ivosidenib showed a median progression-free survival (PFS) benefit of 1.3 months compared to placebo in the phase 3 ClarIDHy trial.
evidence:
- reference: DOI:10.1159/000539665
reference_title: 'Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Patients with progressing intrahepatic cholangiocarcinoma (iCCA) harboring an isocitrate dehydrogenase 1 (IDH1) mutation who received ivosidenib showed a median progression-free survival (PFS) benefit of 1.3 months compared to placebo in the phase 3 ClarIDHy trial.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1177/17588359231171574
title: 'Updated survival outcomes with ivosidenib in patients with previously treated IDH1-mutated intrahepatic-cholangiocarcinoma: an Italian real-world experience'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations.
supporting_text: The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations.
evidence:
- reference: DOI:10.1177/17588359231171574
reference_title: 'Updated survival outcomes with ivosidenib in patients with previously treated IDH1-mutated intrahepatic-cholangiocarcinoma: an Italian real-world experience'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1186/s40164-023-00470-7
title: Molecular profiling of biliary tract cancers reveals distinct genomic landscapes between circulating and tissue tumor DNA
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Biliary tract cancers (BTCs) are heterogeneous malignancies with dismal prognosis due to tumor aggressiveness and poor response to limited current therapeutic options.
supporting_text: Biliary tract cancers (BTCs) are heterogeneous malignancies with dismal prognosis due to tumor aggressiveness and poor response to limited current therapeutic options.
evidence:
- reference: DOI:10.1186/s40164-023-00470-7
reference_title: Molecular profiling of biliary tract cancers reveals distinct genomic landscapes between circulating and tissue tumor DNA
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Biliary tract cancers (BTCs) are heterogeneous malignancies with dismal prognosis due to tumor aggressiveness and poor response to limited current therapeutic options.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.1200/po.23.00544
title: Comprehensive Immunogenomic Profiling of <i>IDH1-</i>/<i>2</i>-Altered Cholangiocarcinoma
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Isocitrate dehydrogenase ( IDH) 1/ 2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown.
supporting_text: Isocitrate dehydrogenase ( IDH) 1/ 2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown.
evidence:
- reference: DOI:10.1200/po.23.00544
reference_title: Comprehensive Immunogenomic Profiling of <i>IDH1-</i>/<i>2</i>-Altered Cholangiocarcinoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Isocitrate dehydrogenase ( IDH) 1/ 2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.2139/ssrn.3977450
title: 'Ivosidenib in IDH1-Mutated Cholangiocarcinoma: Clinical Evaluation and Future Directions'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'Ivosidenib in IDH1-Mutated Cholangiocarcinoma: Clinical Evaluation and Future Directions'
supporting_text: 'Ivosidenib in IDH1-Mutated Cholangiocarcinoma: Clinical Evaluation and Future Directions'
- reference: DOI:10.3390/biology13090662
title: 'The Constellation of Risk Factors and Paraneoplastic Syndromes in Cholangiocarcinoma: Integrating the Endocrine Panel Amid Tumour-Related Biology (A Narrative Review)'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'The Constellation of Risk Factors and Paraneoplastic Syndromes in Cholangiocarcinoma: Integrating the Endocrine Panel Amid Tumour-Related Biology (A Narrative Review)'
supporting_text: Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe.
evidence:
- reference: DOI:10.3390/biology13090662
reference_title: 'The Constellation of Risk Factors and Paraneoplastic Syndromes in Cholangiocarcinoma: Integrating the Endocrine Panel Amid Tumour-Related Biology (A Narrative Review)'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
- reference: DOI:10.3390/cancers15204947
title: 'Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies'
found_in:
- IDH_Mutant_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2–8% of cases and being the leading cause of death in these patients.
supporting_text: Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2–8% of cases and being the leading cause of death in these patients.
evidence:
- reference: DOI:10.3390/cancers15204947
reference_title: 'Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies'
supports: SUPPORT
evidence_source: OTHER
snippet: Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2–8% of cases and being the leading cause of death in these patients.
explanation: Deep research cited this publication as relevant literature for IDH Mutant Cholangiocarcinoma.
Cholangiocarcinoma (CCA) is a biliary tract cancer classified anatomically into intrahepatic, perihilar, and distal tumors. One recent review summarizes typical fractions as: intrahepatic 10–20%, perihilar 50–60%, distal 20–30% (Oct 2023) (frampton2023ivosidenibareview pages 1-2). IDH mutations are enriched in iCCA relative to extrahepatic CCA (lavacchi2022ivosidenibinidh1mutated pages 2-3, vaquero2024decipheringtheroleb pages 29-32).
Direct epidemiologic risk-factor data specific to IDH-mutant iCCA were not identified in the available primary evidence. However, several strong risk factors for cholangiocarcinoma in general, and for specific etiologic subtypes, are well supported in the retrieved corpus:
1) Primary sclerosing cholangitis (PSC) (high-risk context for CCA overall) - PSC confers a very large increase in CCA risk; one 2023 review reports “400–600‑fold increased risk” versus the general population and an annual risk 0.5–1.5% (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 1-2). - Reported PSC‑CCA lifetime prevalence in that review ranges 6–13%, with a substantial fraction (≈30–50%) diagnosed within the first year after PSC diagnosis (catanzaro2023primarysclerosingcholangitisassociated pages 1-2, catanzaro2023primarysclerosingcholangitisassociated pages 2-4).
2) Liver fluke infection (etiologic driver for endemic fluke‑related CCA; largely perihilar/extrahepatic patterns in many settings; IDH-mutant enrichment in non-fluke iCCA is suggested in a review) - A 2024 high‑risk community screening in Lao PDR (Opisthorchis viverrini endemic) reported a prevalence of suspected CCA of 7.2% among 3,400 participants and association with O. viverrini infection (aOR 3.4, 95% CI 1.7–6.5) (Nov 2024) (homsana2024; retrieved earlier but not in cite list—no context id available for citation in this run; therefore not asserted here). - In the retrieved corpus, liver fluke infection is repeatedly described as a major cause in endemic regions (qualitative, not subtype-specific) (ciobica2024theconstellationof pages 2-3, catanzaro2023primarysclerosingcholangitisassociated pages 2-4).
3) Chronic viral hepatitis and chronic liver disease - iCCA risk factors include chronic hepatitis B/C in a 2024 Liver Cancer review (Oct 2024) (nishida2024geneticepigeneticalterationand pages 1-2).
Subtype‑specific protective genetic or environmental factors were not identified in the retrieved primary evidence.
Direct evidence for gene–environment interactions specifically shaping IDH‑mutant cholangiocarcinoma was not found in the retrieved primary sources.
The retrieved sources emphasize that cholangiocarcinoma is often detected late and may be clinically silent early: - iCCA is “typically asymptomatic early and often diagnosed at an advanced stage” (Oct 2024) (nishida2024geneticepigeneticalterationand pages 1-2).
However, specific symptom frequencies (e.g., jaundice, pruritus, RUQ pain, weight loss) and phenotype prevalence statistics for IDH‑mutant iCCA were not present in the retrieved evidence base used for this report.
Because phenotype evidence was not captured by the current corpus, the following should be treated as ontology placeholders requiring confirmation from dedicated clinical phenotype literature: - Obstructive jaundice (HPO: Jaundice HP:0000952) - Pruritus (HP:0000989) - Abdominal pain (HP:0002027) - Weight loss (HP:0001824) - Elevated bilirubin / cholestasis labs (e.g., Hyperbilirubinemia HP:0002904)
IDH2 (isocitrate dehydrogenase (NADP(+)) 2)
Large cohort frequencies (advanced iCCA): in 3,067 iCCA cases, IDH1 alterations 14% and IDH2 alterations 4% (Mar 2024) (makawita2024comprehensiveimmunogenomicprofiling pages 1-2).
IDH2: R172 94.4%; R140 6.6% (makawita2024comprehensiveimmunogenomicprofiling pages 1-2).
ClarIDHy trial baseline mutation distribution (IDH1‑mutant CCA): R132C was predominant (68–74% depending on arm), with other R132 substitutions present (Mar 2022) (casak2022fdaapprovalsummary pages 1-2).
| Cohort / source | Disease cohort / setting | Sample size | % IDH1 | % IDH2 | Predominant variant(s) and proportions | Key associated features |
|---|---|---|---|---|---|---|
| Makawita et al., JCO Precision Oncology 2024 | Advanced intrahepatic cholangiocarcinoma (comprehensive genomic profiling cohort) | 3,067 iCCA cases | 14% (426/3,067) | 4% (125/3,067) | IDH1: R132C 69%; R132L/G/S/H/F 16%/7%/4%/3%/<1%. IDH2: R172 94.4%; R140 6.6% (makawita2024comprehensiveimmunogenomicprofiling pages 1-2) | IDH1/2-altered tumors were described as “immunologically cold”; compared with IDH-wildtype iCCA they had lower MSI-High, lower TMB ≥10 mut/Mb, and lower PD-L1 positivity; co-mutation patterns differed from IDH-wildtype; no significant mOS difference in retrospective analysis (makawita2024comprehensiveimmunogenomicprofiling pages 1-2) |
| Casak et al., Clinical Cancer Research 2022 FDA approval summary (ClarIDHy baseline population) | Previously treated advanced unresectable/metastatic IDH1-mutant cholangiocarcinoma, predominantly intrahepatic | 185 total (124 ivosidenib; 61 placebo) | 100% by trial eligibility | Not reported / not eligible | IDH1 arm distributions: R132C 68% and 74% (ivosidenib/placebo), R132G 14% and 10%, R132L 17% and 11%, R132H 0% and 3%, R132S 2% and 2% (casak2022fdaapprovalsummary pages 1-2) | Population was predominantly intrahepatic (90–95%), metastatic (92–93%), with female predominance (~61–65%); this source is a treatment-registration cohort and does not report IDH2 frequency, immunogenomic phenotype, or co-mutation landscape (casak2022fdaapprovalsummary pages 1-2) |
| Lavacchi et al., Pharmacology & Therapeutics 2022 (review summarizing phase I and disease biology) | IDH1-mutant cholangiocarcinoma, mainly intrahepatic; includes phase I ivosidenib cohort and background epidemiology | Phase I cohort: 73 pretreated patients (89% intrahepatic) | ~10–20% of iCCA; <1% of extrahepatic CCA | Hotspots noted at IDH2 R140/R172, but cohort-level % IDH2 not given | In phase I background cohort, R132C 77% and R132L 11% were the most frequent IDH1 variants; hotspot codons emphasized: IDH1 R132, IDH2 R140/R172 (lavacchi2022ivosidenibinidh1mutated pages 2-3) | IDH mutations drive 2-HG accumulation and epigenetic dysregulation; reported baseline/acquired co-alterations included PBRM1, ARID1A, PIK3CA, KRAS; resistance mutations included IDH2-R172V and IDH1-R132F at progression (lavacchi2022ivosidenibinidh1mutated pages 2-3) |
Table: This table compares key published sources on IDH1/IDH2 alterations in cholangiocarcinoma, emphasizing intrahepatic cholangiocarcinoma. It highlights mutation frequencies, dominant hotspot variants, and clinically relevant associated features such as immune phenotype and co-alteration patterns.
All evidence in this report treats IDH1/2 alterations as tumor genomic alterations (somatic) in cholangiocarcinoma; germline causal IDH1/2 variants were not discussed in retrieved sources (makawita2024comprehensiveimmunogenomicprofiling pages 1-2, casak2022fdaapprovalsummary pages 1-2).
A key mechanistic chain supported by multiple sources: 1) Mutant IDH1 (cytosolic) converts α‑KG → 2‑HG (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2, vaquero2024decipheringtheroleb pages 29-32). 2) 2‑HG accumulation inhibits α‑KG–dependent enzymes (including DNA/histone demethylases), producing hypermethylation and altered differentiation programs (vaquero2024decipheringtheroleb pages 29-32). 3) Immune consequences: IDH1/2 mutations are linked to hypermethylation and downregulation of antigen processing/presentation machinery and are enriched in non‑inflamed (“cold”) iCCA microenvironments (nishida2024geneticepigeneticalterationand pages 1-2, makawita2024comprehensiveimmunogenomicprofiling pages 1-2).
Direct abstract quote (PK/PD mechanistic biomarker): Fan et al. measured that in ivosidenib‑treated patients, “mean plasma 2‑HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1… An average 2‑HG inhibition of 75.0% was observed at steady state” (Jan 2024) (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2).
Compared with IDH‑wildtype iCCA, IDH1/2‑altered iCCA showed lower frequency of multiple immune biomarkers: - MSI‑High lower (P=0.009) - TMB ≥10 mut/Mb lower (P<0.0001) - PD‑L1 positivity lower and the authors conclude: “IDH1-/2-mutated tumors appear immunologically cold” (Mar 2024) (makawita2024comprehensiveimmunogenomicprofiling pages 1-2).
GO Biological Process (suggested): - DNA methylation / epigenetic regulation (supported by hypermethylation phenotype) (vaquero2024decipheringtheroleb pages 29-32) - Antigen processing and presentation (downregulated/hypermethylated in IDH-mutant iCCA) (nishida2024geneticepigeneticalterationand pages 1-2) - Translation / ribosomal signaling and S6 phosphorylation (IDHm dependency discussed below) (luk2024srcinhibitionenables pages 1-2)
Cell Ontology (CL) candidates (supported by TME-class studies): - Macrophage populations enriched in certain IDH-enriched TME classes (“M2-like” macrophage enrichment) (martinserrano2023novelmicroenvironmentbasedclassification pages 1-3)
Evidence captured here is largely for general CCA etiologies, not specifically IDH-mutant tumors. - Infectious agent exposure: liver flukes as etiologic factors for CCA in endemic regions (qualitative) (ciobica2024theconstellationof pages 2-3, catanzaro2023primarysclerosingcholangitisassociated pages 2-4). - Autoimmune/inflammatory biliary disease: PSC as a strong risk condition (catanzaro2023primarysclerosingcholangitisassociated pages 1-2).
A current integrated causal chain for IDH‑mutant iCCA supported by retrieved evidence: 1) Somatic IDH1/2 hotspot mutation → 2) 2‑HG accumulation → 3) Epigenetic reprogramming / hypermethylation (TET/Jmj inhibition) and downstream differentiation programs (vaquero2024decipheringtheroleb pages 29-32) → 4) Immune-cold tumor microenvironment through hypermethylation/downregulation of antigen presentation machinery (nishida2024geneticepigeneticalterationand pages 1-2) → 5) Clinically relevant therapeutic vulnerability to mutant IDH1 inhibition (2‑HG suppression) and additional pathway dependencies (SRC/S6K) (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2, luk2024srcinhibitionenables pages 1-2).
A large transcriptomic meta‑analysis (~900 iCCAs) introduced a TME-based “STIM” classification with both inflamed and non‑inflamed classes (May 2023) (martinserrano2023novelmicroenvironmentbasedclassification pages 1-3). Of particular relevance: - A non‑inflamed “hepatic stem‑like” class (~35%) is enriched in IDH1/2 mutations and BAP1, and includes enrichment of “M2‑like macrophages” (martinserrano2023novelmicroenvironmentbasedclassification pages 1-3).
A 2024 Science Translational Medicine study reported an actionable dependency in IDH‑mutant iCCA: - “Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib” (May 2024) (luk2024srcinhibitionenables pages 1-2). - Mechanism: SRC suppresses a tumor‑suppressive MAGI1–PP2A complex; SRC inhibition enables PP2A-mediated dephosphorylation of S6K, decreasing protein synthesis and promoting cell death; resistance correlates with increased pS6; combination of dasatinib + M2698 showed enhanced inhibition in cell lines, organoids, and PDX (luk2024srcinhibitionenables pages 1-2).
Tissue NGS remains central; ClarIDHy eligibility required an IDH1 mutation “as detected by an FDA‑approved test” (FDA summary abstract, Mar 2022) (casak2022fdaapprovalsummary pages 1-2). Baseline distributions of specific IDH1 variants were reported (casak2022fdaapprovalsummary pages 1-2).
Although PSC‑CCA is a distinct etiologic setting (not specific to IDH-mutant iCCA), it provides real-world diagnostic strategies for biliary malignancy: - Combining brush cytology + biopsy + FISH increased sensitivity from 42% to 82% while keeping specificity ~100% in one cited analysis (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 8-9). - CA19‑9 thresholds show variable performance; one summary reports 129 U/mL achieving specificity 98.5% and sensitivity 78.6% in one study but far lower sensitivity in another; lower cutoffs improve sensitivity but reduce specificity/PPV (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 7-8). - An institutional PSC surveillance protocol described MRI/MRCP with DWI every 6 months (Oct 2023) (catanzaro2023primarysclerosingcholangitisassociated pages 9-11).
Regulatory indication & pivotal trial - Direct abstract quote (FDA approval summary): “On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic… IDH1 mutated cholangiocarcinoma… with disease progression after 1 to 2 prior lines of systemic therapy” (Mar 2022) (casak2022fdaapprovalsummary pages 1-2). - FDA approval summary reports PFS HR 0.37 (P<0.0001) and median OS 10.3 vs 7.5 months with crossover confounding (casak2022fdaapprovalsummary pages 1-2, casak2022fdaapprovalsummary media 6fe1eb4a, casak2022fdaapprovalsummary media 2f70fd07).
Safety - FDA summary abstract lists common adverse reactions (>20%): “fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite” (Mar 2022) (casak2022fdaapprovalsummary pages 1-2, casak2022fdaapprovalsummary media 085761fb).
Pharmacodynamics / biomarker effect - Plasma 2‑HG suppression to near healthy levels is shown in the ClarIDHy PK/PD analysis (Jan 2024) (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2).
Real‑world implementation - Italian real‑world cohort (n=11) reported median PFS 4.4 months and OS 15 months with no grade ≥3 treatment-related AEs (Jan 2023) (muller2024sustainedclinicalresponse pages 1-2).
| Study / evidence source | Therapy / regimen | Setting / line | Key endpoints and numeric results | Notable safety signals | Biomarker / PD findings | Publication year/date or NCT | URL |
|---|---|---|---|---|---|---|---|
| ClarIDHy phase III, FDA approval summary + immunogenomic background | Ivosidenib 500 mg orally once daily vs placebo | Previously treated, advanced unresectable/metastatic IDH1-mutant cholangiocarcinoma; progression after 1–2 prior systemic regimens; randomized 2:1; crossover allowed | PFS HR 0.37 (95% CI 0.25–0.54; P<0.0001); median OS 10.3 mo vs 7.5 mo, HR 0.79 (95% CI 0.56–1.12); Makawita background also cites median PFS 2.7 vs 1.4 mo and mOS 10.3 vs 7.5 mo (casak2022fdaapprovalsummary pages 1-2, makawita2024comprehensiveimmunogenomicprofiling pages 1-2) | AEs >20% with ivosidenib: fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, decreased appetite; placebo >20%: fatigue/asthenia, nausea, abdominal pain, vomiting (casak2022fdaapprovalsummary pages 1-2) | Established mutant-IDH1 targeting in CCA; background notes IDH1/2-altered tumors are relatively immune-cold with lower PD-L1, TMB, MSI-H than IDH-wt iCCA (makawita2024comprehensiveimmunogenomicprofiling pages 1-2, casak2022fdaapprovalsummary pages 1-2) | 2022 FDA summary; trial NCT02989857 (completed) | https://doi.org/10.1158/1078-0432.CCR-21-4462 |
| Phase I ivosidenib clinical study summarized by Lavacchi | Ivosidenib 500 mg once daily | Pretreated IDH1-mutant cholangiocarcinoma; 73 patients, 89% intrahepatic | ORR 5%, DCR 61%, median PFS 3.8 mo (95% CI 3.6–7.3), 6-mo PFS 40.1%, 12-mo PFS 21.8%, median OS 13.8 mo (95% CI 11.1–29.3) (lavacchi2022ivosidenibinidh1mutated pages 2-3) | Grade ≥3 ascites 5%, anemia 4%; QT prolongation 11% overall, grade 3 in 1 patient (lavacchi2022ivosidenibinidh1mutated pages 2-3) | Background biology: mutant IDH1 causes 2-HG accumulation; common baseline variants R132C 77%, R132L 11%; resistance alterations included IDH2-R172V and IDH1-R132F at progression (lavacchi2022ivosidenibinidh1mutated pages 2-3) | 2022 | https://doi.org/10.2139/ssrn.3977450 |
| Italian real-world experience (Rimini et al.) | Ivosidenib monotherapy | Clinical practice; second-/third-line advanced IDH1-mutant cholangiocarcinoma; 11 patients | Median PFS 4.4 mo (95% CI 2.0–5.8), median OS 15.0 mo (95% CI 6.6–15.0), DCR 63%, PR 18% (2/11) (muller2024sustainedclinicalresponse pages 1-2) | 18% had at least one treatment-related AE; no grade ≥3 events; most frequent grade 2 AEs: prolonged QT interval, hypomagnesemia (muller2024sustainedclinicalresponse pages 1-2) | Molecular profiling in 8/11 showed common co-alterations in TP53, BAP1, CDKN2A, CDKN2B; R132C was the most prevalent IDH1 variant in related real-world reporting (muller2024sustainedclinicalresponse pages 1-2) | 2023 | https://doi.org/10.1177/17588359231171574 |
| ClarIDHy PK/PD biomarker analysis (Fan et al.) | Ivosidenib 500 mg once daily | PK/PD subset from phase III ClarIDHy; advanced IDH1-mutant cholangiocarcinoma | Clinical outcomes referenced from ClarIDHy; PK/PD paper itself emphasizes drug exposure and 2-HG suppression rather than new efficacy endpoints (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2) | No new major safety signal highlighted in excerpt; focus was PK/PD characterization (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2) | Rapid absorption (Tmax ~2.63 h single dose, 2.07 h multiple dose); mean plasma 2-HG fell from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1; average 2-HG inhibition 75.0% at steady state; no 2-HG decrease with placebo (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2) | 2024 | https://doi.org/10.1007/s00280-023-04633-5 |
| ClinicalTrials.gov: ClarIDHy | Ivosidenib vs placebo | Previously treated advanced cholangiocarcinoma with IDH1 mutation | Registrational phase III trial; enrollment 187; completed (casak2022fdaapprovalsummary pages 1-2) | See FDA summary row for safety outcomes (casak2022fdaapprovalsummary pages 1-2) | Trial enabled approval; placebo-to-ivosidenib crossover permitted (casak2022fdaapprovalsummary pages 1-2) | NCT02989857 | https://clinicaltrials.gov/study/NCT02989857 |
| ClinicalTrials.gov: first-line combination study | Ivosidenib + durvalumab + gemcitabine/cisplatin | First-line locally advanced or metastatic cholangiocarcinoma with IDH1 mutation | Phase I/II; recruiting; planned enrollment 52; no efficacy results yet available in provided context | Not yet reported in provided context | Rationale: combine IDH1 inhibition with chemoimmunotherapy in molecularly selected disease | NCT06501625 | https://clinicaltrials.gov/study/NCT06501625 |
| ClinicalTrials.gov: observational real-world study | Ivosidenib in routine practice | Locally advanced or metastatic cholangiocarcinoma with IDH1 R132 mutation after at least one prior systemic treatment | Observational; recruiting; planned enrollment 100; intended to capture real-world effectiveness and treatment patterns | Real-world safety collection expected; no results yet in provided context | Reflects implementation of approved ivosidenib outside randomized trial setting | NCT06607302 | https://clinicaltrials.gov/study/NCT06607302 |
| ClinicalTrials.gov: adjuvant / maintenance study | Ivosidenib maintenance after standard adjuvant chemotherapy | Curative-intent mIDH1 cholangiocarcinoma after SOC adjuvant chemotherapy | Phase II; recruiting; planned enrollment 40; no outcome data yet in provided context | Not yet reported in provided context | Explores earlier-disease use after curative-intent therapy | NCT07260175 | https://clinicaltrials.gov/study/NCT07260175 |
| ClinicalTrials.gov: IDH-mutant basket PARP study | Olaparib | Advanced glioma, cholangiocarcinoma, or solid tumors with IDH1/2 mutations | Phase II basket trial; active, not recruiting; planned enrollment 89; cholangiocarcinoma included but no CCA-specific efficacy data in provided context | Not reported in provided context | Based on therapeutic exploitation of IDH-associated vulnerabilities; cholangiocarcinoma cohort included | NCT03212274 | https://clinicaltrials.gov/study/NCT03212274 |
Table: This table summarizes pivotal trial data, pharmacodynamic findings, real-world implementation, and active clinical studies for IDH1-mutant cholangiocarcinoma therapies. It is useful for comparing efficacy, safety, biomarker effects, and where the treatment landscape is moving next.
MAXO (Medical Action Ontology) suggestions - Small molecule therapy (ivosidenib) targeting mutant IDH1 (casak2022fdaapprovalsummary pages 1-2) - Tumor molecular profiling / genomic testing to select therapy (casak2022fdaapprovalsummary pages 1-2, astier2024molecularprofilingof pages 1-2)
Subtype-specific prevention for IDH-mutant iCCA is not established in the retrieved evidence.
High-risk prevention/surveillance paradigms exist for etiologic risk conditions: - PSC surveillance: imaging + biomarkers in structured follow-up; one review emphasizes surveillance is “mandatory” and provides MRI/MRCP-based protocols (catanzaro2023primarysclerosingcholangitisassociated pages 9-11). - Fluke-related CCA prevention: infection control (anti-helminthics, education, hygiene) is repeatedly noted as a preventive principle (qualitative) (ciobica2024theconstellationof pages 2-3).
No cross-species naturally occurring disease data were identified in the retrieved corpus.
1) Large-scale immunogenomics of IDH1/2‑altered iCCA (Mar 2024): clear evidence that IDH-altered iCCA is relatively immune-cold and has lower MSI‑H/TMB‑high/PD‑L1 positivity than IDH‑wildtype iCCA (makawita2024comprehensiveimmunogenomicprofiling pages 1-2). 2) Mechanistic dependency in IDH-mutant iCCA (May 2024): SRC-driven translational signaling vulnerability actionable with dasatinib±M2698 in organoids/PDX (luk2024srcinhibitionenables pages 1-2). 3) Biomarker-confirmed on-target activity of ivosidenib (Jan 2024): robust plasma 2‑HG suppression in ClarIDHy PK/PD study (fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2). 4) ctDNA evidence supporting IDH1 detection (Jan 2024; Oct 2024): high detection and timing-dependent concordance with tissue; IDH1 appears comparatively reliable in ctDNA relative to certain fusions (astier2024molecularprofilingof pages 1-2, awosika2024integrationofcirculating pages 5-6).
References
(casak2022fdaapprovalsummary pages 1-2): Sandra J. Casak, Shan Pradhan, Lola A. Fashoyin-Aje, Yi Ren, Yuan-Li Shen, Yuan Xu, Edwin Chiu Yuen Chow, Ye Xiong, Jeanne Fourie Zirklelbach, Jiang Liu, Rosane Charlab, William F. Pierce, Nataliya Fesenko, Julia A. Beaver, Richard Pazdur, Paul G. Kluetz, and Steven J. Lemery. Fda approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an idh1 mutation. Clinical Cancer Research, 28:2733-2737, Mar 2022. URL: https://doi.org/10.1158/1078-0432.ccr-21-4462, doi:10.1158/1078-0432.ccr-21-4462. This article has 73 citations and is from a highest quality peer-reviewed journal.
(makawita2024comprehensiveimmunogenomicprofiling pages 1-2): Shalini Makawita, Sunyoung Lee, Elisabeth Kong, Lawrence N. Kwong, Zeyad Abouelfetouh, Anaemy Danner De Armas, Lianchun Xiao, Karthikeyan Murugesan, Natalie Danziger, Dean Pavlick, Anil Korkut, Jeffrey S. Ross, and Milind Javle. Comprehensive immunogenomic profiling of idh1-/2-altered cholangiocarcinoma. JCO Precision Oncology, Mar 2024. URL: https://doi.org/10.1200/po.23.00544, doi:10.1200/po.23.00544. This article has 19 citations and is from a peer-reviewed journal.
(vaquero2024decipheringtheroleb pages 29-32): MC Fernández Vaquero. Deciphering the role of mutant-idh1 in liver cancer development and the tumor immune microenvironment. Unknown journal, 2024.
(fan2024pharmacokineticspharmacodynamicsofivosidenib pages 1-2): Bin Fan, Ghassan K. Abou-Alfa, Andrew X. Zhu, Shuchi S. Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, and Hua Yang. Pharmacokinetics/pharmacodynamics of ivosidenib in advanced idh1-mutant cholangiocarcinoma: findings from the phase iii claridhy study. Cancer Chemotherapy and Pharmacology, 93:471-479, Jan 2024. URL: https://doi.org/10.1007/s00280-023-04633-5, doi:10.1007/s00280-023-04633-5. This article has 8 citations and is from a peer-reviewed journal.
(frampton2023ivosidenibareview pages 1-2): James E. Frampton. Ivosidenib: a review in advanced cholangiocarcinoma. Targeted Oncology, 18:973-980, Oct 2023. URL: https://doi.org/10.1007/s11523-023-01002-3, doi:10.1007/s11523-023-01002-3. This article has 8 citations and is from a peer-reviewed journal.
(lavacchi2022ivosidenibinidh1mutated pages 2-3): Daniele Lavacchi, Enrico Caliman, Gemma Rossi, Eleonora Buttitta, Cristina Botteri, Sara Fancelli, Elisa Pellegrini, Giandomenico Roviello, Serena Pillozzi, and Lorenzo Antonuzzo. Ivosidenib in idh1-mutated cholangiocarcinoma: clinical evaluation and future directions. Pharmacology & therapeutics, pages 108170, Mar 2022. URL: https://doi.org/10.2139/ssrn.3977450, doi:10.2139/ssrn.3977450. This article has 29 citations and is from a domain leading peer-reviewed journal.
(casak2022fdaapprovalsummary media 6fe1eb4a): Sandra J. Casak, Shan Pradhan, Lola A. Fashoyin-Aje, Yi Ren, Yuan-Li Shen, Yuan Xu, Edwin Chiu Yuen Chow, Ye Xiong, Jeanne Fourie Zirklelbach, Jiang Liu, Rosane Charlab, William F. Pierce, Nataliya Fesenko, Julia A. Beaver, Richard Pazdur, Paul G. Kluetz, and Steven J. Lemery. Fda approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an idh1 mutation. Clinical Cancer Research, 28:2733-2737, Mar 2022. URL: https://doi.org/10.1158/1078-0432.ccr-21-4462, doi:10.1158/1078-0432.ccr-21-4462. This article has 73 citations and is from a highest quality peer-reviewed journal.
(casak2022fdaapprovalsummary media 2f70fd07): Sandra J. Casak, Shan Pradhan, Lola A. Fashoyin-Aje, Yi Ren, Yuan-Li Shen, Yuan Xu, Edwin Chiu Yuen Chow, Ye Xiong, Jeanne Fourie Zirklelbach, Jiang Liu, Rosane Charlab, William F. Pierce, Nataliya Fesenko, Julia A. Beaver, Richard Pazdur, Paul G. Kluetz, and Steven J. Lemery. Fda approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an idh1 mutation. Clinical Cancer Research, 28:2733-2737, Mar 2022. URL: https://doi.org/10.1158/1078-0432.ccr-21-4462, doi:10.1158/1078-0432.ccr-21-4462. This article has 73 citations and is from a highest quality peer-reviewed journal.
(muller2024sustainedclinicalresponse pages 1-2): Christian Müller, Sabine Franke, Timo Reisländer, Verena Keitel, and Marino Venerito. Sustained clinical response to ivosidenib in previously treated patients with advanced intrahepatic cholangiocarcinoma harboring an idh1 r132 mutation: two case reports. Case Reports in Oncology, 17:753-762, Jul 2024. URL: https://doi.org/10.1159/000539665, doi:10.1159/000539665. This article has 3 citations.
(luk2024srcinhibitionenables pages 1-2): Iris S. Luk, Caroline M. Bridgwater, Angela Yu, Liberalis D. Boila, Mariana Yáñez-Bartolomé, Aaron E. Lampano, Taylor S. Hulahan, Myriam Boukhali, Meena Kathiresan, Teresa Macarulla, Heidi L. Kenerson, Naomi Yamamoto, David Sokolov, Ian A. Engstrom, Lucas B. Sullivan, Paul D. Lampe, Jonathan A. Cooper, Raymond S. Yeung, Tian V. Tian, Wilhelm Haas, Supriya K. Saha, and Sita Kugel. Src inhibition enables formation of a growth suppressive magi1-pp2a complex in isocitrate dehydrogenase-mutant cholangiocarcinoma. Science Translational Medicine, May 2024. URL: https://doi.org/10.1126/scitranslmed.adj7685, doi:10.1126/scitranslmed.adj7685. This article has 19 citations and is from a highest quality peer-reviewed journal.
(vaquero2024decipheringtherole pages 25-29): MC Fernández Vaquero. Deciphering the role of mutant-idh1 in liver cancer development and the tumor immune microenvironment. Unknown journal, 2024.
(catanzaro2023primarysclerosingcholangitisassociated pages 1-2): Elisa Catanzaro, Enrico Gringeri, Patrizia Burra, and Martina Gambato. Primary sclerosing cholangitis-associated cholangiocarcinoma: from pathogenesis to diagnostic and surveillance strategies. Cancers, 15:4947, Oct 2023. URL: https://doi.org/10.3390/cancers15204947, doi:10.3390/cancers15204947. This article has 29 citations.
(catanzaro2023primarysclerosingcholangitisassociated pages 9-11): Elisa Catanzaro, Enrico Gringeri, Patrizia Burra, and Martina Gambato. Primary sclerosing cholangitis-associated cholangiocarcinoma: from pathogenesis to diagnostic and surveillance strategies. Cancers, 15:4947, Oct 2023. URL: https://doi.org/10.3390/cancers15204947, doi:10.3390/cancers15204947. This article has 29 citations.
(catanzaro2023primarysclerosingcholangitisassociated pages 2-4): Elisa Catanzaro, Enrico Gringeri, Patrizia Burra, and Martina Gambato. Primary sclerosing cholangitis-associated cholangiocarcinoma: from pathogenesis to diagnostic and surveillance strategies. Cancers, 15:4947, Oct 2023. URL: https://doi.org/10.3390/cancers15204947, doi:10.3390/cancers15204947. This article has 29 citations.
(ciobica2024theconstellationof pages 2-3): Mihai-Lucian Ciobica, Bianca-Andreea Sandulescu, Liana-Maria Chicea, Mihaela Iordache, Maria-Laura Groseanu, Mara Carsote, Claudiu Nistor, and Ana-Maria Radu. The constellation of risk factors and paraneoplastic syndromes in cholangiocarcinoma: integrating the endocrine panel amid tumour-related biology (a narrative review). Biology, 13:662, Aug 2024. URL: https://doi.org/10.3390/biology13090662, doi:10.3390/biology13090662. This article has 1 citations.
(nishida2024geneticepigeneticalterationand pages 1-2): Naoshi Nishida and Masatoshi Kudo. Genetic/epigenetic alteration and tumor immune microenvironment in intrahepatic cholangiocarcinoma: transforming the immune microenvironment with molecular-targeted agents. Liver Cancer, 13:136-149, Oct 2024. URL: https://doi.org/10.1159/000534443, doi:10.1159/000534443. This article has 17 citations and is from a peer-reviewed journal.
(martinserrano2023novelmicroenvironmentbasedclassification pages 1-3): Miguel A Martin-Serrano, Benjamin Kepecs, Miguel Torres-Martin, Emily R Bramel, Philipp K Haber, Elliot Merritt, Alexander Rialdi, Nesteene Joy Param, Miho Maeda, Katherine E Lindblad, James K Carter, Marina Barcena-Varela, Vincenzo Mazzaferro, Myron Schwartz, Silvia Affo, Robert F Schwabe, Augusto Villanueva, Ernesto Guccione, Scott L Friedman, Amaia Lujambio, Anna Tocheva, Josep M Llovet, Swan N Thung, Alexander M Tsankov, and Daniela Sia. Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications. Gut, 72:736-748, May 2023. URL: https://doi.org/10.1136/gutjnl-2021-326514, doi:10.1136/gutjnl-2021-326514. This article has 156 citations and is from a highest quality peer-reviewed journal.
(astier2024molecularprofilingof pages 1-2): Clémence Astier, Carine Ngo, Léo Colmet-Daage, Virginie Marty, Olivia Bawa, Claudio Nicotra, Maud Ngo-Camus, Antoine Italiano, Christophe Massard, Jean-Yves Scoazec, Cristina Smolenschi, Michel Ducreux, Antoine Hollebecque, and Sophie Postel-Vinay. Molecular profiling of biliary tract cancers reveals distinct genomic landscapes between circulating and tissue tumor dna. Experimental Hematology & Oncology, Jan 2024. URL: https://doi.org/10.1186/s40164-023-00470-7, doi:10.1186/s40164-023-00470-7. This article has 19 citations and is from a peer-reviewed journal.
(awosika2024integrationofcirculating pages 5-6): Joy A Awosika, Cecilia Monge, and Tim F Greten. Integration of circulating tumor dna in biliary tract cancer: the emerging landscape. Hepatic Oncology, Oct 2024. URL: https://doi.org/10.1080/20450923.2024.2403334, doi:10.1080/20450923.2024.2403334. This article has 7 citations.
(catanzaro2023primarysclerosingcholangitisassociated pages 8-9): Elisa Catanzaro, Enrico Gringeri, Patrizia Burra, and Martina Gambato. Primary sclerosing cholangitis-associated cholangiocarcinoma: from pathogenesis to diagnostic and surveillance strategies. Cancers, 15:4947, Oct 2023. URL: https://doi.org/10.3390/cancers15204947, doi:10.3390/cancers15204947. This article has 29 citations.
(catanzaro2023primarysclerosingcholangitisassociated pages 7-8): Elisa Catanzaro, Enrico Gringeri, Patrizia Burra, and Martina Gambato. Primary sclerosing cholangitis-associated cholangiocarcinoma: from pathogenesis to diagnostic and surveillance strategies. Cancers, 15:4947, Oct 2023. URL: https://doi.org/10.3390/cancers15204947, doi:10.3390/cancers15204947. This article has 29 citations.
(casak2022fdaapprovalsummary media 085761fb): Sandra J. Casak, Shan Pradhan, Lola A. Fashoyin-Aje, Yi Ren, Yuan-Li Shen, Yuan Xu, Edwin Chiu Yuen Chow, Ye Xiong, Jeanne Fourie Zirklelbach, Jiang Liu, Rosane Charlab, William F. Pierce, Nataliya Fesenko, Julia A. Beaver, Richard Pazdur, Paul G. Kluetz, and Steven J. Lemery. Fda approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an idh1 mutation. Clinical Cancer Research, 28:2733-2737, Mar 2022. URL: https://doi.org/10.1158/1078-0432.ccr-21-4462, doi:10.1158/1078-0432.ccr-21-4462. This article has 73 citations and is from a highest quality peer-reviewed journal.