Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports

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Abstract

Introduction

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.

Case Presentations

We describe 2 consecutive patients with previously treated unresectable and metastatic iCCA harboring an IDH1 R132 mutation who achieved durable clinical responses with ivosidenib 500 mg once daily for >12 months until disease progression. In one case with a mixed response, a single progressive liver metastasis was additionally treated locally with interstitial brachytherapy, while ivosidenib was continued until further progression. Ivosidenib therapy resulted in long-term disease control with PFS of 20 and 13 months and duration of treatment of 26 and 13 months, respectively, with no relevant side effects.

Conclusion

Patients with unresectable or metastatic IDH1-mutated iCCA can achieve sustained clinical responses for >12 months with ivosidenib. No new safety signals were observed during long-term treatment with ivosidenib.

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Most cited references 15

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Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.

Juan Ignacio Valle, Harpreet Singh Wasan, Daniel H Palmer … (2010)

There is no established standard chemotherapy for patients with locally advanced or metastatic biliary tract cancer. We initially conducted a randomized, phase 2 study involving 86 patients to compare cisplatin plus gemcitabine with gemcitabine alone. After we found an improvement in progression-free survival, the trial was extended to the phase 3 trial reported here. We randomly assigned 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer to receive either cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter on days 1 and 8, every 3 weeks for eight cycles) or gemcitabine alone (1000 mg per square meter on days 1, 8, and 15, every 4 weeks for six cycles) for up to 24 weeks. The primary end point was overall survival. After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplatin-gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80; P<0.001). The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group (P<0.001). In addition, the rate of tumor control among patients in the cisplatin-gemcitabine group was significantly increased (81.4% vs. 71.8%, P=0.049). Adverse events were similar in the two groups, with the exception of more neutropenia in the cisplatin-gemcitabine group; the number of neutropenia-associated infections was similar in the two groups. As compared with gemcitabine alone, cisplatin plus gemcitabine was associated with a significant survival advantage without the addition of substantial toxicity. Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer. (ClinicalTrials.gov number, NCT00262769.) 2010 Massachusetts Medical Society

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Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Jesus Banales, Jose Marin, Angela Lamarca … (2020)

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.

Lenny Dang, David W White, Stefan Gross … (2009)

Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.

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Author and article information

Journal

Journal ID (nlm-ta): Case Rep Oncol

Journal ID (iso-abbrev): Case Rep Oncol

Journal ID (hwp): CRO

Journal ID (publisher-id): CRO

Title: Case Reports in Oncology

Publisher: S. Karger AG (Basel, Switzerland )

ISSN (Electronic): 1662-6575

Publication date (Electronic): 15 July 2024

Publication date Collection: Jan-Dec 2024

Publication date PMC-release: 15 July 2024

Volume: 17

Issue: 1

Pages: 753-762

Affiliations

[a ]Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Magdeburg, Magdeburg, Germany

[b ]Institute of Pathology, University Hospital of Magdeburg, Magdeburg, Germany

[c ]Servier Germany GmbH, Medical Affairs Oncology/Haematology, Munich, Germany

Author notes

Correspondence to: Marino Venerito, m.venerito@ 123456med.ovgu.de

Article

Publisher ID: 539665

DOI: 10.1159/000539665

PMC ID: 11250517

PubMed ID: 39015644

SO-VID: a245490d-7977-42d9-92f1-714dd3942f91

License:

This article is licensed under the Creative Commons Attribution 4.0 International License (CC BY) ( http://www.karger.com/Services/OpenAccessLicense). Usage, derivative works and distribution are permitted provided that proper credit is given to the author and the original publisher.

History

Date received : 2 February 2024

Date accepted : 29 May 2024

Date: 2024

Page count

Figures: 3, Tables: 1, References: 15, Pages: 10

Funding

This research received no external funding. Publication fees were covered by Servier Deutschland GmbH.

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Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports

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Abstract

Introduction

Case Presentations

Conclusion

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Karger: Oncology

Most cited references 15

Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.

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Most referenced authors 756