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NCCN guidelines for cca

Recommendations from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

  • IDH1 mutations have been reported in approximately 10% to 20% of intrahepatic CCA cases. Activating IDH1 mutations can lead to high levels of 2-HG accumulation and impact normal liver cells1,a
  • “Testing for IDH1 mutations is recommended in patients with unresectable or metastatic intrahepatic CCA or extrahepatic CCA”2
  • Ivosidenib (TIBSOVO) is recommended as an NCCN category 1 subsequent-line systemic treatment option for patients with unresectable or metastatic progressive CCA with IDH1 mutations2,b

2-HG, 2-hydroxyglutarate; CCA, cholangiocarcinoma; NCCN, National Comprehensive Cancer Network® (NCCN®).

aImpairment of normal differentiation, accumulation of hepatic progenitor cells, and malignant transformation to intrahepatic CCA.1

bTo view the most recent and complete version of the guidelines, visit NCCN.org.2

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Genetic alterations

IDH1 mutations are common genetic alterations in cholangiocarcinoma

mIDH1 is an early driver mutation that occurs in up to 20% of intrahepatic cholangiocarcinoma cases in the United States3,4

Biomarker testing for mIDH1 can be performed by next generation sequencing of tumor tissue using an FDA-approved companion diagnostic5

Biomarker testing combined with targeted therapy could improve survival outcomes in cholangiocarcinoma5

TIBSOVO® (ivosidenib tablets) selectively inhibits mIDH1 and may play an important role in filling an unmet need in the treatment of advanced cholangiocarcinoma5,6

IDH1, isocitrate dehydrogenase-1; mIDH1, mutated IDH1.

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IDH1 mutations

IDH1 mutations and cholangiocarcinoma

IDH1 mutations can play a critical role in the development of cholangiocarcinoma

IDH1 mutations confer gain-of-function activity7

  • Isocitrate dehydrogenase (IDH) is a key enzyme in the citric acid cycle that catalyzes the conversion of isocitrate to α-ketoglutarate (α-KG)8
  • Cancer-associated mutations in IDH1 catalyze the reduction of α-KG to the oncometabolite 2-hydroxyglutarate (2‑HG)7
  • Accumulation of 2-HG leads to oncogenesis
    • Elevated levels of 2-HG have been observed across multiple tumors with IDH1/2 mutations, including acute myeloid leukemia, glioma, and cholangiocarcinoma7,9,10
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Incidence and survival

Cholangiocarcinoma incidence and survival

Incidence of intrahepatic cholangiocarcinoma is increasing in the United States11

idh1-cca-table idh1-cca-table
  • Cholangiocarcinoma is the second most common primary liver cancer and is associated with a poor prognosis11,12
    • Overall age-adjusted incidence: 3.65 per 100,000 (p-y)11
  • Incidence of intrahepatic cholangiocarcinoma increased 148.8% (0.80 to 1.99) from 2001 to 201711
  • Most patients (67%) are ≥65 years at diagnosis11
  • Largely due to a lack of specific symptoms, most patients (~70%) are diagnosed at late stages when the disease is unresectable12

Prognosis For Cholangiocarcinoma
The 5-year relative survival rate for metastatic intrahepatic cholangiocarcinoma is 3%13,c

P-y, person-years.

cFor patients whose initial diagnoses were given after their cancer had already metastasized.13

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References: 1. Aguado-Fraile E, Tassinari A, Ishii Y, et al. Molecular and morphological changes induced by ivosidenib correlate with efficacy in mutant-IDH1 cholangiocarcinoma. Future Oncol. 2021;17(16):2057-2074. doi:10.2217/fon-2020-1274 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Biliary Tract Cancers V.2.2024. © National Comprehensive Cancer Network, Inc., 2024. All rights reserved. Accessed April 19, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 3. Mondesir J, Willekens C, Touat M, de Botton S. IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. J Blood Med. 2016;7:171-180. doi:10.2147/JBM.S70716 4. Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol. 2019;10(4):751-765. doi:10.21037/jgo.2019.03.10 5. Virgil H. FDA approves Oncomine Dx Target Test as a companion diagnostic for ivosidenib in IDH1+ cholangiocarcinoma. Cancer Network. Accessed February 22, 2024. https://www.cancernetwork.com/view/fda-approves-oncomine-dx-target-test-asa-companion-diagnostic-for-ivosidenib-in-idh1-cholangiocarcinoma. 6. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023. 7. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-744. doi:10.1093/annonc/mdw013 8. Kumari A. Citric acid cycle. In: Sweet Biochemistry: Remembering Structures, Cycles, and Pathways by Mnemonics. 1st ed. Elsevier Inc; 2018:7-11. 9. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225-234. doi:10.1016/j.ccr.2010.01.020 10. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72-79. doi:10.1634/theoncologist.2011-0386 11. Javle M, Lee S, Azad NS, et al. Temporal changes in cholangiocarcinoma incidence and mortality in the United States from 2001 to 2017. Oncologist. 2022;27(10):874-883. doi:10.1093/oncolo/oyac150 12. Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13(5):261-280. doi:10.1038/nrgastro.2016.51 13. Survival rates for bile duct cancer. American Cancer Society. Last revised March 1, 2023. Accessed February 22, 2024. https://www.cancer.org/cancer/types/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html

 

TIBSOVO® (ivosidenib tablets) was studied in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial—one of the largest clinical trials to date of a targeted therapy in cholangiocarcinoma1-3

cca-efficacy-modal cca-efficacy-modal

CCA, cholangiocarcinoma; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IDH1, isocitrate dehydrogenase-1; mIDH1, mutated IDH1; NGS, next-generation sequencing; QD, once a day; RECIST, Response Evaluation Criteria in Solid Tumors.

References: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022. 2. Data on file. Servier Pharmaceuticals LLC. 3. Zhu AX, Macarulla T, Javle MM, et al. Final results from the ClarIDHy Phase III study of ivosidenib versus placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 (IDH1) mutation. EMJ Oncol. 2021;9(suppl 2):2-5. doi:10.1200/JCO.2021.39.3_suppl.266

TIBSOVO® was studied in a patient population reflective of that seen in a clinical practice1,2

Selected baseline demographics and disease characteristics (N=185)1

  TIBSOVO
(n=124)		 Placebo
(n=61)
Demographics
Median age, years (min, max) 61 (33,80) 63 (40,83)
Sex
Male 36% 40%
Female 65% 61%
Race
White 57% 57%
Asian 12% 13%
Black 0.8% 1.6%
Native Hawaiian/Other Pacific Islander 0.8% 0%
American Indian or Alaska Native 0.8% 0
Disease characteristics
Prior lines of therapy
1 prior line of therapy 53% 54%
2 prior lines of therapy 47% 46%
ECOG PS
0 40% 31%
1 60% 67%
IDH1 mutation
R132C 68% 74%
R132L 17% 12%
R132G 14% 10%
R132H 0% 3.3%
R132S 1.6% 1.6%
Cholangiocarcinoma type at initial diagnosis
Intrahepatic 90% 95%
Metastatic disease 93% 92%

ECOG PS: Eastern Cooperative Oncology Group Performance Status.

References: 1.  Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023. 2. Data on file. Servier Pharmaceuticals LLC.

 

Indication

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

  • In patients with cholangiocarcinoma, the most common adverse reactions (≥15%) were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. The most common laboratory abnormalities (≥10%) were hemoglobin decreased, aspartate aminotransferase increased, and bilirubin increased.

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Advise women not to breastfeed.

Please see Full Prescribing Information.

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Indication & Important Safety Information

INDICATION

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.