A New Frontier in Cholangiocarcinoma Management and Treatment


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This content was developed in collaboration with Servier Pharmaceuticals and Onc Live

Earlier in my career, when I first started to treat biliary cancers, like cholangiocarcinoma, there was a hesitancy rooted in a shared belief that it would be difficult, if not impossible, to enroll sufficient participants to conduct a successful clinical trial program targeting this patient population.

Dr. Rachna T. Shroff, Associate Professor of Medicine at the University of Arizona Cancer Center

Dr. Rachna T. Shroff, Associate Professor of Medicine at the University of Arizona Cancer Center

Cholangiocarcinoma is an aggressive cancer with increasing incidence in the U.S. and globally, particularly for intrahepatic cholangiocarcinoma (disease developing in the bile ducts within the liver).1-3 Patients with cholangiocarcinoma typically show no symptoms in the early stages of their disease.4 For years, there have been no established methods for early detection and screening. As a result, nearly eight out of 10 patients are diagnosed with advanced disease.2,5 The best available treatment has been complete surgical resection, with treatment of unresectable disease limited to palliative care.6

However, in recent years, we have seen incredible advances in cholangiocarcinoma research. I was fortunate to be part of an effort to establish a research program for biliary cancers. We believed that “if you build it, they will come.” In just a few years, the program was seeing more than 400 patients a year (versus ~50 patients a year before the start of the program). I have also had the honor of serving as an investigator in the ClarIDHy study,7 the first and only randomized Phase 3 trial to evaluate patients with previously treated IDH1-mutated cholangiocarcinoma.

Figure. Summary of progression-free survival results from the ClarIDHy study.7

Figure. Summary of progression-free survival results from the ClarIDHy study.7

The ClarIDHy study is evidence of the feasibility of conducting a global targeted-therapy trial in what is considered a rare disease. Importantly, it highlights the advantage of engaging key opinion leaders and other stakeholders, including physicians, patient advocacy groups, and patients, in designing a study in cholangiocarcinoma to encourage patient participation and allow maximum patient access to a treatment with promising clinical benefit. This trial showed a new way to approach and think about drug development and the most appropriate design for clinical trials in a rare disease space.

The results from ClarIDHy7 formed the basis for the U.S. Food and Drug Administration (FDA) approval of TIBSOVO® (ivosidenib tablets), the first and only targeted therapy for adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation. Prior to this approval, the only treatment option for later stages of the disease was chemotherapy.2 A molecular companion diagnostic test to identify patients with IDH1 mutations was also approved alongside TIBSOVO. Present in up to 20% of patients in the U.S., IDH1 mutations remain the most prevalent alterations in cholangiocarcinoma, and they are not associated with prognosis.3

IDH1 mutations are major drivers of disease progression. The ability to identify IDH1 mutations as early as possible through diagnostic testing is a major innovation for treating physicians. Now, with the availability of an FDA-approved companion diagnostic test for IDH1 mutations, physicians can identify which patients are eligible to receive and may benefit from treatment with TIBSOVO. IDH1 mutation testing can also enable physicians to identify more readily the underlying disease behind patients’ symptoms, since cholangiocarcinoma-related symptoms are similar to those of other potential malignancies, including liver/bile duct or pancreatic cancer. The evidence provided by IDH1 mutation testing can help physicians make informed disease management decisions.

Being asymptomatic in its early stages, cholangiocarcinoma is often advanced at diagnosis.4,5 Consequently, just a few patients (~25%) can benefit from surgical resection, a potential curative treatment option for the disease.2 However, rates of recurrence following resection remain high.2 With patients continuing to experience considerable burden from disease symptoms and treatment,8-10 robust biomarkers are invaluable for accurate diagnosis of the disease and for predicting treatment response.2 Through early testing, eligible patients harboring an IDH1 mutation can now benefit from an effective treatment.

As we enter this new frontier in cholangiocarcinoma treatment and management, I want to emphasize the importance of IDH1 mutation testing and its role in treatment planning and disease management. I also encourage patients to discuss IDH1 mutation testing with their oncologist to see if they could benefit from early testing.

To learn more about TIBSOVO in cholangiocarcinoma, visit www.tibsovopro.com. For support after being prescribed TIBSOVO, visit www.servierone.com.

Rachna T. Shroff, MD, MS, is an Associate Professor of Medicine and Chief of GI Medical Oncology as well as Leader of the Gastrointestinal Clinical Research Team at the University of Arizona Cancer Center. She is the Director of the University of Arizona Cancer Center Clinical Trials Office as well as the Director of the Arizona Clinical Trials Network (ACTN), and Associate Dean for Clinical and Translational Research for the University of Arizona College of Medicine in Tucson. She came to the Cancer Center from MD Anderson Cancer Center in Houston, TX where she served as faculty from 2010 – 2018 after completing her medical oncology fellowship there.

Dr. Shroff was an investigator for the ClarIDHy study and is a paid spokesperson for Servier Pharmaceuticals.

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with a susceptible IDH1 mutation as detected by an FDA-approved test with:

Acute Myeloid Leukemia (AML)

  • Newly-diagnosed AML who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
  • Relapsed or refractory AML.

Locally Advanced or Metastatic Cholangiocarcinoma

  • Locally advanced or metastatic cholangiocarcinoma who have been previously treated.


Differentiation Syndrome in AML: In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

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 (e.g., 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.


  • In patients with AML, the most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
  • In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
  • In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
  • In patients with cholangiocarcinoma, the most common adverse reactions (≥15%) were fatigue (43%), nausea (41%), abdominal pain (35%), diarrhea (35%), cough (27%), decreased appetite (24%), ascites (23%), vomiting (23%), anemia (18%), and rash (15%). The most common laboratory abnormalities (≥10%) were hemoglobin decreased (40%), aspartate aminotransferase increased (34%), and bilirubin increased (30%).

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.

Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Please see Full Prescribing Information, including BOXED WARNING for AML patients.

To learn more about TIBSOVO in cholangiocarcinoma, visit www.tibsovopro.com. For support after being prescribed TIBSOVO, visit www.servierone.com.


1. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21(5):594-599.

2. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588.

3. 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.

4. Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(9):512-522.

5. Patel N, Benipal B. Incidence of Cholangiocarcinoma in the USA from 2001 to 2015: A US Cancer Statistics Analysis of 50 States. Cureus. 2019;11(1):e3962.

6. Anderson CD, Pinson CW, Berlin J, Chari RS. Diagnosis and treatment of cholangiocarcinoma. Oncologist. 2004;9(1):43-57.

7. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796-807.

8. Chamberlain CX, Faust E, Goldschmidt D, et al. Burden of illness for patients with cholangiocarcinoma in the United States: a retrospective claims analysis. J Gastrointest Oncol. 2021;12(2):658-668.

9. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281.

10. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690-701.

US-02041 11/2021