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Study Design

The ClarIDHy trial for TIBSOVO was the first phase 3 trial to show clinical benefit with targeted therapy in mIDH1 CCA and one of the largest to date1-3

The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival, objective response rate, safety, and quality of life.1,2

TIBSOVO was studied in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in a CCA patient population reflective of that seen in clinical practice.1-3

Recommendation from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)4

Ivosidenib (TIBSOVO) is recommended as an NCCN category 1 subsequent-line systemic treatment option for patients with unresectable or metastatic progressive CCA with IDH1 mutations.4,a

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

mIDH1, mutated isocitrate dehydrogenase-1; NCCN, National Comprehensive Cancer Network® (NCCN®).

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Progression-free survival

TIBSOVO delivered significant improvements in PFS1

PFS for TIBSOVO vs placebo1,2

CCA Efficacy chart
CCA Efficacy chart

CI, confidence interval; HR, hazard ratio.

bPatients were censored if they were missing a baseline assessment, missing documented progression or death before data cutoff, started alternate anticancer systemic treatment, or had documented progression or death following 95 days or more from the previous adequate assessment.2

  • None of the patients assigned to placebo had PFS of 6 months or greater2
  • The median PFS was nearly twice as long for patients assigned to TIBSOVO compared with placebo (2.7 months [95% CI, 1.6-4.2] versus 1.4 months [95% CI, 1.4-1.6])2
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Treatment duration within ClarIDHy trial

Treatment duration within ClarIDHy trial

MEDIAN TREATMENT DURATION

2.8 months

with TIBSOVO1

(range, 0.1 to 34.4 months)

VS

1.6 months

with placebo5

(range, 0 to 6.9 months)

Treatment duration for all patients treated with TIBSOVO5

Chart of treatment duration
Chart of treatment duration

cOngoing as of data cutoff (May 31, 2020).

Treatment duration for all patients treated with placebo, including those who crossed over to TIBSOVO5

Chart of treatment duration placebo
Chart of treatment duration placebo

cOngoing as of data cutoff (May 31, 2020).

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Overall survival (OS) data with TIBSOVO

Overall survival (OS) data with TIBSOVO

OS for TIBSOVO vs placebo (intent-to-treat set)2,d

  TIBSOVO
n=126 		Placebo
n=61 		Placebo (adjusted for crossover)
n=61
Number of events (%) 100 (79.4) 50 (82.0) 49 (80.3)
Median OS, months 10.3 7.5 5.1
12-month rate 43%
(95% CI, 34%-51%)		 36%
(95% CI, 24%-48%)		 36%
(95% CI, 24%-48%)

CI, confidence interval; HR, hazard ratio; RPSFT, rank-preserving structural failure time.

Chart of efficacy treatment duration
Chart of efficacy treatment duration

dOS results are based on the final analysis of OS (based on 150 deaths), which occurred 16 months after the final analysis of PFS.1

ePatients without documentation of death at the time of the data cutoff for analysis were censored at the date the subject was last known to be alive or the data cutoff date, whichever was earlier.2

  • Among the 61 patients in the placebo arm, 70% crossed over to receive TIBSOVO1
    • These patients continued to be grouped within their original randomized assignment for analysis purposes3
    • As a result, OS data may be confounded by the crossover2
  • A statistical model known as rank-preserving structural failure time (RPSFT) was used to recreate the placebo curve as if crossover had not occurred6,f,g
  • When adjusted for crossover, median OS for the placebo group was 5.1 months (95% CI, 3.8-7.6 months; HR, 0.49 [95% CI, 0.34-0.70])5

fThis prespecified model, known as RPSFT is one the most commonly used statistical methods to adjust for treatment switching in oncology trials. This sensitivity analysis was exploratory, and appropriate multiplicity adjustments were not applied.6

gThe RPSFT model is based on the assumption that the treatment effect of TIBSOVO is the same for all individuals, regardless of when treatment is received. This assumption was not verified.5

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More than half (51%) of patients receiving TIBSOVO achieved stable disease2

More than half (51%) of patients receiving TIBSOVO achieved stable disease2

Disease control rate2,h

53%

with TIBSOVO

VS

28%

with placebo

ORR, objective response rate; SD, stable disease.

hThe disease control rate (ORR + SD) was due mostly to the SD rate (an ORR rate of 2% [3 partial responses] and an SD rate of 51% with TIBSOVO vs an ORR of 0% and an SD rate of 28% with placebo).

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Health-related quality of life (QoL)

Health-related quality of life (QoL)

  • CCA is associated with an impaired QoL, a metric that is increasingly regarded as a crucial endpoint in clinical trials7
  • Health-related QoL was assessed using two tools; the EORTC QLQ-C30, a generic cancer questionnaire, and the EORTC QLQ-BIL21, a disease-specific module5
  • TIBSOVO was favored on physical functioning, as well as subscales such as pain, emotional functioning, cognitive functioning, dyspnea, anxiety, and tiredness3
  • Analyses of the QoL data were limited by small sample sizes.5 Assessments depicted were at Cycle 2 Day 18,i

EORTC QLC-C30 global health status/QoL and functional subscales4

graph graph
Higher scores indicate a favorable outcome.

EORTC QLQ-C30 symptoms subscales5

graph graph
Lower scores indicate a favorable outcome.

EORTC QLQ-BIL21 subscales5

graph graph
Lower scores indicate a favorable outcome.

These QoL analyses were exploratory, and appropriate multiplicity adjustments were not applied. Results of these individual components need cautious interpretation and could represent chance findings.

CI, confidence interval; EORTC QLQ-BIL21, EORTC QLQ cholangiocarcinoma and gallbladder cancer module; EORTC QLC-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; LS, least squares.

i At baseline: n=53 for placebo and n=114 for TIBSOVO (QLQ-c30); n=52 for placebo and n=108 for TIBSOVO (QLQ-BIL21). At Cycle 2 Day 1: n=24 for placebo and n=68 for TIBSOVO (QLQ-C30); n=23 for placebo and n=68 for TIBSOVO (QLQ-BIL21). At Cycle 3 Day 1: n=12 for placebo and n=52 for TIBSOVO (QLQ-C30); n=12 for placebo and n=52 for TIBSOVO (QLQ-BIL21).5

Consider TIBSOVO as a second-line targeted treatment
for mIDH1 CCA.1

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See the safety profile of TIBSOVO 

References: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023. 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 4. 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. 5. Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 2021;7(11):1669-1677. doi:10.1001/jamaoncol.2021.3836 6. Bennett I, Paracha N, Abrams K, Ray J. Accounting for uncertainty in decision analytic models using rank preserving structural failure time modeling: application to parametric survival models. Value Health. 2018;21(1):105-109. doi:10.1016/j.jval.2017.07.008 7. Kaupp-Roberts SD, Yadegarfar G, Friend E, et al. Validation of the EORTC QLQ-BIL21 questionnaire for measuring quality of life with cholangiocarcinoma and cancer of the gallbladder. BR J Cancer. 2016; 115(9):1032-1038. doi:10.1038/bjc.2016.284 8. Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. Supplementary online content. JAMA Oncol. 2021;7(11):1669-1677. doi:10.1001/jamaoncol.2021.3836

 

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.