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TIBSOVO (ivosidenib tablets) is the only therapy that was studied in a phase 3 trial specifically designed for newly diagnosed patients with mIDH1 AML1

TIBSOVO + azacitidine was studied in a global, phase 3, multicenter, randomized, double-blind, placebo-controlled trial in an IC-ineligible patient population reflective of that seen in clinical practice.1,2

AGILE study design See baseline characteristics

AML, acute myeloid leukemia; IC, induction chemotherapy; mIDH1, mutant isocitrate dehydrogenase‑1.

TIBSOVO + azacitidine is proven to significantly increase overall survival (OS)1

More than threefold improvement in mOS with TIBSOVO + AZA vs AZA alone1,3

TIBSOVO + Azacitidine Rates of CR and CRh graph TIBSOVO + Azacitidine Rates of CR and CRh graph

Improvements in OS were seen in patients on TIBSOVO + AZA regardless of baseline status, including de novo status, region, age, baseline ECOG PS score, sex, race, baseline cytogenetic risk status, WHO classification of AML, baseline white blood cell count, and baseline percentage of bone marrow blasts.4

Primary OS analysis

24.0 months mOS with TIBSOVO + azacitidine (95% CI, 11.3-34.1) vs 7.9 months with azacitidine alone (95% CI, 4.1-11.3) 1,a

  • 56% reduction in risk of death (HR, 0.44 [95% Cl, 0.27-0.73]; P=0.0010)1
  • The percentage of OS events at the time of analysis was 39% (n=28) and 62% (n=46) in the TIBSOVO + azacitidine and placebo + azacitidine arms, respectively1

Long-term follow-up OS analysis

29.3 months mOS with TIBSOVO + azacitidine (95% CI, 13.2-NR) vs 7.9 months with azacitidine alone (95% CI, 4.1-11.3) 3,b

  • 58% reduction in risk of death (HR, 0.42 [95% Cl, 0.27-0.65]; P<0.0001)3

aIn the primary analysis from the AGILE study, 146 patients were 1:1 randomized: 72 to TIBSOVO + AZA and 74 to PBO + AZA.1,3 The data cutoff date of the primary analysis from the AGILE study was March 2021 with a median follow-up of 15.1 months for the OS analysis.

bIn the long-term follow-up analysis from the AGILE study, 148 patients were 1:1 randomized: 73 to TIBSOVO + AZA and 75 to PBO + AZA.2,4 The data cutoff date of the long-term follow-up analysis from the AGILE study was June 2022 with a median follow-up of 28.6 months for the OS analysis.

For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response1

Overall survival benefit with TIBSOVO + azacitidine increased over time compared to azacitidine alone

Greater than 3X increase in OS rates at 24 and 36 months with TIBSOVO + azacitidine3

Greater Than Three Times Increase in Overall Survival Chart Greater Than Three Times Increase in Overall Survival Chart

AML, acute myeloid leukemia; AZA, azacitidine; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio; PBO, placebo; WHO, World Health Organization.

TIBSOVO + azacitidine demonstrated rapid and durable remissions

TIBSOVO + azacitidine demonstrated significantly higher rates of CR and CR+CRh compared with azacitidine (P<0.0001)1,c

TIBSOVO-azacitidine-combo Chart TIBSOVO-azacitidine-combo-mobile Chart
  • Median duration of CR was not estimable (NE) as of the data cutoff date in the TIBSOVO + azacitidine arm (95% CI,13.0-NE) and was 11.2 months in the azacitidine arm (95% CI, 3.2-NE)1
  • Of the patients who achieved CR with TIBSOVO + azacitidine2,5:
    • 88% remained in remission at 12 months (95% CI, 67.5-96.2)d
    • 59% remained in remission at 24 months (95% CI, 17.7-85.1)d
  • 38% of patients receiving TIBSOVO + azacitidine achieved CR by Week 24 compared with 11% of patients in the azacitidine arm4

Median time to response with TIBSOVO + azacitidine

  • First response (CR, CRi, CRp, PR, or MLFS): 2 months (range, 2-8)5
  • CR: 4 months (range, 2-12)1
  • CR+CRh: 4 months (range, 2-12)1

cCR was defined as <5% blasts in the bone marrow and no Auer rods, absence of extramedullary disease, full recovery of peripheral blood counts (absolute neutrophil count ≥1000/μL and platelets ≥100,000/μL), and independence of red blood cell transfusions.5 CRh was defined as <5% blasts in the bone marrow and no Auer rods, absence of extramedullary disease, and partial recovery of peripheral blood counts (absolute neutrophil count >500/μL and platelets >50,000/μL).

dPer Kaplan-Meier estimation.

CR, complete remission; CRh, complete remission with partial hematologic recovery; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; MLFS, morphologic leukemia-free state; PR, partial remission.

TIBSOVO + azacitidine resulted in rapid neutrophil recovery and reduction in bone marrow blasts

Rapid and sustained neutrophil recovery with TIBSOVO + azacitidine5,6,e-g

Change in median absolute neutrophil count (ANC) from baseline

change-in-absolute-combo Chart change-in-absolute-combo Chart

eBL denotes baseline, defined as a median ANC value of 0.2 x 109/L for the TIBSOVO + AZA arm and placebo + AZA arm; CxDy indicates Cycle x Day y.6

fShading denotes neutropenia and severe neutropenia, defined as ANC values of <1.0 x 109/L and <0.5 x 109/L, respectively.6

gMedian values are presented to avoid the potential masking influence of outliers resulting from differentiation of leukocytosis, which may be possible with reporting the mean values.6

TIBSOVO + azacitidine demonstrated an increase in ANC recovery by the end of Cycle 14,5

Change in mean ANC from baseline

combo-demonstrated-an-increase-in-ANC-recovery-by-end-of-cycle Chart combo-demonstrated-an-increase-in-ANC-recovery-by-end-of-cycle Chart

BL denotes baseline, defined as the last assessment before start of study treatment; CxDy indicates Cycle x Day y; error bars indicate mean +/- standard error.

Notable decreases in bone marrow blasts were observed from baseline to Week 9 and sustained throughout treatment with TIBSOVO + azacitidine5

Change in bone marrow blasts from baseline

change-in-bone-marrow-combo Chart change-in-bone-marrow-combo Chart

BL denotes baseline, defined as the last assessment before start of study treatment; error bars indicate mean +/- standard error.

  • Participants in the trial were to follow a study center visit schedule that included a bone marrow aspirate/biopsy and peripheral blood sampling to evaluate IDH1-mutated cells and to assess disease status and response5

AZA, azacitidine; IDH1, isocitrate dehydrogenase‑1.

Significant improvements in event-free survival (EFS)1,h

Treatment with TIBSOVO + azacitidine resulted in significant improvements in EFS compared with azacitidine1

Endpoint TIBSOVO + azacitidine
(n=72)		 Placebo + azacitidine
(n=74)
EFS, events (%) 47 (65) 62 (84)
Treatment failure 43 (60) 59 (80)
Relapse 3 (4) 2 (3)
Death 1 (1) 1 (1)
Hazard ratioi (95% CI) 0.35 (0.17-0.72)
P valuej 0.0038

hEFS was defined as time from randomization until treatment failure (ie, failure to achieve CR by Week 24), relapse from remission, or death from any cause, whichever occurred first.1

iHazard ratio was estimated using a Cox proportional hazards model stratified by the randomization stratification factors (type of AML and geographic region) with placebo + azacitidine as the denominator.

jTwo-sided P value boundary for EFS is 0.0095 and was calculated from the log-rank test stratified by the randomization stratification factors (type of AML and geographic region).

TIBSOVO + azacitidine demonstrated higher EFS rates compared to azacitidine alone5

efs-12-month Chart
efs-18-month Chart

AML, acute myeloid leukemia; CR, complete remission.

More than half of patients achieved transfusion independence with TIBSOVO + azacitidine

Transfusion independence among patients who were transfusion dependent at baseline3,k,l

transfusion-independence-at-baseline-chart Chart transfusion-independence-at-baseline-chart Chart

Postbaseline RBC and platelet transfusion independence regardless of baseline transfusion status4

postbaseline-transfusion-independence-chart Chart postbaseline-transfusion-independence-chart Chart

kPostbaseline transfusion independence is defined as a period of ≥56 days with no transfusion after the start of study treatment and on or before the end of study treatment + 28 days, disease progression, confirmed relapse, death, or data cutoff date, whichever was earlier.3

lThe 95% confidence interval in the transfusion independence analysis was 37.2-69.9 for the TIBSOVO + azacitidine arm and 7.2-32.1 for the placebo + azacitidine arm.3

RBC, red blood cell.

NCCN Guidelines® recommends ivosidenib (TIBSOVO) + azacitidine as a category 1 preferred treatment option for newly diagnosed patients

≥18 years of age with mIDH1 AML who are not candidates for intensive remission induction therapy7

View efficacy data for TIBSOVO monotherapy

References: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023. 2. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344 3. de Botton S, Montesinos P, Vives Polo S, et al. Updated efficacy and safety data from the AGILE study in patients with newly-diagnosed acute myeloid leukemia treated with ivosidenib + azacitidine compared to placebo + azacitidine. Poster presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL. 4. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia: supplementary appendix. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344 5. Data on file. Servier Pharmaceuticals LLC. 6. Fathi AT, Douglas Smith B, Angiolillo A, et al. Time to resolution of myelosuppression and associated hospitalization in patients with newly diagnosed acute myeloid leukemia treated with ivosidenib+azacitidine compared with azacitidine+placebo. Poster presented at: Eleventh Annual Meeting of the Society of Hematologic Oncology (SOHO 2023); September 6-9, 2023; Houston, TX. Poster AML-446. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed March 1, 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.

AGILE study design1

agile-study-design-outlined Chart agile-study-design-mobile-outlined Chart
  • Efficacy was established on the basis of event-free survival (EFS), overall survival (OS), and rate and duration of complete remission (CR)2,a,b
  • Treatment failure was defined as failure to achieve CR by Week 24. A CRh response was considered to be a treatment failure2,c
aCR was defined as <5% blasts in the bone marrow and no Auer rods, absence of extramedullary disease, full recovery of peripheral blood counts (absolute neutrophil count ≥1000/μL and platelets ≥100,000/μL), and independence of red blood cell transfusions.3
bEFS was defined as time from randomization until treatment failure (ie, failure to achieve CR by Week 24), relapse from remission, or death from any cause, whichever occurred first.2
cCRh was defined as >5% blasts in the bone marrow and no Auer rods, absence of extramedullary disease, and partial recovery of peripheral blood counts (absolute neutrophil count >500/μL and platelets >50,000/μL).3
The trial was initially powered for 200 participants. However, the Independent Data Monitoring Committee suggested halting enrollment after 146 patients when a clinically important difference between the two treatment groups was achieved.3

AML, acute myeloid leukemia; CRh, complete remission with partial hematologic recovery; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EORTC QLC-C30, European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EQ-5D-FL, 5-level EuroQol Five Dimensions Questionnaire (descriptive system and visual analogue scale); HMA, hypomethylating agent; IV, intravenous; LVEF, left ventricular ejection fraction; mIDH1, mutated isocitrate dehydrogenase-1; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; ORR, objective response rate; QD, once a day; SC, subcutaneous.

References: 1. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344 2. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023. 3. Data on file. Servier Pharmaceuticals LLC.

Baseline patient demographics and disease characteristics1

  TIBSOVO® (500 mg daily)
+ azacitidine (n=72)		 Placebo + azacitidine
(n=74)
Median age, years (min, max) 76 (58, 84) 76 (45, 94)
Age categories, n (%)
<65 years 4 (6) 4 (5)
≥65 years to <75 years 29 (40) 27 (36)
≥75 years 39 (54) 43 (58)
Cytogenetic risk status,a n (%)
Favorable 3 (4) 7 (9)
Intermediate 48 (67) 44 (59)
Poor 16 (22) 20 (27)
Other 3 (4) 1 (1)
Missing 2 (3) 2 (3)
ECOG PS, n (%)
0 14 (19) 10 (14)
1 32 (44) 40 (54)
2 26 (36) 24 (32)
Transfusion dependent at baseline,b n (%) 39 (54) 40 (54)
Type of AML, n (%)
De novo AML 54 (75) 53 (72)
Secondary AML 18 (25) 21 (28)
Therapy-related AML 2 (3) 1 (1)
MDS related 10 (14) 12 (16)
MPN related 4 (6) 8 (11)

aCytogenic risk status: Investigators used the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).

bPatients were defined as transfusion dependent if they received any RBC or platelet transfusion within 56 days prior to the first dose of study treatment.

AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group Performance Status; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; NCCN, National Comprehensive Cancer Network®; RBC, red blood cell.

Reference: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023.

 

Indications

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

Newly Diagnosed Acute Myeloid Leukemia (AML)

  • In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy

Relapsed or Refractory AML

  • For the treatment of adult patients with relapsed or refractory AML

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML
Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome in AML: Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. 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.

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 (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, electrolyte abnormalities, or 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 AML, the most adverse reactions including laboratory abnormalities (≥25%) are leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphate decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia

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, including BOXED WARNING for AML patients.

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INDICATIONS

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

Newly Diagnosed Acute Myeloid Leukemia (AML)

  • In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy
Indications & Important Safety Information

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.