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Now approved in combination with azacitidine

For patients with newly diagnosed aml

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

Prescribing Information Press Release more
Proven to deliver strong and durable results1,2

TIBSOVO (ivosidenib tablets) is the only therapy that was studied in a phase 3 trial specifically designed for newly diagnosed patients with mIDH1 AML1,2

TIBSOVO + azacitidine was studied in a global, phase 3, multicenter, randomized, double-blind, placebo-controlled trial.

AGILE study design

TIBSOVO + azacitidine was studied in an IC-ineligible patient population reflective of that seen in clinical practice.1

See baseline characteristics

AML, acute myeloid leukemia; IC, induction chemotherapy; mIHD1, mutant isocitrate dehydrogenase-1.

OVERALL SURVIVAL

Threefold improvement in overall survival (OS) with TIBSOVO + azacitidine1

TIBSOVO + azacitidine delivered a median OS of 24.0 months vs 7.9 months with azacitidine.

os-combo-chart
Endpoint TIBSOVO + azacitidine
(n=72)1		 Placebo + azacitidine
(n=74)1
OS, events (%) 28 (39) 46 (62)
Median OS, months (95% CI) 24.0 (11.3-34.1) 7.9 (4.1-11.3)
Hazard ratioa (95% CI) 0.44 (0.27-0.73)
P valueb 0.0010
Endpoint TIBSOVO + azacitidine
(n=72)1
OS, events (%) 28 (39)
Median OS, months (95% CI) 24.0 (11.3-34.1)
Hazard ratioa (95% CI) 0.44 (0.27-0.73)
P valueb 0.0010
Endpoint Placebo + azacitidine
(n=74)1
OS, events (%) 46 (62)
Median OS, months (95% CI) 7.9 (4.1-11.3)
Hazard ratioa (95% CI) 0.44 (0.27-0.73)
P valueb 0.0010

The two-sided P value boundary for OS is 0.0034.

a Hazard 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.

bTwo-sided P value was calculated from the log-rank test stratified by the randomization stratification factors (type of AML and geographic region).

Overall survival benefit was consistent across subgroups, 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.3

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

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EVENT-FREE SURVIVAL

Significant improvements in event-free survival (EFS)1

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 ratioc (95% CI) 0.35 (0.17-0.72)
P valued 0.0038
Treatment with TIBSOVO + azacitidine resulted in significant improvements in EFS compared with azacitidine1
Endpoint TIBSOVO + azacitidine
(n=72)
EFS, events (%) 47 (65)
Treatment failure 43 (60)
Relapse 3 (4)
Death 1 (1)
Hazard ratioc (95% CI) 0.35 (0.17-0.72)
P valued 0.0038
Treatment with TIBSOVO + azacitidine resulted in significant improvements in EFS compared with azacitidine1
Endpoint Placebo + azacitidine
(n=74)
EFS, events (%) 62 (84)
Treatment failure 59 (80)
Relapse 2 (3)
Death 1 (1)
Hazard ratioc (95% CI) 0.35 (0.17-0.72)
P valued 0.0038

The two-sided P value boundary for EFS is 0.0095.

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

dTwo sided P value was calculated from the 1-sided log-rank test stratified by the randomization stratification factors (type of AML and geographic region).

  • 12-month EFS rate: 37.4% with TIBSOVO + azacitidine (95% CI, 25.9-48.9) vs 12.2% with azacitidine (95% CI, 4.3-24.4)4
  • 18-month EFS rate: 33.3% with TIBSOVO + azacitidine (95% CI, 20.9-46.2) vs 6.1% with azacitidine (95% CI, 0.7-20.9)4

AML, acute myeloid leukemia; CI, confidence interval; EFS, event-free survival, defined as time from randomization until treatment failure (ie, failure to achieve complete remission by Week 24), relapse from remission, or death from any cause, whichever occurred first.

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CR+CRh

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

TIBSOVO-azacitidine-combo
  • Median duration of complete response 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)4
  • Of the patients who achieved CR or CRh with TIBSOVO + azacitidine4:
    • 80.5% remained in remission at 12 months (95% CI, 54.4-92.5)e
    • 53.6% remained in remission at 24 months (95% CI, 17.0-80.3)e
  • 37.5% of patients receiving TIBSOVO + azacitidine achieved CR by Week 24 compared with 10.8% of patients in the azacitidine arm3

Median time to response with TIBSOVO + azacitidine

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

ePer Kaplan-Meier estimation.

CI, confidence interval; CR, complete remission, 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 transfusions4; CRh, complete remission with partial hematological recovery, 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)4; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; MLFS, morphologic leukemia-free state; PR, partial remission.

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TRANSFUSION INDEPENDENCE

Nearly 50% conversion to transfusion independence2,3

Among patients who were transfusion dependent at baseline, a higher percentage of patients converted to transfusion independence with TIBSOVO + azacitidine than with azacitidine

nearly-50-combo

Regardless of baseline transfusion status, more patients experienced postbaseline red blood cell and platelet transfusion independence with TIBSOVO + azacitidine than with azacitidine3

nearly-50-combo

Postbaseline 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.4

HEMATOLOGIC IMPROVEMENT

TIBSOVO + azacitidine enabled improvements in key hematologic parameters3

TIBSOVO + azacitidine resulted in rapid neutrophil recovery3

Change in absolute neutrophil count from baseline

change-in-absolute-combo

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.

TIBSOVO + azacitidine resulted in decreased bone marrow blasts4

Change in bone marrow blasts from baseline

change-in-bone-marrow-combo

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 response4

AZA, azacitidine; IDH1, isocitrate dehydrogenase-1.

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

References: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022. 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. 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 4. Data on file. Servier Pharmaceuticals LLC.

 
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AGILE study design1

study-design-combo-modal study-design-combo-modal
  • Efficacy was established on the basis of event-free survival (EFS), overall survival (OS), and rate and duration of complete remission (CR)2
  • EFS was defined as time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurred first2
  • Treatment failure was defined as failure to achieve CR by Week 24. A CRh response was considered to be a treatment failure2
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; CR, complete remission, 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 transfusions3; CRh, complete remission with partial hematological recovery, 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; 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 syndrome; MPN, myeloproliferative neoplasm; ORR, objective response rate; QD, once a day; SC subcutaneous.

References: 1. Montesinos P, Recher C, Zarzycka E, et al. AGILE: A phase 3, double-blind, randomized, placebo-controlled study of ivosidenib in combination with azacitidine in adults with newly diagnosed acute myeloid leukemia and an IDH1 mutation. Poster presented at: 3rd International Academy for Clinical Hematology (IACH) Annual Meeting; October 1-3, 2020; virtual. 2. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022. 3. Data on file. Servier Pharmaceuticals LLC.

Baseline patient demographics and disease characteristics1
  TIBSOVO® (500 mg daily)
+ azacitidine (n=72)		 Placebo + azacitidine
(n=74)
Demographics
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) 40 (54)
≥75 years 39 (54) 43 (58)
Disease characteristics
ECOG PS, n (%)
0 14 (19) 10 (14)
1 32 (44) 40 (54)
2 26 (36) 24 (32)
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)
Transfusion dependent at baseline,b n (%) 39 (54) 40 (54)
Type of AML, %
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)

AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group Performance Status; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; NCCN, National Comprehensive Cancer Network®.

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

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

Reference: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022.

 

Indications

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible 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

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: In the combination study AG120-C-009, 15% (11/71) of patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome. 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. Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine, 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

In the monotherapy clinical trial AG120-C-001, 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. 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 (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 AML, the most common 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

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 1 month after the last dose.

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

 

INDICATIONS

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible 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
  • Adult patients with relapsed or refractory AML.
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.