IMPORTANT SAFETY INFORMATION PRESCRIBING INFORMATION REFERENCES

In IC-ineligible patients with newly diagnosed AML TIBSOVO + AZACITIDINE IS PROVEN TO SIGNIFICANTLY
INCREASE OVERALL SURVIVAL (OS) IN mIDH1 AML

More than threefold improvement in mOS with TIBSOVO + AZA vs AZA alone1,5,a,b

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 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.5 The data cutoff date was June 2022 with a median follow-up of 28.6 months for the OS analysis.

AZA, azacitidine; CI, confidence interval; HR, hazard ratio; IC, induction chemotherapy; mIDH1, mutated isocitrate dehydrogenase-1; mOS, median overall survival; PBO, placebo.

Please see Important Safety Information and Full Prescribing Information, including BOXED WARNING for AML patients.
OVERALL
SURVIVAL
CR/CRh
HEMATOLOGIC
PARAMETERS
TRANSFUSION
INDEPENDENCE
EFS
SAFETY
TIBSOVO + AZA
NEWLY DIAGNOSED MONOTHERAPY
NEWLY DIAGNOSED MONOTHERAPY
R/R DOSING mIDH1 / MOA NCCN
GUIDELINES SUMMARY

More than threefold improvement in mOS with TIBSOVO + AZA vs AZA alone1,5,a,b

56% reduction in risk of death per the primary OS analysis (95% CI, 0.27-0.73)1
58% reduction in risk of death per the long-term follow-up OS analysis (95% CI, 0.27-0.65)5
Overall survival benefit was consistent across subgroups: 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.6
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 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.5 The data cutoff was June 2022 with a median follow-up of 28.6 months for the OS analysis.
AZA, azacitidine; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio; mOS, median overall survival; PBO, placebo; WHO, World Health Organization.

Study design

TIBSOVO is the only therapy studied in a phase 3 trial for newly diagnosed mIDH1 AML1

TIBSOVO + azacitidine was studied in a global, phase 3, multicenter, randomized, double-blind, placebo-controlled trial1,4

The trial was initially powered for 200 participants. However, the Independent Data Monitoring Committee suggested halting enrollment after 146 patients when a statistical difference between the two treatment groups was achieved.2

IV, intravenous; mIDH1, mutated isocitrate dehydrogenase-1; QD, once a day; SC, subcutaneous.

Selected baseline demographics and disease characteristics

TIBSOVO + azacitidine was studied in an IC-ineligible patient population reflective of that seen in clinical practice1

aCytogenic risk status: Investigators used the NCCN Guidelines®.
bPatients were defined as transfusion dependent at baseline if they received any red blood cell or platelet transfusion within 56 days prior to the first dose of study treatment.
IC, induction chemotherapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; NCCN, National Comprehensive Cancer Network®.

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

Greater than 3X increase in OS rates at 24 and at 36 months with TIBSOVO + azacitidine5

REFERENCES

1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022.
2. Data on file. Servier Pharmaceuticals LLC.
3. 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
4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.4.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed July 20, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.
5. 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.
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. 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
8. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463-471. doi:10.1182/blood.2019002140
9. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984
10. Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene. 2018;37(15):1949-1960. doi:10.1038/s41388-017-0077-z
11. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553-567. doi:10.1016/j.ccr.2010.11.015
12. Megías-Vericat JE, Ballesta-López O, Barragán E, Montesinos P. IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood Lymphat Cancer. 2019;9:19-32. doi:10.2147/BLCTT.S177913
13. Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systemic review and meta-analysis. Clin Cancer Res. 2017;23(15):4511-4522. doi:10.1158/1078-0432.CCR-16-2628
14. Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: Guideline from the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017;141(10):1342-1393. doi:10.5858/arpa.2016-0504-CP

INDICATIONS &
IMPORTANT SAFETY INFORMATION

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.

© 2023 Servier Pharmaceuticals LLC. Boston, MA 02210. Customer Servier: 1-800-807-6124. Servier and the Servier Logo are registered trademarks of LES LABORATOIRES
SERVIER. TIBSOVO is a registered trademark of SERVIER PHARMACEUTICALS LLC, a wholly owned, indirect subsidiary of LES LABORATOIRES SERVIER.
US-02579  10/2023

REFERENCES

1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022.
2. Data on file. Servier Pharmaceuticals LLC.
3. 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
4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.4.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed July 20, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.
5. 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.
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. 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
8. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463-471. doi:10.1182/blood.2019002140
9. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984
10. Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene. 2018;37(15):1949-1960. doi:10.1038/s41388-017-0077-z
11. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553-567. doi:10.1016/j.ccr.2010.11.015
12. Megías-Vericat JE, Ballesta-López O, Barragán E, Montesinos P. IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood Lymphat Cancer. 2019;9:19-32. doi:10.2147/BLCTT.S177913
13. Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systemic review and meta-analysis. Clin Cancer Res. 2017;23(15):4511-4522. doi:10.1158/1078-0432.CCR-16-2628
14. Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: Guideline from the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017;141(10):1342-1393. doi:10.5858/arpa.2016-0504-CP

INDICATIONS &
IMPORTANT SAFETY INFORMATION

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.

© 2023 Servier Pharmaceuticals LLC. Boston, MA 02210. Customer Servier: 1-800-807-6124. Servier and the Servier Logo are registered trademarks of LES LABORATOIRES
SERVIER. TIBSOVO is a registered trademark of SERVIER PHARMACEUTICALS LLC, a wholly owned, indirect subsidiary of LES LABORATOIRES SERVIER.
US-02579  10/2023