Servier Bolsters Position as the Leader in Mutant IDH Inhibition with Positive New IDH1-Mutated Acute Myeloid Leukemia Data at ASCO

Updated data from Phase 3 AGILE study show additional extension in median overall survival to 29.3 months with TIBSOVO^® (ivosidenib tablets) in combination with azacitidine and confirm continued benefit of TIBSOVO as first-line treatment of newly-diagnosed acute myeloid leukemia (AML)

Analysis of Phase 1 expansion study identifies clinical and molecular characteristics of AML patients with an exceptional response to TIBSOVO

BOSTON, June 5, 2023 /PRNewswire/ -- Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, today presented updated efficacy and safety data from the global Phase 3 AGILE study of TIBSOVO^® (ivosidenib tablets) in combination with the chemotherapy azacitidine for newly-diagnosed acute myeloid leukemia (AML), and a new analysis of treatment response to TIBSOVO, an inhibitor of the mutated isocitrate dehydrogenase-1 (IDH1) enzyme at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO). As the first IDH1 mutation specific targeted therapy to demonstrate improved overall survival (OS) in combination with azacitidine compared to azacitidine plus placebo, TIBSOVO was also recently approved by the European Commission as the first IDH1 inhibitor in Europe.

"Servier has been leading the research and clinical development of IDH inhibitors as a novel therapeutic approach for a broad range of hard-to-treat cancers," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "We are pleased to present new data at ASCO that further demonstrate the significant clinical and survival benefits of first-line treatment with TIBSOVO and azacitidine for patients with IDH1-mutated AML."

The AGILE trial is a global Phase 3 double blinded placebo-controlled study of TIBSOVO in combination with azacitidine vs azacitidine plus placebo in adults with previously untreated IDH1-mutated AML who were ineligible to receive intensive chemotherapy. TIBSOVO in combination with azacitidine demonstrated a three-fold improvement in median OS (24 months) compared to azacitidine plus placebo (7.9 months) as a first-line treatment for IDH1-mutated AML (HR: 0.44; p=0.0005). In long-term follow-up data as of June 2022, at a median follow-up of 28.6 months, median OS was 29.3 months (95% CI 13.2, not reached) for TIBSOVO in combination with azacitidine vs 7.9 months (95% CI 4.1, 11.3) for placebo plus azacitidine (HR 0.42 [0.27, 0.65]; 1-sided p<0.0001).

Additional updated results include:

• At 24 months, OS rates were 53.1% with TIBSOVO in combination with azacitidine, compared to 17.4% with azacitidine plus placebo. At 12 months, OS rates were 62.9% with TIBSOVO in combination with azacytidine, compared to 38.3% with azacitidine plus placebo.
• In the TIBSOVO in combination with azacitidine arm, hemoglobin levels steadily increased from baseline and then stabilized; mean platelet count recovered from baseline values as early as week 8 and remained stable through week 80; and mean neutrophil counts rapidly increased from baseline to weeks 3 and 4 and then stabilized to within the normal range.
• Conversion from baseline transfusion dependence (red blood cell and/or platelet transfusion dependence) to post-baseline transfusion independence was significantly higher with TIBSOVO in combination with azacytidine, compared with azacitidine plus placebo (53.8% vs 17.1%, respectively; 1-sided p=0.0004).

"IDH1 mutations have been explored for their connection to disease biology across various cancers, and patients with IDH1-mutated AML have historically faced a poor prognosis and limited treatment options if they are not eligible for intensive chemotherapy," said Stephane de Botton, MD, PhD, Head of Drug Development in Acute Leukemias in the Department of Hematology at the Gustave Roussy Cancer Center. "These updated results solidify the robust benefit of first-line treatment with TIBSOVO in combination with azacitidine in the extension of median overall survival by more than five months compared to the initial analysis."

TIBSOVO in combination with azacitidine demonstrated a safety profile consistent with previously published data. There were fewer neutropenic fever events (27.8% vs 33.8%) and infections (34.7% vs 51.4%) with TIBSOVO in combination with azacitidine than with azacitidine plus placebo. Treatment-emergent adverse events led to discontinuation of TIBSOVO in combination with azacitidine or azacitidine plus placebo in 26.4% and 25.7% of patients, respectively.

The Phase 3 AGILE study was the basis of the FDA approval for TIBSOVO in combination with azacitidine for newly diagnosed AML, and the original study results were published in the New England Journal of Medicine.

In addition, a Phase 1 dose escalation study was conducted to evaluate the clinical and molecular characteristics of patients with IDH1-mutated relapsed/refractory AML who achieved an exceptional response to treatment with TIBSOVO.

Of 179 patients with R/R AML who received TIBSOVO in the study, 57 (31.8%) achieved complete response (CR)/CR with partial hematologic recovery (CRh). Of these, 13 patients (22.8% of responders, 7.3% of cohort) achieved exceptional response, defined as a duration of CR/CRh response (DOCRCRh) without hematopoietic stem cell transplantation of more than 12 months, and eight (14.0% of responders, 4.5% of cohort) had a DOCRCRh of more than two years. The 13 exceptional responders all achieved a complete response, with a median DOCRCRh of 43 months. No patient with DOCRCRh > 32 months relapsed.

Clinical and molecular characteristics among patients who achieved an exceptional response included a low mutational burden, lack of receptor tyrosine kinase (RTK) pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response.

"With a five-year survival rate of approximately 29.5%, the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. Moreover, for up to 10 percent of AML patients, the IDH1-mutation contributes to the development of acute leukemia," said Eytan Stein, MD, Chief, Leukemia Service and Director, Program for Drug Development in Leukemia, Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center. "For these reasons, identifying the characteristics of patients who may respond to targeted therapy for the IDH1-mutation through molecular testing is of significant importance for treatment strategy and prognosis."

TIBSOVO is also approved as the first and only targeted therapy for patients with previously treated IDH1-mutated cholangiocarcinoma.

TIBSOVO is currently approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML and in monotherapy or in combination with azacitidine for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. TIBSOVO was recently approved by the European Commission as a targeted therapy in two indications: in combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive standard induction chemotherapy; as well as in monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy. TIBSOVO has also been approved in the U.S. and Australia for patients with previously treated IDH1-mutated cholangiocarcinoma. TIBSOVO is also approved in China[i] for the treatment of adult patients with relapsed or refractory AML who have a susceptible IDH1 mutation.

About the NCT03173248 AGILE Phase 3 AML Trial
The AGILE trial is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of TIBSOVO in combination with azacitidine compared with placebo in combination with azacitidine, in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy). The study's primary endpoint is event-free survival (EFS), defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission (CR) by Week 24.

Key secondary endpoints included CR rate, defined as the proportion of participants who achieve a CR; overall survival (OS), defined as the time from date of randomization to the date of death due to any cause; CR and complete remission with partial hematologic recovery (CRh) rate, defined as the proportion of participants who achieve a CR or CRh; and objective response rate (ORR), defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS).

About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is the most common leukemia in the adult population, affecting 80% of adults with leukemia^1,2 AML is characterized by clonal expansion of immature blast cells in the peripheral blood and bone marrow resulting in ineffective erythropoiesis and bone marrow failure.^1,3,4 In the U.S., the incidence is over 20,000 cases per year, with the average age at diagnosis being 65 years.¹ The global incidence of AML increased by 87.3% from 1990 to 2017, with a higher incidence in males than females.⁵ The overall prognosis for patients with AML is poor; the five-year relative survival is 30.5% (2012-2015).⁶ Untreated, death usually ensues within months of diagnosis secondary to infection or bleeding.² Even with current treatments, as many as 70% of patients aged ≥65 years will die within one year of diagnosis.²

About Servier in Oncology
Servier is a global leader in oncology focused on delivering meaningful therapeutic progress for the patients it serves. Governed by a non-profit foundation, Servier approaches innovation with a long-term vision, free of influence from investors and outside pressure to chase short-term monetary targets.

As a leader in oncology, Servier has significantly accelerated its investment in difficult and hard-to-tread cancers, with more than 50% of its research and development dedicated to delivering significant advances in areas of high unmet need throughout oncology with the potential to change the lives of the patients it serves. Within these areas, Servier is the leader in mutant IDH inhibition, with the first ever mutant IDH inhibitor approved in the U.S. and the European Union, and the company continues to drive the science behind targeted mutant IDH inhibition throughout its pipeline.

Servier's commitment to therapeutic progress guides its collaboration strategy. While many companies across the industry are scaling back investments, Servier is actively building alliances, completing acquisitions, conducting licensing deals and entering new partnerships that can help to accelerate access to therapies for patients in need. With the company's commercial expertise, global reach, scientific expertise and commitment to clinical excellence, Servier is dedicated to bringing the promise of tomorrow to the patients it serves.

Press contact
Servier
Nathan Mellor
[email protected]

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TIBSOVO IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. 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 

Relapsed or Refractory AML

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

Locally Advanced or Metastatic Cholangiocarcinoma

• For the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated

IMPORTANT SAFETY INFORMATION

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 (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.

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 
• In patients with cholangiocarcinoma, the most common adverse reactions (≥15%) are fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. The most common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma are 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

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

*Servier has an exclusive collaboration and license agreement with CStone for the development and commercialization of TIBSOVO (ivosidenib tablets) in Mainland China, Taiwan, Hong Kong, Macau and Singapore

^I Conditional NDA approval for this indication from NMPA. In Mainland China, Taiwan, Hong Kong, Macau and Singapore,

1. Vakiti A, Mewawalla P, Wood SK. Acute Myeloid Leukemia. In: StatPearls. StatPearls Publishing; 2022. Accessed January 19, 2023. http://www.ncbi.nlm.nih.gov/books/NBK507875/.

2. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441-e441. doi:10.1038/bcj.2016.50

3. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. Longo DL, ed. N Engl J Med. 2015;373(12):1136-1152. doi:10.1056/NEJMra1406184

4. Licht JD, Sternberg DW. The molecular pathology of acute myeloid leukemia. Hematology. 2005;2005(1):137-142. doi:10.1182/asheducation-2005.1.137

5. Yi M, Li A, Zhou L, Chu Q, Song Y, Wu K. The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: estimates based on the global burden of disease study 2017. J Hematol OncolJ Hematol Oncol. 2020;13(1):72. doi:10.1186/s13045-020-00908-z

6. National Cancer Institute. Acute Myeloid Leukemia — Cancer Stat Facts. Accessed January 19, 2023. https://seer.cancer.gov/statfacts/html/amyl.html

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