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
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
, 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
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
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
," said Susan Pandya, M.D., Vice President Clinical Development and Head of
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
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
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
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
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).
mutations have been explored for their connection to disease biology across various
, and patients with
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
in the Department of Hematology at the Gustave Roussy
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
The Phase 3 AGILE study was the basis of the FDA approval for TIBSOVO in combination with azacitidine for newly diagnosed
, 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
relapsed/refractory AML who achieved an exceptional response to treatment with TIBSOVO.
Of 179 patients with
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
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
. Moreover, for up to 10 percent of
contributes to the development of
," said Eytan Stein, MD, Chief,
Service and Director, Program for Drug Development in
Center. "For these reasons, identifying the characteristics of patients who may respond to targeted therapy for the
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
TIBSOVO is currently approved in the U.S. as monotherapy for the treatment of adults with
IDH1-mutant relapsed or refractory AML
relapsed or refractory AML and in monotherapy or in combination with azacitidine for adults with newly diagnosed
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
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
. TIBSOVO is also approved in China[i] for the treatment of adult patients with
relapsed or refractory AML
who have a susceptible
About the NCT03173248 AGILE Phase 3
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)
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).
Acute Myeloid Leukemia
Acute myeloid leukemia (AML)
is the most common
in the adult population, affecting 80% of adults with leukemia1,2
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
increased by 87.3% from 1990 to 2017, with a higher incidence in males than females.5 The overall prognosis for patients with
is poor; the five-year relative survival is 30.5% (2012-2015).6 Untreated, death usually ensues within months of diagnosis secondary to
Even with current treatments, as many as 70% of patients aged ≥65 years will die within one year of diagnosis.2
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
, Servier has significantly accelerated its investment in difficult and hard-to-tread
, with more than 50% of its research and development dedicated to delivering significant advances in areas of high unmet need throughout
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.
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To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same. The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice.
TIBSOVO IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. PATIENTS
, 6 (86%) patients recovered. Of the 34 patients with
relapsed or refractory AML
, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO.
occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant
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
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
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 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
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,
, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with
In patients with
, the most common adverse reactions including laboratory abnormalities (≥25%) are leukocytes decreased,
QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.
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
*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,