Phase 3 Data Demonstrate TIBSOVO(R) (ivosidenib tablets) in Combination with Azacitidine Significantly Improves Event-Free Survival
PR93632
Phase 3 Data Demonstrate TIBSOVO(R) (ivosidenib tablets) in Combination with Azacitidine Significantly Improves Event-Free Survival and Overall Survival in Patients with Previously Untreated IDH1-mutated Acute Myeloid Leukemia
PARIS and BOSTON, Dec. 11, 2021 /PRNewswire=KYODO JBN/--
-- TIBSOVO in combination with azacitidine compared to placebo plus azacitidine
also demonstrated significant improvements in complete remission rate, complete
remission and complete remission with partial hematologic recovery rate and
objective response rate
-- Safety profile was favorable and consistent with previously published data
-- Data from the Phase 3 AGILE trial of patients with previously untreated
IDH1-mutated acute myeloid leukemia will be presented in an oral session on
Monday, December 13, 2021, and featured in the official press program of the
63rd American Society of Hematology Annual Meeting
Servier, a growing leader in oncology committed to bringing the promise of
tomorrow to the patients we serve, today announced Phase 3 data demonstrating
that TIBSOVO(R) (ivosidenib tablets) in combination with the chemotherapy
azacitidine significantly improved event-free survival (EFS) and overall
survival (OS) compared to azacitidine plus placebo in adults with previously
untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for
intensive chemotherapy. These data from the global AGILE study will be
presented in an oral session on Monday, December 13, 2021 from 2:45 - 4:15 PM
ET, Abstract #697 and featured in the official press program during the 63rd
American Society of Hematology Annual Meeting and Exposition.
Logo - https://mma.prnewswire.com/media/1389607/Servier_Logo.jpg
Treatment with TIBSOVO in combination with azacitidine demonstrated a
statistically significant improvement in EFS (hazard ratio [HR] = 0.33, 95% CI
0.16, 0.69, 1-sided P = 0.0011 (1,2)). In addition, the combination of TIBSOVO
with azacitidine showed a statistically significant improvement in OS (HR =
0.44 [95% CI 0.27, 0.73]; 1-sided P = 0.0005), with a median OS of 24.0 months
in the ivosidenib + azacitidine arm vs 7.9 months in the placebo + azacitidine
arm.
"These significant findings from the AGILE Phase 3 study for TIBSOVO bolster
our growing body of evidence supporting the rationale to target IDH1 mutations
early in blood cancers like acute myeloid leukemia," said Susan Pandya, M.D.,
Vice President Clinical Development & Head of Cancer Metabolism Global
Development Oncology & Immuno-Oncology, Servier Pharmaceuticals. "Up to 10
percent of patients with AML have mutations in the IDH1 enzyme, and current
treatment options are limited, especially for those who are newly diagnosed and
are not eligible for intensive chemotherapy."
Additional Study Results
Investigators reported on results of key secondary endpoints of the AGILE trial
including:
-- Complete remission (CR) rate was 47.2% (n=34/72) for TIBSOVO in
combination with azacitidine vs. 14.9% (n=11/74) for placebo plus
azacitidine (p < 0.0001).
-- CR + complete remission with partial hematologic recovery rate (CR +
CRh rate) was 52.8% (n=38/72) for TIBSOVO in combination with
azacitidine vs. 17.6% (n=13/74) for placebo plus azacitidine
(p < 0.0001).
-- Objective response rate (ORR) was 62.5% (n=45/72) for TIBSOVO in
combination with azacitidine vs. 18.9% (n=14/74) for placebo plus
azacitidine (p < 0.0001).
"We are excited about the potential to bring a new treatment option to patients
with previously untreated IDH1-mutated AML. This further extends the
significant clinical benefit for patients with acute myeloid leukemia and IDH1
mutations," said Patrick Therasse, M.D., Ph.D., Vice President, Head of Late
Stage and Life Cycle Management in Oncology and Immuno-Oncology Therapeutic
Area, Servier Group.
Acute myeloid leukemia is a rapidly progressing type of cancer, and the
prognosis is often poor," said Stephane De Botton, M.D. Ph.D., Principle
Investigator and Head of Multidisciplinary Hematology Committee at the Institut
Gustave Roussy, Villejuif, France. "Our goal with treatment is to prolong
overall survival, and the impressive clinical benefit following treatment with
TIBSOVO in combination with azacitidine is incredibly promising for these
patients with previously untreated IDH1-mutated acute myeloid leukemia."
Common all-grade adverse events (AEs) occurring in more than 20 percent of
patients receiving TIBSOVO in combination with azacitidine vs. placebo plus
azacitidine were nausea (42.3% vs. 38.4%), vomiting (40.8% vs 26.0%), diarrhea
(35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile
neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), neutropenia
(28.2% vs 16.4%), constipation (26.8% vs 52.1%) and pneumonia (23.9% vs 31.5%).
The AGILE study has halted further enrollment due to compelling efficacy data
for TIBSOVO.
Servier is in discussions with regulatory health authorities regarding
submissions to expand the currently approved indications for TIBSOVO.
TIBSOVO[*] is currently approved in the U.S. as monotherapy for the treatment
of adults with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML),
and for adults with newly diagnosed IDH1-mutant AML who are > or = 75 years old
or who have comorbidities that preclude the use of intensive induction
chemotherapy. Recently, TIBSOVO was approved as a first and only targeted
therapy for patients with previously treated IDH1-mutated cholangiocarcinoma.
About 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 (> or
= 75 years old or who have comorbidities that preclude the use of intensive
induction chemotherapy). The study's primary endpoint is 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.
Other key secondary endpoints included complete remission rate (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 a cancer of the blood and bone marrow marked by
rapid disease progression and is the most common acute leukemia affecting
adults with approximately 20,000 new cases in the U.S., and 43,000 cases in
Europe each year(3,4). The majority of patients with AML eventually relapse.
Relapsed or refractory AML has a poor prognosis(5). The five-year survival rate
is approximately 27%(3). For 6 to 10 percent of AML patients, the mutated IDH1
enzyme blocks normal blood stem cell differentiation, contributing to the
genesis of acute leukemia(6).
About Servier Pharmaceuticals
Servier Pharmaceuticals, LLC is a commercial-stage company with a passion for
innovation and improving the lives of patients, their families and caregivers.
A privately held company, Servier has the unique freedom to devote its time and
energy toward putting those who require our treatment and care first, with
future growth driven by innovation in areas of unmet medical need.
As a growing leader in oncology, Servier is committed to finding solutions that
will address today's challenges. The company's oncology portfolio of innovative
medicines is designed to bring more life-saving treatments to a greater number
of patients, across the entire spectrum of disease and in a variety of tumor
types.
Servier believes co-creation is fundamental to driving innovation and is
actively building alliances, acquisitions, licensing deals and partnerships
that bring solutions and accelerate access to therapies. With our commercial
expertise, global reach, scientific expertise and commitment to clinical
excellence, Servier Pharmaceuticals is dedicated to bringing the promise of
tomorrow to the patients that we serve.
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About Servier Group
Servier is a global pharmaceutical group governed by a Foundation. With a
strong international presence in 150 countries and a total revenue of 4.7
billion euros in 2020, Servier employs 22,500 people worldwide. Servier is an
independent group that invests over 20% of its brand-name revenue in Research
and Development every year. To accelerate therapeutic innovation for the
benefit of patients, the Group is committed to open and collaborative
innovation with academic partners, pharmaceutical groups, and biotech
companies. It also integrates the patient's voice at the heart of its
activities.
A leader in cardiology, the ambition of the Servier Group is to become a
renowned and innovative player in oncology. Its growth is based on a sustained
commitment to cardiovascular and metabolic diseases, oncology, neuroscience and
immuno-inflammatory diseases. To promote access to healthcare for all, the
Servier Group also offers a range of quality generic drugs covering most
pathologies.
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About TIBSOVO(R) (ivosidenib tablets)
TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the
treatment of adult patients with a susceptible IDH1 mutation as detected by an
FDA-approved test with:
Acute Myeloid Leukemia (AML)
-- Newly-diagnosed AML who are > or = 75 years old or who have
comorbidities that preclude use of intensive induction chemotherapy.
-- Relapsed or refractory AML.
Locally Advanced or Metastatic Cholangiocarcinoma
-- Locally advanced or metastatic cholangiocarcinoma who have been
previously treated.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME IN AML
Patients treated with TIBSOVO have experienced symptoms of differentiation
syndrome, which can be fatal if not treated. 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 clinical trial, 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.
Differentiation syndrome is associated with rapid proliferation and
differentiation of myeloid cells and may be life-threatening or fatal if not
treated. 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 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 HT(3) 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-Barre Syndrome: Guillain-Barre 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-Barre syndrome.
ADVERSE REACTIONS
-- In patients with AML, the most common adverse reactions including
laboratory abnormalities (> or = 20%) were hemoglobin decreased (60%),
fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium
decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium
decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid
increased (32%), potassium decreased (32%), alkaline phosphatase
increased (30%), mucositis (28%), aspartate aminotransferase increased
(27%), phosphatase decreased (25%), electrocardiogram QT prolonged
(24%), rash (24%), creatinine increased (24%), cough (23%), decreased
appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
-- In patients with newly diagnosed AML, the most frequently reported
Grade > or = 3 adverse reactions (> or = 5%) were fatigue (14%),
differentiation syndrome (11%), electrocardiogram QT prolonged (11%),
diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse
reactions (> or = 5%) were differentiation syndrome (18%),
electrocardiogram QT prolonged (7%), and fatigue (7%). There was one
case of posterior reversible encephalopathy syndrome (PRES).
-- In patients with relapsed or refractory AML, the most frequently
reported Grade > or = 3 adverse reactions (> or = 5%) were
differentiation syndrome (13%), electrocardiogram QT prolonged (10%),
dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%).
Serious adverse reactions (> or = 5%) were differentiation syndrome
(10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%).
There was one case of progressive multifocal leukoencephalopathy
(PML).
-- In patients with cholangiocarcinoma, the most common adverse reactions
(> or = 15%) were fatigue (43%), nausea (41%), abdominal pain (35%),
diarrhea (35%), cough (27%), decreased appetite (24%), ascites (23%),
vomiting (23%), anemia (18%), and rash (15%). The most common
laboratory abnormalities (> or = 10%) were hemoglobin decreased (40%),
aspartate aminotransferase increased (34%), and bilirubin increased
(30%).
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 at least 1 month after the last dose.
Please see Full Prescribing Information (
), including BOXED WARNING for AML patients.
References
1. Data on file. Servier. July 30, 2021
2. ClinicalTrials.gov. Study of AG-120 (Ivosidenib) vs. Placebo in Combination
with Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia
With an IDH1 Mutation (AGILE). Available at:
https://clinicaltrials.gov/ct2/show/NCT03173248. Accessed July 2021.
3. National Cancer Institute Surveillance, Epidemiology, and End Results
Program. Cancer Stat Facts: Acute Myeloid Leukemia (AML).
https://seer.cancer.gov/statfacts/html/amyl.html. Accessed July 2021.
4. American Cancer Society. Acute Myeloid Leukemia (AML).
https://www.cancer.org/content/dam/CRC/PDF/Public/8674.00.pdf. Accessed July
2021.
5. Kumar C. Genetic Abnormalities and Challenges in the Treatment of Acute
Myeloid Leukemia. Genes Cancer. 2011; 2:95-107.
6. DiNardo CD, Stein EM, de Botton S, et al. Durable Remissions from Ivosidenib
in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med 2018;378:2386-98.
* Servier has an exclusive license agreement with CStone for the development
and commercialization of TIBSOVO (ivosidenib tablets) in Mainland China,
Taiwan, Hong Kong, Macau and Singapore.
SOURCE: Servier Pharmaceuticals
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