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VANFLYTA
® Now Available in U.S. for Patients with Newly Diagnosed
FLT3-ITD Positive AML
2023-08-09
·
BioSpace
上市批准
临床结果
优先审批
加速审批
临床研究
BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Daiichi Sankyo (TSE: 4568) today announced that
VANFLYTA
® (
quizartinib
) is now available by prescription in the U.S.
VANFLYTA
is the first and only
FLT3 inhibitor
FLT3
inhibitor to be approved by the U.S. Food and Drug Administration (FDA) specifically for
FLT3-ITD positive acute myeloid leukemia (AML)
and across the three phases of treatment – induction, consolidation and maintenance in patients without transplant – for newly diagnosed
AML
.
VANFLYTA
was approved by the FDA on July 20, 2023 in combination with standard
cytarabine
and anthracycline induction and
cytarabine
consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed
AML
that is FLT3-ITD positive as detected by an FDA-approved test.
VANFLYTA
is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with
VANFLYTA
in this setting has not been demonstrated. “With
VANFLYTA
now available by prescription in the U.S., physicians and patients have a new treatment option for the aggressive FLT3-ITD subtype of
acute myeloid leukemia
,” said Dan Switzer, Head of U.S. Oncology Business, Daiichi Sankyo, Inc. “VANFLTYA is the first
FLT3 inhibitor
FLT3
inhibitor to be developed and approved specifically for
FLT3-ITD positive AML
and has demonstrated potential to change the way the disease is treated.” In the QuANTUM-First trial,
VANFLYTA
combined with standard
cytarabine
and anthracycline induction and standard
cytarabine
consolidation, and continued as maintenance monotherapy following consolidation, resulted in a 22% reduction in the risk of death compared to standard chemotherapy alone (HR = 0.78 [95% CI: 0.62-0.98; 2-sided p=.0324]) in patients with newly diagnosed
FLT3-ITD positive AML
. While complete remission (CR) rates were similar between both arms of the trial, the median duration of CR was more than three times longer at 38.6 months (95% CI: 21.9, NE) for patients receiving
VANFLYTA
compared to 12.4 months for those receiving placebo plus standard chemotherapy alone (95% CI: 8.8-22.7). The results of QuANTUM-First were published in The Lancet.1 The safety of
VANFLYTA
was evaluated in 265 patients with newly diagnosed
FLT3-ITD positive AML
who received
VANFLYTA
once daily (35.4 mg with chemotherapy, 26.5 to 53 mg as maintenance) in the QuANTUM-First trial.
VANFLYTA
is approved with a Boxed WARNING for
QT prolongation
,
torsades de pointes
and
cardiac arrest
. Treatment emergent QT interval prolongation events of any grade were reported in 14% of patients who received
VANFLYTA
, including 3.0% who experienced a grade 3 or 4 event. Of the 265 patients treated with
VANFLYTA
and standard chemotherapy, QTcF >500 ms occurred in 2.3% of patients based on central ECG review and 10% of patients had an increase from baseline QTcF greater than 60 ms. The most common adverse reactions (frequency ≥10% all grades with a difference between arms of ≥2%), including laboratory abnormalities, in patients receiving
VANFLYTA
included
lymphopenia
(60%),
hypokalemia
(59%),
hypoalbuminemia
(53%),
hypophosphatemia
(52%),
alkaline phosphatase
increased (51%),
hypomagnesemia
(44%),
febrile neutropenia
(44%),
diarrhea
(42%),
mucositis
(38%),
nausea
(34%), hypocalcemia (33%), abdominal pain (30%), sepsis (30%), neutropenia (29%), headache (28%), creatine phosphokinase increased (26%), vomiting (25%), upper respiratory tract infection (21%), hypertransaminasemia (19%), thrombocytopenia (18%), decreased appetite (17%), fungal infections (16%), epistaxis (15%), hyperkalemia (15%), herpes virus infection (14%), insomnia (14%), electrocardiogram QT prolonged (14%), hypermagnesemia (14%), hypernatremia (13%), dyspepsia (11%), anemia (11%) and eye irritation (11%). Because of the serious risk of
QT prolongation
,
torsades de pointes
, and
cardiac arrest
,
VANFLYTA
is available only through a restricted program called the VANFLYTA Risk Evaluation and Mitigation Strategy (REMS).
VANFLYTA
may only be prescribed and dispensed by healthcare providers and pharmacies who become certified in the VANFLYTA REMS. More information is available at or by calling 1-855-212-6670. Daiichi Sankyo is committed to ensuring that patients in the U.S. who are prescribed
VANFLYTA
can access the medication and receive appropriate financial support. Provider and patient support and information regarding distribution, access, and reimbursement are now available through Daiichi Sankyo Access Central by visiting or calling 1-866-4-DSI-NOW (1-866-437-4669). Please see for full Prescribing Information including Boxed WARNING and Medication Guide. About
FLT3-ITD Positive Acute Myeloid Leukemia
More than 474,500 new cases of
leukemia
were reported globally in 2020 with more than 311,500 deaths.2
AML
accounts for 23.1% of total
leukemia
cases worldwide and is most common in adults.3,4 In the U.S., an estimated 20,380 new cases of
AML
will be diagnosed in 2023 with the five-year survival rate reported at 31.7%.5,6 A number of gene mutations have been identified in
AML
, and
FLT3
(FMS-like tyrosine kinase 3)
mutations are the most common.7 Up to 37% of newly diagnosed cases of
AML
have a
FLT3
gene mutation and approximately 80% of these have FLT3-ITD mutations, which drive
cancer
growth and contribute to particularly unfavorable prognosis including increased risk of relapse and shorter overall survival.7,8 The five-year survival rate for patients with
FLT3-ITD AML
has been reported at approximately 20%.9 About
VANFLYTA
VANFLYTA
® (
quizartinib
) is an oral, highly potent, type II
FLT3
inhibitor that selectively targets FLT3-ITD mutations and has been specifically developed for patients with
FLT3-ITD positive AML.7
VANFLYTA
is approved in the U.S. in combination with standard
cytarabine
and anthracycline induction and
cytarabine
consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed
AML
that is FLT3-ITD positive as detected by an FDA-approved test.
VANFLYTA
is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with
VANFLYTA
in this setting has not been demonstrated. The FDA had granted Priority Review to the application.
VANFLYTA
also is approved in Japan for the treatment of
AML
that is FLT3-ITD mutation positive, including for use in combination with standard
cytarabine
and anthracycline induction and standard
cytarabine
consolidation chemotherapy and as maintenance monotherapy for adult patients with newly diagnosed
FLT3-ITD positive AML
, and as a monotherapy for
relapsed/refractory AML
that is FLT3-ITD positive as detected by an approved test.
VANFLYTA
is an investigational medicine in all countries outside of Japan and the U.S. About the
VANFLYTA
Clinical Development Program The
VANFLYTA
clinical development program includes a phase 1/2 trial in pediatric and young adult patients with relapsed/refractory FLT3-ITD positive AML in Europe and North America, and several phase 1/2 combination studies as part of a strategic research collaboration with The University of Texas MD Anderson
Cancer
Center. A regulatory application for
VANFLYTA
in newly diagnosed
FLT3-ITD positive AML
is currently under review in the EU based on the results of the QuANTUM-First trial. Important Safety Information WARNING: QT PROLONGATION, TORSADES DE POINTES, and
CARDIAC ARREST
VANFLYTA
® (
quizartinib
) prolongs the QT interval in a dose- and concentration-related manner. Prior to
VANFLYTA
administration and periodically, monitor for
hypokalemia
or
hypomagnesemia
, and correct deficiencies. Perform electrocardiograms (ECGs) to monitor the QTc at baseline, weekly during induction and consolidation therapy, weekly for at least the first month of maintenance, and periodically thereafter. Torsades de pointes and
cardiac arrest
have occurred in patients receiving
VANFLYTA
. Do not administer
VANFLYTA
to patients with severe
hypokalemia
, severe
hypomagnesemia
, or
long QT syndrome
. Do not initiate treatment with
VANFLYTA
or escalate the
VANFLYTA
dose if the QT interval corrected by Fridericia’s formula (QTcF) is greater than 450 ms. Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required. Reduce the
VANFLYTA
dose when used concomitantly with strong
CYP3A
inhibitors, as they may increase
quizartinib
exposure. Because of the risk of QT prolongation,
VANFLYTA
is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the
VANFLYTA
REMS. Indication
VANFLYTA
is indicated in combination with standard
cytarabine
and anthracycline induction and
cytarabine
consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed
acute myeloid leukemia (AML)
that is
FLT3 internal tandem duplication (ITD)–positive
as detected by an FDA-approved test. Limitations of Use:
VANFLYTA
is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with
VANFLYTA
in this setting has not been demonstrated. Contraindications
VANFLYTA
is contraindicated in patients with severe
hypokalemia
, severe
hypomagnesemia
,
long QT syndrome
, or in patients with a history of
ventricular arrhythmias
or
torsades de pointes
. Warnings and Precautions QT Prolongation,
Torsades de Pointes
, and
Cardiac Arrest
(See BOXED WARNING)
VANFLYTA
prolongs the QT interval in a dose- and concentration-dependent manner. The mechanism of QTc interval prolongation is via inhibition of the slow delayed rectifier potassium current, IKs, as compared to all other medications that prolong the QTc interval, which is via the rapid delayed rectifier potassium current, IKr. Therefore, the level of QTc prolongation with
VANFLYTA
that predicts the risk of
cardiac arrhythmias
is unclear. Inhibition of IKs and IKr may leave patients with limited reserve, leading to a higher risk of QT prolongation and serious
cardiac arrhythmias
, including fatal outcomes.
Torsades de pointes
,
ventricular fibrillation
,
cardiac arrest
, and sudden death have occurred in patients treated with
VANFLYTA
. Of the 1,081 patients with
AML
treated with
VANFLYTA
in clinical trials,
torsades de pointes
occurred in approximately 0.2% of patients,
cardiac arrest
occurred in 0.6% of patients, including 0.4% with a fatal outcome, and 0.1% of patients experienced
ventricular fibrillation
. These severe
cardiac arrhythmias
occurred predominantly during the induction phase. Of the 265 patients with newly diagnosed
FLT3-ITD–positive AML
treated with
VANFLYTA
in combination with chemotherapy in the clinical trial, 2.3% were found to have a QTcF greater than 500 ms and 10% of patients had an increase from baseline QTcF greater than 60 ms. The clinical trial excluded patients with a QTcF ≥450 ms or other factors that increased the risk of QT prolongation or arrhythmic events (eg, NYHA Class III or IV
congestive heart failure
,
hypokalemia
, family history of
long QT interval syndrome
). Therefore, avoid use in patients who are at significant risk of developing
torsades de pointes
, including uncontrolled or significant
cardiac disease
,
recent myocardial infarction
,
heart failure
,
unstable angina
,
bradyarrhythmias
,
tachyarrhythmias
,
uncontrolled hypertension
,
high-degree atrioventricular block
,
severe aortic stenosis
, or
uncontrolled hypothyroidism
. Do not initiate treatment with
VANFLYTA
if the QTcF interval is greater than 450 ms. Do not use
VANFLYTA
in patients with severe
hypokalemia
, severe
hypomagnesemia
,
long QT syndrome
, or in patients with a history of
ventricular arrhythmias
or
torsades de pointes
. Perform an ECG and correct
electrolyte abnormalities
prior to initiation of treatment with
VANFLYTA
. During induction and consolidation, perform an ECG prior to initiation and then once weekly during
VANFLYTA
treatment or more frequently as clinically indicated. During maintenance, perform ECGs prior to initiation, once weekly for at least the first month following dose initiation and escalation, and as clinically indicated thereafter. Do not escalate the dose if QTcF is greater than 450 ms. Perform ECG monitoring of the QT interval more frequently in patients who are at significant risk of developing QT interval prolongation and
torsades de pointes
, or following dose escalation. Monitor and correct
hypokalemia
and
hypomagnesemia
prior to and during treatment with
VANFLYTA
. Maintain electrolytes in the normal range. Monitor electrolytes and ECGs more frequently in patients who experience
diarrhea
or
vomiting
. Monitor patients more frequently with ECGs if coadministration of
VANFLYTA
with drugs known to prolong the QT interval is required. Reduce the
VANFLYTA
dose when used concomitantly with strong
CYP3A
inhibitors, as they may increase
quizartinib
exposure. Reduce
VANFLYTA
if QTc increases to greater than 480 ms and less than 500 ms. Interrupt and reduce
VANFLYTA
if QTc increases to greater than 500 ms. Permanently discontinue
VANFLYTA
in patients who develop recurrent QTc greater than 500 ms or QTc interval prolongation with signs or symptoms of life-threatening
arrhythmia
.
VANFLYTA
is available only through a restricted program under a REMS.
VANFLYTA
REMS
VANFLYTA
is available only through a restricted distribution program under a REMS called the VANFLYTA REMS because of the serious risk of QT prolongation,
torsades de pointes
, and
cardiac arrest
. Notable requirements of the VANFLYTA REMS include the following: Prescribers must be certified in the VANFLYTA REMS by enrolling and completing training. Prescribers must counsel patients receiving
VANFLYTA
about the risk of
QT prolongation
,
torsades de pointes
, and
cardiac arrest
, and provide patients with a Patient Wallet Card. Pharmacies that dispense
VANFLYTA
must be certified with the VANFLYTA REMS and must verify prescribers are certified through the VANFLYTA REMS. Further information about the VANFLYTA REMS is available at or by telephone at 1-855-212-6670. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with
VANFLYTA
and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with
VANFLYTA
and for 4 months after the last dose. Adverse Reactions The safety of
VANFLYTA
(35.4 mg orally once daily with chemotherapy, 26.5 mg to 53 mg orally once daily as maintenance) in adult patients with newly diagnosed
FLT3-ITD positive AML
is based on QuANTUM-First. Serious adverse reactions in ≥5% of patients who received
VANFLYTA
plus chemotherapy were:
febrile neutropenia
(11%). Fatal adverse reactions occurred in 10% of patients who received
VANFLYTA
plus chemotherapy, including
sepsis
(5%),
fungal infections
(0.8%),
brain edema
(0.8%), and one case each of
febrile neutropenia
,
pneumonia
,
cerebral infarction
,
acute respiratory distress syndrome
,
pulmonary embolism
,
ventricular dysfunction
, and
cardiac arrest
. Permanent discontinuation due to an adverse reaction in patients in the
VANFLYTA
plus chemotherapy arm occurred in 20% of patients. The most frequent (≥2%) adverse reaction which resulted in permanent discontinuation in the
VANFLYTA
arm was
sepsis
(5%). Dosage interruptions of
VANFLYTA
due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in ≥2% of patients in the
VANFLYTA
arm included
neutropenia
(11%),
thrombocytopenia
(5%), and
myelosuppression
(3%). Dose reductions of
VANFLYTA
due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dosage reductions in ≥2% of patients in the
VANFLYTA
arm were
neutropenia
(9%),
thrombocytopenia
(5%), and electrocardiogram QT prolonged (4%). The most common adverse reactions (≥10% with a difference between arms of ≥2% compared to placebo), including laboratory abnormalities, were decreased lymphocytes, decreased potassium, decreased albumin, decreased phosphorus, increased
alkaline phosphatase
, decreased magnesium,
febrile neutropenia
,
diarrhea
,
mucositis
,
nausea
, decreased calcium,
abdominal pain
,
sepsis
,
neutropenia
,
headache
, increased creatine phosphokinase,
vomiting
,
upper respiratory tract infections
,
hypertransaminasemia
,
thrombocytopenia
, decreased appetite,
fungal infections
,
epistaxis
, increased potassium,
herpesvirus infections
,
insomnia
, QT prolongation, increased magnesium, increased sodium, dyspepsia,
anemia
, and eye irritation. Drug Interactions Strong
CYP3A
Inhibitors
VANFLYTA
is a
CYP3A
substrate. Concomitant use of
VANFLYTA
with a strong
CYP3A
inhibitor increases
quizartinib
systemic exposure, which may increase the risk of
VANFLYTA
adverse reactions. Reduce the dosage of
VANFLYTA
. Strong or Moderate CYP3A Inducers Concomitant use of
VANFLYTA
with strong or moderate CYP3A inducers decreases
quizartinib
systemic exposure, which may reduce
VANFLYTA
efficacy. Avoid concomitant use of
VANFLYTA
with strong or moderate CYP3A inducers. QT Interval–Prolonging Drugs
VANFLYTA
prolongs the QT/QTc interval. Coadministration of
VANFLYTA
with other drugs that prolong the QT interval may further increase the incidence of QT prolongation. Monitor patients more frequently with ECG if coadministration of
VANFLYTA
with drugs known to prolong the QT interval is required. Use in Specific Populations Pregnancy VANFLYTA can cause embryo-fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Lactation Advise women not to breastfeed during treatment with
VANFLYTA
and for one month after the last dose. Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential within 7 days before starting treatment with
VANFLYTA
. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with
VANFLYTA
and for 7 months after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with
VANFLYTA
and for 4 months after the last dose. Infertility Females Based on findings from animal studies,
VANFLYTA
may impair female fertility. These effects on fertility were reversible. Males Based on findings from animal studies,
VANFLYTA
may impair male fertility. These effects on fertility were reversible. Pediatric Use Safety and effectiveness of
VANFLYTA
have not been established in pediatric patients. Geriatric Use No overall differences in safety or efficacy were observed between patients 65 years of age and older and younger adult patients. Renal Impairment No dosage adjustment is recommended in patients with mild to moderate
renal impairment
(CLcr 30 to 89 mL/min).
VANFLYTA
has not been studied in patients with severe
renal impairment
(CLcr <30 mL/min). Hepatic Impairment No dosage adjustment is recommended in patients with mild hepatic impairment or moderate hepatic impairment.
VANFLYTA
has not been studied in patients with severe hepatic impairment. To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc, at 1-877-437- 7763 or the FDA at 1-800-FDA-1088 or fda.gov/medwatch. Please see Full Prescribing Information, including Boxed WARNINGS, and Medication Guide. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with
cancer
, cardiovascular and other diseases with high unmet medical need. For more information, please visit .
VANFLYTA
is a registered trademark of Daiichi Sankyo Company, Limited. Access Central™ is a trademark of Daiichi Sankyo, Inc. Trademarks not owned by Daiichi Sankyo are the property of their respective owners. © 2023 Daiichi Sankyo, Inc. PP-US-VN-0262 08/23 References ____________________________ 1 Erba H et al. The Lancet. April 25, 2023;Online First. S0140-6736(23)00464-6 2 Global
Cancer
Observatory. Population Fact Sheet: World. Updated March 2021 3 American
Cancer
Society: Key Statistics for
Acute Myeloid Leukemia
. Updated January 2023 4 Dong Y et al. Exp Hematol Oncol. 2020;9:14 5 American
Cancer
Society: Key Statistics for
Acute Myeloid Leukemia
. Updated January 2023 6 National
Cancer
Institute SEER Program.
Cancer
Stat Facts:
Acute Myeloid Leukemia
. 7 Daver N et al.
Leukemia
. (2019) 33:299-312 8 Patel JP et al N Engl J Med 2012 Mar 22;366(12):1079-89 9 Frohling et al. Blood (2002) 100 (13): 4372-4380
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适应症
伴有 FLT3/ITD 突变的急性髓系白血病
FLT3阳性急性髓性白血病
急性髓性白血病
[+52]
靶点
FLT3
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[+1]
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