Accelerated Approval of AstraZeneca and Daiichi
Sankyo’s ENHERTU based on the DESTINY-Breast01 trial that showed
clinically meaningful and durable responses
AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo)
today announced that the US Food and Drug Administration (FDA) has
approved ENHERTU® (fam-trastuzumab deruxtecan-nxki) for the
treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer who have received two or more prior
anti-HER2-based regimens in the metastatic setting.
This indication is approved under Accelerated Approval based on
tumor response rate and duration of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in a confirmatory trial.
ENHERTU is a HER2-directed antibody-drug conjugate (ADC) and the
FDA approval is based on the results of the registrational Phase II
trial DESTINY-Breast01 of ENHERTU (5.4 mg/kg) monotherapy in 184
female patients with HER2-positive metastatic breast cancer. All
patients received prior trastuzumab, ado-trastuzumab emtansine, and
66% had prior pertuzumab.
The Phase II trial results showed a confirmed objective response
rate of 60.3% (n=111; 95% CI: 52.9-67.4), including a 4.3% complete
response rate (n=8) and a 56.0% partial response rate (n=103). A
median duration of response of 14.8 months (95% CI: 13.8-16.9) was
demonstrated as of August 1, 2019. In addition, a median
progression-free survival of 16.4 months (95% CI: 12.7-not
estimable), based upon a median duration of follow-up of 11.1
months, was recently presented at the San Antonio Breast Cancer
Symposium and published online in The New England Journal of
Medicine.
José Baselga, Executive Vice President, Oncology R&D, said:
“ENHERTU has shown impressive results in women with HER2-positive
metastatic breast cancer, with the majority of women benefiting
from treatment and the median duration of the response exceeding 14
months. With this first approval, we are proud to bring ENHERTU to
patients with high unmet need and we look forward to further
exploring its potential in additional settings.”
Antoine Yver, Executive Vice President and Global Head, Oncology
R&D, Daiichi Sankyo, said: “The approval of ENHERTU underscores
that this specifically engineered HER2-directed antibody-drug
conjugate is delivering on its intent to establish an important new
treatment for patients with HER2-positive metastatic breast cancer.
Since the beginning of our clinical trial program four years ago,
we have focused on the opportunity to transform the treatment
landscape for patients with HER2-positive metastatic breast cancer,
and we are extremely proud of how quickly we delivered ENHERTU to
patients in the US, as ENHERTU represents one of the
fastest-developed biologics in oncology.”
ENHERTU is approved with a Boxed WARNING for Interstitial Lung
Disease (ILD)/pneumonitis and Embryo-Fetal Toxicity. The safety of
ENHERTU has been evaluated in a pooled analysis from both the Phase
II trial DESTINY-Breast01 and the earlier Phase I trial among a
total of 234 patients with unresectable or metastatic HER2-positive
breast cancer who received at least one dose of ENHERTU (5.4mg/kg).
ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or
pneumonitis occurred in 2.6% of patients—two deaths previously
reported in the Phase I trial and four deaths previously reported
in the Phase II trial DESTINY-Breast01. Patients and physicians
should be aware of ILD/pneumonitis and patients should be actively
monitored for potential signs and symptoms. If ILD/pneumonitis is
identified, it should be managed as per the FDA approved US
Prescribing information. Management may require dose modification
or treatment discontinuation and steroid treatment.
ENHERTU can cause fetal harm when administered to a pregnant
woman. The most common adverse reactions (frequency ≥20%) were
nausea, fatigue, vomiting, alopecia, constipation, decreased
appetite, anemia, neutropenia, diarrhea, leukopenia, cough and
thrombocytopenia.
ENHERTU will be available by prescription in the US within the
coming weeks. AstraZeneca and Daiichi Sankyo are committed to
ensuring that patients in the US who are prescribed ENHERTU can
access the medication and receive necessary financial support.
Provider and patient support, reimbursement and distribution for
ENHERTU in the US will be accessible by visiting www.ENHERTU4U.com
or calling 1-833-ENHERTU (1-833-364-3788).
Please visit www.ENHERTU.com for full Prescribing Information,
including Boxed WARNING, and Medication Guide.
Financial considerations
Following US approval, an amount of $125m is due from
AstraZeneca to Daiichi Sankyo as the first milestone payment in
HER2-positive breast cancer. Upon approval, this will be
capitalized together with the upfront payment already made earlier
in the year 2019.
Future sales of ENHERTU in the US will be recognized by Daiichi
Sankyo. AstraZeneca will report its share of gross profit margin
from the sales in the US as collaboration revenue in the Company’s
financial statements. For further details on the financial
arrangements, please consult the announcement of the collaboration
agreement from March 2019.
IMPORTANT SAFETY INFORMATION
Indication
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor
conjugate indicated for the treatment of adult patients with
unresectable or metastatic HER2-positive breast cancer who have
received two or more prior anti-HER2-based regimens in the
metastatic setting.
This indication is approved under accelerated approval based on
tumor response rate and duration of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in a confirmatory trial.
WARNING: INTERSTITIAL LUNG DISEASE and
EMBRYO-FETAL TOXICITY
- Interstitial lung disease (ILD) and pneumonitis, including
fatal cases, have been reported with ENHERTU. Monitor for and
promptly investigate signs and symptoms including cough, dyspnea,
fever, and other new or worsening respiratory symptoms. Permanently
discontinue ENHERTU in all patients with Grade 2 or higher
ILD/pneumonitis. Advise patients of the risk and to immediately
report symptoms.
- Exposure to ENHERTU during pregnancy can cause embryo-fetal
harm. Advise patients of these risks and the need for effective
contraception.
Contraindications
None.
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease
(ILD), including pneumonitis, can occur in patients treated with
ENHERTU. In clinical studies, of the 234 patients with unresectable
or metastatic HER2-positive breast cancer treated with ENHERTU, ILD
occurred in 9% of patients. Fatal outcomes due to ILD and/or
pneumonitis occurred in 2.6% of patients treated with ENHERTU.
Median time to first onset was 4.1 months (range: 1.2 to 8.3).
Advise patients to immediately report cough, dyspnea, fever,
and/or any new or worsening respiratory symptoms. Monitor patients
for signs and symptoms of ILD. Promptly investigate evidence of
ILD. Evaluate patients with suspected ILD by radiographic imaging.
Consider consultation with a pulmonologist. For asymptomatic
ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to
Grade 0, then if resolved in ≤28 days from date of onset, maintain
dose. If resolved in >28 days from date of onset, reduce dose
one level. Consider corticosteroid treatment as soon as
ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg prednisolone or
equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater),
permanently discontinue ENHERTU. Promptly initiate corticosteroid
treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg
prednisolone or equivalent). Upon improvement, follow by gradual
taper (e.g., 4 weeks).
Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in
patients treated with ENHERTU. Of the 234 patients with
unresectable or metastatic HER2-positive breast cancer who received
ENHERTU, a decrease in neutrophil count was reported in 30% of
patients and 16% had Grade 3 or 4 events. Median time to first
onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was
reported in 1.7% of patients.
Monitor complete blood counts prior to initiation of ENHERTU and
prior to each dose, and as clinically indicated. Based on the
severity of neutropenia, ENHERTU may require dose interruption or
reduction. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC]
<1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2
or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x
109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce
dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and
temperature >38.3ºC or a sustained temperature of ≥38ºC for more
than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one
level.
Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of
developing left ventricular dysfunction. Left ventricular ejection
fraction (LVEF) decrease has been observed with anti-HER2
therapies, including ENHERTU. In the 234 patients with unresectable
or metastatic HER2-positive breast cancer who received ENHERTU, two
cases (0.9%) of asymptomatic LVEF decrease were reported. Treatment
with ENHERTU has not been studied in patients with a history of
clinically significant cardiac disease or LVEF <50% prior to
initiation of treatment.
Assess LVEF prior to initiation of ENHERTU and at regular
intervals during treatment as clinically indicated. Manage LVEF
decrease through treatment interruption. Permanently discontinue
ENHERTU if LVEF of <40% or absolute decrease from baseline of
>20% is confirmed. When LVEF is >45% and absolute decrease
from baseline is 10-20%, continue treatment with ENHERTU. When LVEF
is 40-45% and absolute decrease from baseline is <10%, continue
treatment with ENHERTU and repeat LVEF assessment within 3 weeks.
When LVEF is 40-45% and absolute decrease from baseline is 10-20%,
interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If
LVEF has not recovered to within 10% from baseline, permanently
discontinue ENHERTU. If LVEF recovers to within 10% from baseline,
resume treatment with ENHERTU at the same dose. When LVEF is
<40% or absolute decrease from baseline is >20%, interrupt
ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of
<40% or absolute decrease from baseline of >20% is confirmed,
permanently discontinue ENHERTU. Permanently discontinue ENHERTU in
patients with symptomatic congestive heart failure.
Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant
woman. Advise patients of the potential risks to a fetus. Verify
the pregnancy status of females of reproductive potential prior to
the initiation of ENHERTU. Advise females of reproductive potential
to use effective contraception during treatment and for at least 7
months following the last dose of ENHERTU. Advise male patients
with female partners of reproductive potential to use effective
contraception during treatment with ENHERTU and for at least 4
months after the last dose of ENHERTU.
Adverse Reactions
The safety of ENHERTU was evaluated in a pooled analysis of 234
patients with unresectable or metastatic HER2-positive breast
cancer who received at least one dose of ENHERTU 5.4 mg/kg in
DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered
by intravenous infusion once every three weeks. The median duration
of treatment was 7 months (range: 0.7 to 31).
Serious adverse reactions occurred in 20% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were interstitial lung disease, pneumonia,
vomiting, nausea, cellulitis, hypokalemia, and intestinal
obstruction. Fatalities due to adverse reactions occurred in 4.3%
of patients including interstitial lung disease (2.6%), and the
following events occurred in one patient each (0.4%): acute hepatic
failure/acute kidney injury, general physical health deterioration,
pneumonia, and hemorrhagic shock.
ENHERTU was permanently discontinued in 9% of patients, of which
ILD accounted for 6%. Dose interruptions due to adverse reactions
occurred in 33% of patients treated with ENHERTU. The most frequent
adverse reactions (>2%) associated with dose interruption were
neutropenia, anemia, thrombocytopenia, leukopenia, upper
respiratory tract infection, fatigue, nausea, and ILD. Dose
reductions occurred in 18% of patients treated with ENHERTU. The
most frequent adverse reactions (>2%) associated with dose
reduction were fatigue, nausea, and neutropenia.
The most common adverse reactions (frequency ≥20%) were nausea
(79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation
(35%), decreased appetite (32%), anemia (31%), neutropenia (29%),
diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia
(20%).
Use in Specific Populations
- Pregnancy: ENHERTU can cause fetal harm when
administered to a pregnant woman. Advise patients of the potential
risks to a fetus. There are clinical considerations if ENHERTU is
used in pregnant women, or if a patient becomes pregnant within 7
months following the last dose of ENHERTU.
- Lactation: There are no data regarding the presence of
ENHERTU in human milk, the effects on the breastfed child, or the
effects on milk production. Because of the potential for serious
adverse reactions in a breastfed child, advise women not to
breastfeed during treatment with ENHERTU and for 7 months after the
last dose.
- Females and Males of Reproductive Potential:
Pregnancy testing: Verify pregnancy
status of females of reproductive potential prior to initiation of
ENHERTU. Contraception: Females:
ENHERTU can cause fetal harm when administered to a pregnant woman.
Advise females of reproductive potential to use effective
contraception during treatment with ENHERTU and for at least 7
months following the last dose. Males: Advise male patients with
female partners of reproductive potential to use effective
contraception during treatment with ENHERTU and for at least 4
months following the last dose. Infertility: ENHERTU may impair male reproductive
function and fertility.
- Pediatric Use: Safety and effectiveness of ENHERTU have
not been established in pediatric patients.
- Geriatric Use: Of the 234 patients with HER2-positive
breast cancer treated with ENHERTU 5.4 mg/kg, 26% were ≥65 years
and 5% were ≥75 years. No overall differences in efficacy were
observed between patients ≥65 years of age compared to younger
patients. There was a higher incidence of Grade 3-4 adverse
reactions observed in patients aged ≥65 years (53%) as compared to
younger patients (42%).
- Hepatic Impairment: In patients with moderate hepatic
impairment, due to potentially increased exposure, closely monitor
for increased toxicities related to the topoisomerase
inhibitor.
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi
Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or
fda.gov/medwatch.
Please see accompanying full Prescribing Information,
including Boxed WARNING, and Medication Guide.
NOTES TO EDITORS
About HER2-Positive Breast Cancer
Approximately one in five breast cancers are HER2-positive.
Despite recent improvements and approvals of new medicines, there
remains significant clinical needs for patients with HER2-positive
metastatic breast cancer. This disease remains incurable with
patients eventually progressing after available treatment.
About HER2
HER2 is a tyrosine kinase receptor growth-promoting protein
found on the surface of some cancer cells that is associated with
aggressive disease and poorer prognosis in patients with breast
cancer. To be considered HER2-positive, tumor cancer cells are
usually tested by one of two methods: immunohistochemistry (IHC) or
fluorescent in situ hybridization (FISH). IHC test results are
reported as: 0, IHC 1+, IHC 2+, or IHC 3+. A finding of IHC 3+
and/or FISH amplification is considered positive.
About DESTINY-Breast01
DESTINY-Breast01 is a registrational Phase II, single-arm
open-label, global, multicenter, two-part trial evaluating the
safety and efficacy of ENHERTU in 184 female patients with
HER2-positive unresectable and/or metastatic breast cancer
previously treated with ado-trastuzumab emtansine. The primary
endpoint of the trial is objective response rate, as determined by
independent central review. Secondary objectives include duration
of response, disease control rate, clinical benefit rate,
progression-free survival, overall survival and safety. Enrollment
into DESTINY-Breast01 was completed in September 2018 with 184
patients at more than 100 sites globally.
About the Clinical Development Program
A comprehensive development program for fam-trastuzumab
deruxtecan-nxki is underway globally with five pivotal trials in
HER2-expressing metastatic breast and gastric cancers, including a
trial in patients with metastatic breast cancer and low levels of
HER2 expression (HER2-low). Phase II trials are underway for
HER2-expressing advanced colorectal cancer, as well as metastatic
non-squamous HER2-overexpressing or HER2-mutated non-small cell
lung cancer. Trials in combination with other anticancer
treatments, such as immunotherapy, are also underway.
About ENHERTU
ENHERTU® (fam-trastuzumab deruxtecan-nxki) is the lead product
in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise and
the most advanced program in AstraZeneca’s ADC scientific platform.
ADCs are targeted cancer medicines that deliver cytotoxic
chemotherapy (“payload”) to cancer cells via a linker attached to a
monoclonal antibody that binds to a specific target expressed on
cancer cells.
About the Collaboration between AstraZeneca and Daiichi
Sankyo
In March 2019, AstraZeneca and Daiichi Sankyo entered into a
global collaboration to jointly develop and commercialize
fam-trastuzumab deruxtecan-nxki as a potential new medicine
worldwide, except in Japan where Daiichi Sankyo will maintain
exclusive rights. Daiichi Sankyo will be solely responsible for
manufacturing and supply.
ENHERTU received Priority Review, Breakthrough Therapy
Designation, and Fast Track Designation from the FDA for the
treatment of select patients with HER2-positive metastatic breast
cancer.
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a
quickly-growing portfolio of new medicines that has the potential
to transform patients’ lives and the Company’s future. With at
least six new medicines to be launched between 2014 and 2020, and a
broad pipeline of small molecules and biologics in development, we
are committed to advance Oncology as a growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers. In
addition to our core capabilities, we actively pursue innovative
partnerships and investments that accelerate the delivery of our
strategy, as illustrated by our investment in Acerta Pharma in
hematology.
By harnessing the power of four scientific platforms –
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates – and by championing the development
of personalized combinations, AstraZeneca has the vision to
redefine cancer treatment and one day eliminate cancer as a cause
of death.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, Cardiovascular, Renal &
Metabolism and Respiratory. AstraZeneca operates in over 100
countries and its innovative medicines are used by millions of
patients worldwide. For more information, please visit
www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.
PP-US-8201a-0560
12/19
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