Second US Breakthrough Therapy Designation
for ENHERTU
AstraZeneca and Daiichi Sankyo
Company, Limited’s (Daiichi Sankyo) ENHERTU® (fam-trastuzumab
deruxtecan-nxki) has been granted Breakthrough Therapy Designation
(BTD) in the US for the treatment of patients with HER2-positive
unresectable or metastatic gastric or gastroesophageal junction
adenocarcinoma who have received two or more prior regimens
including trastuzumab.
Gastric cancer is the third
leading cause of cancer mortality with a five-year survival rate of
5% for metastatic disease. Approximately one in five gastric
cancers are considered HER2 positive.
The Food and Drug
Administration’s (FDA) BTD is designed to accelerate the
development and regulatory review of potential new medicines that
are intended to treat a serious condition and address a significant
unmet medical need. The new medicine needs to have shown
encouraging early clinical results that demonstrate substantial
improvement on a clinically significant endpoint over available
medicines.
José Baselga, Executive Vice President, R&D Oncology, said:
“Current therapy options are limited for patients with
HER2-positive metastatic gastric cancer and for those who relapse,
there are no approved HER2-targeted medicines. We look forward to
working with the FDA to further explore the potential of ENHERTU to
become an important new treatment and the first antibody drug
conjugate for this devastating disease.”
Gilles Gallant, Senior Vice President, Global Head, Oncology
Development, Oncology R&D, Daiichi Sankyo, said:
“DESTINY-Gastric01 represents the first randomized trial of ENHERTU
to demonstrate clinically meaningful and statistically significant
results, including objective response and survival increases
compared to physician’s choice of chemotherapy. We are thrilled
that the FDA has granted ENHERTU a second Breakthrough Therapy
Designation.”
The FDA granted BTD based on data from the registrational Phase
II DESTINY-Gastric01 trial and data from the Phase I trial
published in The Lancet Oncology. In DESTINY-Gastric01, patients
treated with ENHERTU a HER2-directed antibody drug conjugate (ADC),
demonstrated a statistically significant and clinically meaningful
improvement in objective response rate (ORR), the primary endpoint,
and overall survival (OS), a key secondary endpoint, versus
patients treated with investigator’s choice of chemotherapy
(irinotecan or paclitaxel monotherapy).
The overall safety and tolerability profile of ENHERTU (6.4
mg/kg) in DESTINY-Gastric01 was consistent with that seen in the
Phase I trial. The most common adverse events (≥30 percent, any
grade) were hematologic and gastrointestinal including neutrophil
count decrease, anemia, nausea and decreased appetite. There were
cases of drug-related interstitial lung disease (ILD) and
pneumonitis, the majority of which were Grade 1 and 2 with two
Grade 3 and one Grade 4. No ILD-related deaths (Grade 5) occurred
in patients with gastric cancer in the Phase I trial or in the
Phase II DESTINY-Gastric01 trial.
The full results of DESTINY-Gastric-01 will be presented at the
2020 American Society of Clinical Oncology ASCO20 Virtual
Scientific Program.
ENHERTU received SAKIGAKE designation in March 2018 by Japan’s
Ministry of Health, Labour and Welfare (MHLW) for potential use in
the same HER2-positive gastric cancer patient population and was
recently submitted to the MHLW for approval. This is the second BTD
granted for ENHERTU in the US.
ENHERTU recently received accelerated approval in the U.S. and
approval in Japan under the early conditional approval system for
the treatment of adult patients with unresectable or metastatic
HER2 positive metastatic breast cancer who have received two or
more prior anti-HER2 based regimens.
U.S. FDA-Approved Indication for ENHERTU
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.
– ENDS –
NOTES TO EDITORS
Gastric Cancer
Gastric (stomach) cancer is the fifth most common cancer
worldwide and the third leading cause of cancer mortality; there
were approximately one million new cases reported in 2018 and
783,000 deaths. In the US, it is estimated that 27,600 new cases of
gastric cancer will be diagnosed in 2020 and more than 11,000
people will die from the disease.
Approximately one in five gastric cancers are HER2 positive.
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors including gastric,
breast and lung cancers. Gastric cancer is usually diagnosed in the
advanced stage, but even when diagnosed in earlier stages of the
disease the survival rate remains modest. Recommended 1st-line
treatment for HER2-positive advanced or metastatic gastric cancer
is combination chemotherapy plus trastuzumab, an anti-HER2
medicine, which has been shown to improve survival outcomes when
added to chemotherapy. For gastric cancer that progresses on
1st-line treatment, there are no other approved HER2-targeting
medicines.
DESTINY-Gastric01
DESTINY-Gastric01 is a registrational Phase II, open-label,
randomized, multi-center trial testing the safety and efficacy of
ENHERTU in a primary cohort of 188 patients from Japan and South
Korea with HER2-expressing advanced gastric cancer or
gastroesophageal junction adenocarcinoma (defined as IHC3+ or
IHC2+/ISH+) who have progressed on two or more prior treatment
regimens including fluoropyrimidine (5-FU) and platinum
chemotherapy and trastuzumab. Patients were randomized 2:1 to
receive ENHERTU or investigator’s choice of chemotherapy
(paclitaxel or irinotecan monotherapy). Patients were treated with
ENHERTU 6.4mg/kg once every three weeks or chemotherapy. The
primary endpoint of the trial is ORR, as assessed by an independent
review committee. Secondary endpoints include OS, progression-free
survival, duration of response disease control rate and time to
treatment failure as well as pharmacokinetic and safety
endpoints.
ENHERTU
ENHERTU (fam-trastuzumab deruxtecan-nxki in the US only) is a
HER2-directed ADC and is the lead ADC in the oncology portfolio of
Daiichi Sankyo 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.
ENHERTU Clinical Development
A comprehensive development program is underway globally with
six registrational trials evaluating the efficacy and safety of
ENHERTU monotherapy across multiple HER2-driven cancers including
breast, gastric and lung cancers. Trials in combination with other
anticancer treatments, such as immunotherapy, are also
underway.
Collaboration between AstraZeneca and Daiichi Sankyo
In March 2019, AstraZeneca and Daiichi Sankyo entered into a
global collaboration to jointly develop and commercialize ENHERTU
worldwide, except in Japan where Daiichi Sankyo maintains exclusive
rights. Daiichi Sankyo is solely responsible for manufacturing and
supply.
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 key 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 main therapy areas - Oncology, Cardiovascular, Renal &
Metabolism and Respiratory & Immunology. The Company also is
selectively active in the areas of autoimmunity, neuroscience and
infection. 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
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