Based on DESTINY-Breast04 results which
showed AstraZeneca and Daiichi Sankyo’s ENHERTU reduced risk of
disease progression or death by 50% and increased overall survival
by more than six months versus chemotherapy
AstraZeneca and Daiichi Sankyo’s ENHERTU® (fam-trastuzumab
deruxtecan-nxki) has been approved in the US for the treatment of
adult patients with unresectable or metastatic HER2-low (IHC 1+ or
IHC 2+/ISH-) breast cancer who have received a prior chemotherapy
in the metastatic setting or developed disease recurrence during or
within six months of completing adjuvant chemotherapy.
ENHERTU is a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialized by
AstraZeneca and Daiichi Sankyo.
The approval by the Food and Drug Administration (FDA) was based
on the results from the DESTINY-Breast04 Phase III trial. In the trial,
ENHERTU reduced the risk of disease progression or death by 50%
versus physician’s choice of chemotherapy in patients with HER2-low
metastatic breast cancer with hormone receptor (HR)-positive
disease or HR-negative disease (median progression-free survival
[PFS] 9.9 versus 5.1 months; hazard ratio [HR] 0.50; 95% confidence
interval [CI] 0.40-0.63; p<0.0001). A median overall survival
(OS) of 23.4 months was seen in patients treated with ENHERTU
versus 16.8 months in those treated with chemotherapy, a 36%
reduction in the risk of death (HR 0.64; 95% CI 0.49-0.84;
p=0.001).
Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering
Cancer Center, US, said: “Approximately half of all patients with
breast cancer have tumors that are HER2-low, which have previously
been classified as HER2-negative and have not had effective
treatment options with HER2-targeted medicines. Based on the
promising results of the DESTINY-Breast04 trial, clinicians are
starting to differentiate levels of HER2 expression and redefine
how metastatic breast cancer is classified with a distinct HER2-low
patient population that may be eligible for trastuzumab
deruxtecan.”
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca, said: “The rapid approval of ENHERTU in HER2-low
metastatic breast cancer by the FDA underscores the urgency to
bring this transformational medicine to patients as quickly as
possible. Patients with HER2-low tumors, who are identified through
existing HER2 testing methods, will now have the opportunity to be
treated based upon their HER2 status.”
Ken Keller, Global Head of Oncology Business and President and
CEO, Daiichi Sankyo, Inc, said: “Today’s FDA approval marks a
monumental moment in breast cancer treatment as ENHERTU is the
first-ever HER2-directed medicine to be approved for the treatment
of patients with HER2-low metastatic breast cancer. With the
ground-breaking survival benefit seen in the DESTINY-Breast04
trial, this milestone confirms the importance of targeting lower
levels of HER2 expression in the treatment of metastatic breast
cancer and we are thrilled that we can now offer ENHERTU to even
more patients.”
The approval was granted under the FDA’s Real-Time Oncology
Review program after securing Priority
Review and Breakthrough Therapy
Designation of ENHERTU in the US in this setting. The
expanded approval for ENHERTU in the US, following its previous
approval in 2nd-line HER2-positive metastatic breast cancer,
enables its use across a wide-spectrum of HER2-expressing breast
cancer, including patients with HER2-low disease.
The DESTINY-Breast04 Phase III trial results were presented at
the presidential plenary session of the 2022 American Society of
Clinical Oncology Annual meeting and simultaneously published in
The New England Journal of Medicine
(NEJM).1
The safety profile of ENHERTU was consistent with previous
clinical trials with no new safety concerns identified.
Interstitial lung disease (ILD) or pneumonitis rates were
consistent with those observed in late-line HER2-positive breast
cancer trials of ENHERTU. Overall, 12% of patients had confirmed
ILD or pneumonitis related to treatment as determined by an
independent adjudication committee. The majority of ILD events were
Grade 1 or 2 (10%), with five Grade 3 (1.3%) and no Grade 4 events
reported. There were three (0.8%) ILD-related deaths (Grade 5).
In June 2022, fam-trastuzumab deruxtecan-nxki (ENHERTU) was
added to the NCCN Clinical Practical Guidelines in Oncology (NCCN
Guidelines®) as the Category 1 preferred regimen for patients with
tumors that are HER2 IHC 1+ or 2+ and ISH- who have received at
least one prior line of chemotherapy for metastatic disease and, if
tumor is HR-positive, are refractory to endocrine therapy, based on
the data from DESTINY-Breast04.2
The US regulatory submission for DESTINY-Breast04 was reviewed
under Project Orbis, which provides a framework for concurrent
submission and review of oncology medicines among participating
international partners. As part of Project Orbis, ENHERTU is also
under regulatory review for the same indication by the Australian
Therapeutic Goods Administration, the Brazilian Health Regulatory
Agency (ANVISA), Health Canada and Switzerland’s Swissmedic.
Regulatory applications for ENHERTU are also currently under
review in Europe, Japan and several other countries based on the
DESTINY-Breast04 results.
U.S. Important Safety Information for ENHERTU
Indications 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 a prior anti-HER2-based regimen either: – In the
metastatic setting, or – In the neoadjuvant or adjuvant setting and
have developed disease recurrence during or within six months of
completing therapy
- Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-)
breast cancer who have received a prior chemotherapy in the
metastatic setting or developed disease recurrence during or within
6 months of completing adjuvant chemotherapy
- Locally advanced or metastatic HER2-positive gastric or
gastroesophageal junction adenocarcinoma who have received a prior
trastuzumab-based regimen
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. 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/day prednisolone or equivalent). For symptomatic
ILD/pneumonitis (Grade 2 or greater), permanently discontinue
ENHERTU. Promptly initiate systemic corticosteroid treatment as
soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day
prednisolone or equivalent) and continue for at least 14 days
followed by gradual taper for at least 4 weeks.
Metastatic Breast Cancer and HER2-Mutant
Solid Tumors (5.4 mg/kg) In patients with metastatic breast
cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD
occurred in 12% of patients. Fatal outcomes due to ILD and/or
pneumonitis occurred in 1.0% of patients treated with ENHERTU.
Median time to first onset was 5 months (range: 0.9 to 23).
Locally Advanced or Metastatic Gastric
Cancer (6.4 mg/kg) In patients with locally advanced or
metastatic HER2-positive gastric or GEJ adenocarcinoma treated with
ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to
first onset was 2.8 months (range: 1.2 to 21.0).
Neutropenia Severe neutropenia, including febrile
neutropenia, can occur in patients treated with ENHERTU. Monitor
complete blood counts prior to initiation of ENHERTU and prior to
each dose, and as clinically indicated. 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, then reduce dose by one level. For
febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º
C or a sustained temperature of ≥38º C for more than 1 hour),
interrupt ENHERTU until resolved, then reduce dose by one
level.
Metastatic Breast Cancer and HER2-Mutant
Solid Tumors (5.4 mg/kg) In patients with metastatic breast
cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, a
decrease in neutrophil count was reported in 65% of patients.
Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median
time to first onset of decreased neutrophil count was 22 days
(range: 2 to 664). Febrile neutropenia was reported in 1.1% of
patients.
Locally Advanced or Metastatic Gastric
Cancer (6.4 mg/kg) In patients with locally advanced or
metastatic HER2-positive gastric or GEJ adenocarcinoma treated with
ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in
72% of patients. Fifty-one percent had Grade 3 or 4 decreased
neutrophil count. Median time to first onset of decreased
neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia
was reported in 4.8% of patients.
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. Assess
LVEF prior to initiation of ENHERTU and at regular intervals during
treatment as clinically indicated. Manage LVEF decrease through
treatment interruption. 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. 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.
Metastatic Breast Cancer and HER2-Mutant
Solid Tumors (5.4 mg/kg) In patients with metastatic breast
cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF
decrease was reported in 3.6% of patients, of which 0.4% were Grade
3.
Locally Advanced or Metastatic Gastric
Cancer (6.4 mg/kg) In patients with locally advanced or
metastatic HER2-positive gastric or GEJ adenocarcinoma treated with
ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were
reported; however, on echocardiography, 8% were found to have
asymptomatic Grade 2 decrease in LVEF.
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.
Additional Dose Modifications Thrombocytopenia For
Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt
ENHERTU until resolved to Grade 1 or less, then maintain dose. For
Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt
ENHERTU until resolved to Grade 1 or less, then reduce dose by one
level.
Adverse Reactions Metastatic Breast
Cancer and HER2-Mutant Solid Tumors (5.4 mg/kg) The pooled
safety population reflects exposure to ENHERTU 5.4 mg/kg
intravenously every 3 weeks in 984 patients in Study DS8201-A-J101
(NCT02564900), DESTINY-Breast01, DESTINY-Breast03,
DESTINY-Breast04, and NCT04644237. Among these patients 65% were
exposed for >6 months and 39% were exposed for >1 year. In
this pooled safety population, the most common (≥20%) adverse
reactions, including laboratory abnormalities, were nausea (76%),
decreased white blood cell count (71%), decreased hemoglobin (66%),
decreased neutrophil count (65%), decreased lymphocyte count (55%),
fatigue (54%), decreased platelet count (47%), increased aspartate
aminotransferase (48%), vomiting (44%), increased alanine
aminotransferase (42%), alopecia (39%), increased blood alkaline
phosphatase (39%), constipation (34%), musculoskeletal pain (32%),
decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and
respiratory infection (24%).
Metastatic Breast Cancer
DESTINY-Breast03 The safety of ENHERTU was evaluated in 257
patients with unresectable or metastatic HER2-positive breast
cancer who received at least one dose of ENHERTU 5.4 mg/kg
intravenously every three weeks in DESTINY-Breast03. The median
duration of treatment was 14 months (range: 0.7 to 30).
Serious adverse reactions occurred in 19% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were vomiting, interstitial lung disease,
pneumonia, pyrexia, and urinary tract infection. Fatalities due to
adverse reactions occurred in 0.8% of patients including COVID-19
and sudden death (one patient each).
ENHERTU was permanently discontinued in 14% of patients, of
which ILD/pneumonitis accounted for 8%. Dose interruptions due to
adverse reactions occurred in 44% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose
interruption were neutropenia, leukopenia, anemia,
thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis.
Dose reductions occurred in 21% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose
reduction were nausea, neutropenia, and fatigue.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were nausea (76%), decreased white blood cell count
(74%), decreased neutrophil count (70%), increased aspartate
aminotransferase (67%), decreased hemoglobin (64%), decreased
lymphocyte count (55%), increased alanine aminotransferase (53%),
decreased platelet count (52%), fatigue (49%), vomiting (49%),
increased blood alkaline phosphatase (49%), alopecia (37%),
hypokalemia (35%), constipation (34%), musculoskeletal pain (31%),
diarrhea (29%), decreased appetite (29%), respiratory infection
(22%), headache (22%), abdominal pain (21%), increased blood
bilirubin (20%), and stomatitis (20%).
HER2-Low Metastatic Breast Cancer
DESTINY-Breast04 The safety of ENHERTU was evaluated in 371
patients with unresectable or metastatic HER2-low (IHC 1+ or IHC
2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously
every 3 weeks in DESTINY-Breast04. The median duration of treatment
was 8 months (range: 0.2 to 33) for patients who received
ENHERTU.
Serious adverse reactions occurred in 28% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea,
musculoskeletal pain, sepsis, anemia, febrile neutropenia,
hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to
adverse reactions occurred in 4% of patients including
ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic
colitis, disseminated intravascular coagulation, dyspnea, febrile
neutropenia, general physical health deterioration, pleural
effusion, and respiratory failure (1 patient each).
ENHERTU was permanently discontinued in 16% of patients, of
which ILD/pneumonitis accounted for 8%. Dose interruptions due to
adverse reactions occurred in 39% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose
interruption were neutropenia, fatigue, anemia, leukopenia,
COVID-19, ILD/pneumonitis, increased transaminases, and
hyperbilirubinemia. Dose reductions occurred in 23% of patients
treated with ENHERTU. The most frequent adverse reactions (>2%)
associated with dose reduction were fatigue, nausea,
thrombocytopenia, and neutropenia.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were nausea (76%), decreased white blood cell count
(70%), decreased hemoglobin (64%), decreased neutrophil count
(64%), decreased lymphocyte count (55%), fatigue (54%), decreased
platelet count (44%), alopecia (40%), vomiting (40%), increased
aspartate aminotransferase (38%), increased alanine
aminotransferase (36%), constipation (34%), increased blood
alkaline phosphatase (34%), decreased appetite (32%),
musculoskeletal pain (32%), diarrhea (27%), and hypokalemia
(25%).
Locally Advanced or Metastatic Gastric
Cancer (6.4 mg/kg) The safety of ENHERTU was evaluated in
187 patients with locally advanced or metastatic HER2-positive
gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients
intravenously received at least one dose of either ENHERTU (N=125)
6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2
biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The
median duration of treatment was 4.6 months (range: 0.7 to 22.3)
for patients who received ENHERTU.
Serious adverse reactions occurred in 44% of patients receiving
ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients
who received ENHERTU were decreased appetite, ILD, anemia,
dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor
hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of
patients: disseminated intravascular coagulation, large intestine
perforation, and pneumonia occurred in one patient each (0.8%).
ENHERTU was permanently discontinued in 15% of patients, of
which ILD accounted for 6%. Dose interruptions due to adverse
reactions occurred in 62% of patients treated with ENHERTU. The
most frequent adverse reactions (>2%) associated with dose
interruption were neutropenia, anemia, decreased appetite,
leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia,
upper respiratory tract infection, diarrhea, and hypokalemia. Dose
reductions occurred in 32% of patients treated with ENHERTU. The
most frequent adverse reactions (>2%) associated with dose
reduction were neutropenia, decreased appetite, fatigue, nausea,
and febrile neutropenia.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were decreased hemoglobin (75%), decreased white
blood cell count (74%), decreased neutrophil count (72%), decreased
lymphocyte count (70%), decreased platelet count (68%), nausea
(63%), decreased appetite (60%), increased aspartate
aminotransferase (58%), fatigue (55%), increased blood alkaline
phosphatase (54%), increased alanine aminotransferase (47%),
diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation
(24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia
(22%).
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 883 patients with breast cancer
treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.6% were
≥75 years. No overall differences in efficacy within clinical
studies 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 (60%) as compared to
younger patients (48%). Of the 125 patients with locally advanced
or metastatic HER2-positive gastric or GEJ adenocarcinoma treated
with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and
14% were ≥75 years. No overall differences in efficacy or safety
were observed between patients ≥65 years of age compared to younger
patients.
- Renal Impairment: A higher incidence of Grade 1 and 2
ILD/pneumonitis has been observed in patients with moderate renal
impairment. Monitor patients with moderate or severe renal
impairment.
- 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
WARNINGS, and Medication
Guide.
Notes
Financial considerations Following this approval for
ENHERTU in the US, an amount of $200m is due from AstraZeneca to
Daiichi Sankyo as a milestone payment for the HER2-low breast
cancer post chemotherapy indication. The milestone will be
capitalized as an addition to the upfront payment made by
AstraZeneca to Daiichi Sankyo in 2019 and subsequent capitalized
milestones, and will be amortized through the profit and loss
statement.
Sales of ENHERTU in the US are recognized by Daiichi Sankyo.
AstraZeneca reports its share of gross profit margin from ENHERTU
sales in the US as collaboration revenue in the Company’s financial
statements.
Further details on the financial arrangements were set out in
the March 2019 announcement of the
collaboration.
Breast cancer and HER2 expression Breast cancer is the
most common cancer and is one of the leading causes of
cancer-related deaths worldwide and in the US.3,4 More than two
million patients with breast cancer were diagnosed in 2020
resulting in nearly 685,000 deaths globally.3 In the US, more than
290,000 patients are expected to be diagnosed in 2022, resulting in
more than 43,000 deaths.5
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors including breast,
gastric, lung and colorectal cancers, and is one of many biomarkers
expressed in breast cancer tumors.6
HER2 expression is currently determined by an
immunohistochemistry (IHC) test which estimates the amount of HER2
protein on a cancer cell, and/or an in-situ hybridization (ISH)
test, which counts the copies of the HER2 gene in cancer cells.6,7
HER2 tests provide IHC and ISH scores across the full HER2 spectrum
and are routinely used to determine appropriate treatment options
for patients with metastatic breast cancer.
HER2-positive cancers are currently defined as HER2 expression
measured as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are
defined as HER2 expression measured as IHC 0, IHC 1+ or IHC
2+/ISH-.6 However, approximately half of all breast cancers are
HER2-low, defined as an HER2 score of IHC 1+ or IHC 2+/ISH-.8-10
HER2-low occurs in both HR-positive and HR-negative disease.11
Previously, patients with HR-positive metastatic breast cancer
and HER2-low disease had limited effective treatment options
following progression on endocrine (hormone) therapy.9,12
Additionally, few targeted options were available for those with
HR-negative disease.13 Now with the approval of ENHERTU, patients
with HER2-low tumors may be eligible for HER2-directed therapy.
DESTINY-Breast04 DESTINY-Breast04 is a global,
randomized, open-label, Phase III trial evaluating the efficacy and
safety of ENHERTU (5.4mg/kg) versus physician’s choice of
chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or
nab-paclitaxel) in patients with HR-positive or HR-negative,
HER2-low unresectable and/or metastatic breast cancer previously
treated with one or two prior lines of chemotherapy. Patients were
randomized 2:1 to receive either ENHERTU or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with
HR-positive disease based on blinded independent central review
(BICR). Key secondary endpoints include PFS based on BICR in all
randomized patients (HR-positive and HR-negative disease), OS in
patients with HR-positive disease and OS in all randomized patients
(HR-positive and HR-negative disease). Other secondary endpoints
include PFS based on investigator assessment, objective response
rate based on BICR and on investigator assessment, duration of
response based on BICR and safety.
DESTINY-Breast04 enrolled 557 patients at multiple sites in
Asia, Europe and North America. For more information about the
trial, visit ClinicalTrials.gov.
ENHERTU ENHERTU is a HER2-directed ADC. Designed using
Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the
lead ADC in the oncology portfolio of Daiichi Sankyo and the most
advanced program in AstraZeneca’s ADC scientific platform. ENHERTU
consists of a HER2 monoclonal antibody attached to a topoisomerase
I inhibitor payload, an exatecan derivative, via a stable
tetrapeptide-based cleavable linker.
ENHERTU (5.4mg/kg) is approved in more than 30 countries for the
treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer who have received a (or one or more)
prior anti-HER2-based regimen either in the metastatic setting, or
in the neoadjuvant or adjuvant setting and have developed disease
recurrence during or within six months of completing therapy based
on the results from the DESTINY-Breast03 trial.
ENHERTU (5.4mg/kg) is approved in several countries 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 based on the results from the
DESTINY-Breast01 trial.
ENHERTU (5.4mg/kg) is approved in the US for the treatment of
adult patients with unresectable or metastatic HER2-low (IHC 1+ or
IHC 2+/ISH-) breast cancer who have received a prior chemotherapy
in the metastatic setting or developed disease recurrence during or
within six months of completing adjuvant chemotherapy based on the
results from the DESTINY-Breast04 trial.
ENHERTU (6.4mg/kg) is approved in several countries for the
treatment of adult patients with locally advanced or metastatic
HER2-positive gastric or gastroesophageal junction adenocarcinoma
who have received a prior trastuzumab-based regimen based on the
results from the DESTINY-Gastric01 trial.
ENHERTU development program A comprehensive development
program is underway globally, evaluating the efficacy and safety of
ENHERTU monotherapy across multiple HER2-targetable cancers,
including breast, gastric, lung and colorectal cancers. Trials in
combination with other anticancer treatments, such as
immunotherapy, are also underway.
Regulatory applications for ENHERTU in breast, gastric and
non-small cell lung cancer are currently under review in several
other countries based on the DESTINY-Breast01, DESTINY-Breast03,
DESTINY-Breast04, DESTINY-Gastric01, DESTINY-Gastric02 and
DESTINY-Lung01 trials, respectively.
Daiichi Sankyo collaboration Daiichi Sankyo Company,
Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca
entered into a global collaboration to jointly develop and
commercialize ENHERTU (a HER2-directed ADC) in March 2019, and
datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July
2020, except in Japan where Daiichi Sankyo maintains exclusive
rights. Daiichi Sankyo is responsible for the manufacturing and
supply of ENHERTU and datopotamab deruxtecan.
AstraZeneca in breast cancer Driven by a growing
understanding of breast cancer biology, AstraZeneca is challenging
and redefining the current clinical paradigm for how breast cancer
is classified and treated to deliver even more treatments to
patients in need – with the bold ambition to one day eliminate
breast cancer as a cause of death.
AstraZeneca has a comprehensive portfolio of approved and
promising compounds in development that leverage different
mechanisms of action to address the biologically diverse breast
cancer tumor environment.
AstraZeneca aims to continue to transform outcomes for
HR-positive breast cancer with foundational medicines fulvestrant
and goserelin and the next-generation oral selective estrogen
receptor degrader (SERD) and potential new medicine
camizestrant.
PARP inhibitor olaparib is a targeted treatment option that has
been studied in HER2-negative early and metastatic breast cancer
patients with an inherited BRCA mutation. AstraZeneca with Merck
& Co., Inc. (MSD outside the US and Canada) continue to
research olaparib in metastatic breast cancer patients with an
inherited BRCA mutation and are exploring new opportunities to
treat these patients earlier in their disease.
Building on the initial approvals of ENHERTU, a HER2-directed
ADC, in previously treated HER2-positive metastatic breast cancer,
AstraZeneca and Daiichi Sankyo are exploring its potential in
earlier lines of treatment and in new breast cancer settings.
To bring much needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is testing immunotherapy durvalumab in combination with
other oncology medicines, including olaparib and ENHERTU,
evaluating the potential of AKT kinase inhibitor, capivasertib, in
combination with chemotherapy, and collaborating with Daiichi
Sankyo to explore the potential of TROP2-directed ADC, datopotamab
deruxtecan.
AstraZeneca in oncology AstraZeneca is leading a
revolution in oncology with the ambition to provide cures for
cancer in every form, following the science to understand cancer
and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a
global, science-led biopharmaceutical company that focuses on the
discovery, development, and commercialization of prescription
medicines in Oncology, Rare Diseases, and BioPharmaceuticals,
including Cardiovascular, Renal & Metabolism, and Respiratory
& Immunology. Based in Cambridge, UK, AstraZeneca operates in
over 100 countries and its innovative medicines are used by
millions of patients worldwide. Please visit astrazeneca-us.com and
follow the Company on Twitter @AstraZenecaUS.
References
- Modi S, et al. Trastuzumab Deruxtecan in Previously Treated
HER2-Low Advanced Breast Cancer. N Engl J Med. 2022; 387:9-20.
- Referenced with permission from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer
V2.2022. © National Comprehensive Cancer Network, Inc. 2022. All
rights reserved. Accessed August 2022. To view the most recent and
complete version of the guideline, go online to NCCN.org. NCCN
makes no warranties of any kind whatsoever regarding their content,
use or application and disclaims any responsibility for their
application or use in any way.
- Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN
Estimates of Incidence and Mortality Worldwide for 36 Cancers in
185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
- Centers for Disease Control and Prevention. Available at:
https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/. Accessed August
2022.
- American Cancer Society. Cancer Facts & Figures 2022.
Available at:
https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html.
Accessed August 2022.
- Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2)
in Cancers: Overexpression and Therapeutic Implications. Mol Biol
Int. 2014; 852748.
- Wolff A, et al. Human Epidermal Growth Factor Receptor 2
Testing in Breast Cancer: American Society of Clinical
Oncology/College of American Pathologists Clinical Practice
Guideline Focused Update. Arch Pathol Lab Med. 2018; 142(11):
1364-1382.
- Schalper K, et al. A retrospective population-based comparison
of HER2 immunohistochemistry and fluorescence in situ hybridization
in breast carcinomas. Arch Pathol Lab Med. 2014;138:213-219.
- Schettini F, et al. Clinical, pathological, and PAM50 gene
expression features of HER2-low breast cancer. npj Breast Cancer.
2021; 7:1; https://doi.org/10.1038/s41523-020-00208-2.
- Denkert C, et al. Clinical and molecular characteristics of
HER2-low-positive breast cancer: pooled analysis of individual
patient data from four prospective, neoadjuvant clinical trials.
2021. Lancet Oncol; 22:1151-61.
- Miglietta F, et al. Evolution of HER2-low expression from
primary to recurrent breast cancer. NPJ Breast Cancer. 2021; 7:
137; 10.1038/s41523-021-00343-4.
- Matutino A, et al. Hormone receptor-positive, HER2-negative
metastatic breast cancer: redrawing the lines. Current Oncology.
2018; 25(S1):S131-S141.
- American Cancer Society. Breast Cancer Hormone Receptor Status.
Available at:
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html.
Accessed August 2022.
Dr. Modi has financial interests related to AstraZeneca and
Daiichi Sankyo.
###
ENHERTU® is a registered trademark of Daiichi
Sankyo Company, Limited PP-US-EN-1765 08/22
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Media Inquiries Brendan McEvoy +1 302 885 2677 Chelsea
Ford +1 302 885 2677 US Media Mailbox: usmediateam@astrazeneca.com
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