Based on DESTINY-Breast06 Phase III trial
which demonstrated a statistically significant and clinically
meaningful progression-free survival benefit for ENHERTU
If approved, AstraZeneca and Daiichi
Sankyo’s ENHERTU will be the first HER2 directed therapy and ADC
for patients prior to receiving chemotherapy for metastatic breast
cancer
ENHERTU also granted Breakthrough Therapy
Designation in the US for this patient population
AstraZeneca and Daiichi Sankyo’s supplemental Biologics License
Application (sBLA) for ENHERTU® (fam-trastuzumab deruxtecan-nxki)
has been accepted and granted Priority Review in the US for the
treatment of adult patients with unresectable or metastatic
HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with
membrane staining) breast cancer who have received at least one
endocrine therapy in the metastatic setting based on positive
results from the DESTINY-Breast06 Phase III trial which compared
ENHERTU to chemotherapy.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that, if approved, would offer
significant improvements over available options by demonstrating
safety or efficacy improvements, preventing serious conditions or
enhancing patient compliance. The Prescription Drug User Fee Act
date, the FDA action date for their regulatory decision, is
anticipated during the first quarter of 2025.
ENHERTU was also recently granted Breakthrough Therapy
Designation (BTD) by the FDA in this setting. BTD accelerates the
development and regulatory review of potential new medicines
intended to treat a serious condition and address a significant
unmet medical need.
HR-positive, HER2-negative is the most common breast cancer
subtype, accounting for approximately 70% of all breast cancers.1
Despite being classified as HER2-negative, many of these tumors
still carry some level of HER2 expression.2 It is estimated that up
to 85-90% of tumors historically classified as HR-positive,
HER2-negative may be HER2-low or HER2-ultralow.3,4
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “While endocrine therapies are widely used in
the initial treatment of HR-positive metastatic breast cancer, most
patients see limited benefit with additional lines of treatment,
and subsequent chemotherapy is often associated with poor response
rates and outcomes. The results from DESTINY-Breast06 show that
ENHERTU has the potential to evolve the current HR-positive
treatment landscape and become the first targeted treatment for
patients with HER2-low or HER2-ultralow expression following
endocrine therapy.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “This
Priority Review highlights the potential to expand the existing
indication of ENHERTU in HER2-low metastatic breast cancer to
include use in an earlier disease setting as well as in a broader
patient population that includes HER2-ultralow. We look forward to
working closely with the FDA with the goal of bringing ENHERTU to
more patients as quickly as possible.”
The sBLA is based on data from the DESTINY-Breast06 Phase III
trial presented at the 2024 American Society of Clinical Oncology
(ASCO) Annual Meeting and recently published in The New England
Journal of Medicine.
In the trial, ENHERTU reduced the risk of disease progression or
death by 37% by blinded independent central review (BICR) versus
chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI]:
0.53-0.75; p< 0.0001) in the overall trial population. Median
PFS was 13.2 months with ENHERTU compared to 8.1 months with
chemotherapy.
Results were consistent between patients with HER2-low
expression and HER2-ultralow expression. In the primary endpoint
analysis of patients with HER2-low expression, ENHERTU showed a
median PFS of 13.2 months compared to 8.1 months for chemotherapy
(HR 0.62; 95% CI 0.51-0.74; p<0.0001). In a prespecified
exploratory analysis of patients with HER2-ultralow expression,
ENHERTU showed a median PFS of 13.2 months versus 8.3 months,
respectively (HR 0.78; 95% CI 0.50-1.21).
The safety profile of ENHERTU in DESTINY-Breast06 was consistent
with previous clinical trials of ENHERTU in breast cancer with no
new safety concerns identified.
ENHERTU is a specifically engineered HER2-directed DXd antibody
drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly
developed and commercialized by AstraZeneca and Daiichi Sankyo.
ENHERTU is already approved in more than 65 countries, including
the US, for patients with HER2-low metastatic breast cancer who
have received a prior systemic therapy 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.
IMPORTANT SAFETY INFORMATION
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor
conjugate indicated for the treatment of adult patients with:
- Unresectable or metastatic HER2-positive (IHC 3+ or ISH
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, as determined by an FDA-approved test, who have
received a prior chemotherapy in the metastatic setting or
developed disease recurrence during or within 6 months of
completing adjuvant chemotherapy
- Unresectable or metastatic non-small cell lung cancer (NSCLC)
whose tumors have activating HER2 (ERBB2) mutations, as detected by
an FDA-approved test, and who have received a prior systemic
therapy This indication is approved under accelerated approval
based on objective 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.
- Locally advanced or metastatic HER2-positive (IHC 3+ or IHC
2+/ISH positive) gastric or gastroesophageal junction (GEJ)
adenocarcinoma who have received a prior trastuzumab-based
regimen
- Unresectable or metastatic HER2-positive (IHC3+) solid tumors
who have received prior systemic treatment and have no satisfactory
alternative treatment options This indication is approved under
accelerated approval based on objective 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.
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. A higher incidence of Grade 1 and 2 ILD/pneumonitis has
been observed in patients with moderate renal impairment. 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.
HER2-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC,
and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred
in 12% of patients. Median time to first onset was 5.5 months
(range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis
occurred in 1.0% of patients treated with ENHERTU.
HER2-Positive 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).
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.
HER2-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC,
and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease
in neutrophil count was reported in 63% of patients. Seventeen
percent had Grade 3 or 4 decreased neutrophil count. Median time to
first onset of decreased neutrophil count was 22 days (range: 2 to
939). Febrile neutropenia was reported in 1% of patients.
HER2-Positive 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.
HER2-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC,
and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF
decrease was reported in 3.8% of patients, of which 0.6% were Grade
3.
HER2-Positive 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 7 months
after the last dose of ENHERTU. Advise male patients with female
partners of reproductive potential to use effective contraception
during treatment with ENHERTU and for 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
HER2-Positive and HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4
mg/kg intravenously every 3 weeks in 1799 patients in Study
DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02,
DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02,
DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65%
were exposed for >6 months and 38% were exposed for >1 year.
In this pooled safety population, the most common (≥20%) adverse
reactions, including laboratory abnormalities, were nausea (73%),
decreased white blood cell count (70%), decreased hemoglobin (66%),
decreased neutrophil count (63%), decreased lymphocyte count (58%),
fatigue (56%), decreased platelet count (48%), increased aspartate
aminotransferase (47%), increased alanine aminotransferase (43%),
vomiting (40%), increased blood alkaline phosphatase (38%),
alopecia (34%), constipation (33%), decreased appetite (32%),
decreased blood potassium (31%), diarrhea (29%), musculoskeletal
pain (24%), and abdominal pain (20%).
HER2-Positive 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 once 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%),
decreased blood potassium (35%), constipation (34%),
musculoskeletal pain (31%), diarrhea (29%), decreased appetite
(29%), headache (22%), respiratory infection (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 once 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 decreased blood
potassium (25%).
HER2-Mutant Unresectable or Metastatic
NSCLC (5.4 mg/kg)
DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and
6.4 mg/kg [n=50]); however, only the results for the recommended
dose of 5.4 mg/kg intravenously every 3 weeks are described below
due to increased toxicity observed with the higher dose in patients
with NSCLC, including ILD/pneumonitis.
The safety of ENHERTU was evaluated in 101 patients with
HER2-mutant unresectable or metastatic NSCLC who received ENHERTU
5.4 mg/kg intravenously once every three weeks until disease
progression or unacceptable toxicity in DESTINY‑Lung02. Nineteen
percent of patients were exposed for >6 months.
Serious adverse reactions occurred in 30% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea,
nausea, pleural effusion, and increased troponin I. Fatality
occurred in 1 patient with suspected ILD/pneumonitis (1%).
ENHERTU was permanently discontinued in 8% of patients. Adverse
reactions which resulted in permanent discontinuation of ENHERTU
were ILD/pneumonitis, diarrhea, decreased blood potassium,
hypomagnesemia, myocarditis, and vomiting. Dose interruptions of
ENHERTU due to adverse reactions occurred in 23% of patients.
Adverse reactions which required dose interruption (>2%)
included neutropenia and ILD/pneumonitis. Dose reductions due to an
adverse reaction occurred in 11% of patients.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were nausea (61%), decreased white blood cell count
(60%), decreased hemoglobin (58%), decreased neutrophil count
(52%), decreased lymphocyte count (43%), decreased platelet count
(40%), decreased albumin (39%), increased aspartate
aminotransferase (35%), increased alanine aminotransferase (34%),
fatigue (32%), constipation (31%), decreased appetite (30%),
vomiting (26%), increased alkaline phosphatase (22%), and alopecia
(21%).
HER2-Positive 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 decreased blood
potassium. 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%), decreased blood potassium (30%), vomiting (26%),
constipation (24%), increased blood bilirubin (24%), pyrexia (24%),
and alopecia (22%).
HER2-Positive (IHC3+) Unresectable or
Metastatic Solid Tumors
The safety of ENHERTU was evaluated in 347 adult patients with
unresectable or metastatic HER2-positive (IHC3+) solid tumors who
received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in
DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and
DESTINY-CRC02. The median duration of treatment was 8.3 months
(range 0.7 to 30.2).
Serious adverse reactions occurred in 34% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were sepsis, pneumonia, vomiting, urinary tract
infection, abdominal pain, nausea, pneumonitis, pleural effusion,
hemorrhage, COVID-19, fatigue, acute kidney injury, anemia,
cellulitis, and dyspnea. Fatalities due to adverse reactions
occurred in 6.3% of patients including ILD/pneumonitis (2.3%),
cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The
following events occurred in one patient each (0.3%): acute kidney
injury, cerebrovascular accident, general physical health
deterioration, pneumonia, and hemorrhagic shock.
ENHERTU was permanently discontinued in 15% of patients, of
which ILD/pneumonitis accounted for 10%. Dose interruptions due to
adverse reactions occurred in 48% of patients. The most frequent
adverse reactions (>2%) associated with dose interruption were
decreased neutrophil count, anemia, COVID-19, fatigue, decreased
white blood cell count, and ILD/pneumonitis. Dose reductions
occurred in 27% of patients treated with ENHERTU. The most frequent
adverse reactions (>2%) associated with dose reduction were
fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and
diarrhea.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were decreased white blood cell count (75%), nausea
(69%), decreased hemoglobin (67%), decreased neutrophil count
(66%), fatigue (59%), decreased lymphocyte count (58%), decreased
platelet count (51%), increased aspartate aminotransferase (45%),
increased alanine aminotransferase (44%), increased blood alkaline
phosphatase (36%), vomiting (35%), decreased appetite (34%),
alopecia (34%), diarrhea (31%), decreased blood potassium (29%),
constipation (28%), decreased sodium (22%), stomatitis (20%), and
upper respiratory tract infection (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 after 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 7 months after
the last dose. Males: Advise male patients with female partners of
reproductive potential to use effective contraception during
treatment with ENHERTU and for 4 months after 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 1287 patients with HER2-positive
or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg, 22% were
≥65 years and 3.8% 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 (59%) as compared to younger patients (49%). Of the 101
patients with HER2-mutant unresectable or metastatic NSCLC treated
with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years.
No overall differences in efficacy or safety were observed between
patients ≥65 years of age compared to younger patients. Of the 125
patients with HER2-positive locally advanced or metastatic 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. Of the 192
patients with HER2-positive (IHC 3+) unresectable or metastatic
solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02,
DESTINY-Lung01, or DESTINY-CRC02, 39% were 65 years or older and 9%
were 75 years or older. 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 renal impairment more
frequently. The recommended dosage of ENHERTU has not been
established for patients with severe renal impairment (CLcr <30
mL/min).
- Hepatic Impairment: In patients with moderate hepatic
impairment, due to potentially increased exposure, closely monitor
for increased toxicities related to the topoisomerase inhibitor,
DXd. The recommended dosage of ENHERTU has not been established for
patients with severe hepatic impairment (total bilirubin >3
times ULN and any AST).
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
Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the
leading causes of cancer-related deaths worldwide.5 More than two
million breast cancer cases were diagnosed in 2022 with more than
665,000 deaths globally.5 While survival rates are high for those
diagnosed with early breast cancer, only approximately 30% of
patients who are diagnosed with or who progress to metastatic
disease are expected to live five years after their diagnosis.1
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors, including breast
cancer.6 Patients with high levels of HER2 expression (IHC 3+ or
2+/ISH+) are classified as HER2-positive and treated with
HER2-directed therapies, representing approximately 15-20% of all
breast cancers.7 Historically, tumors that were not classified as
HER2-positive were classified as HER2-negative.2
HR-positive, HER2-negative is the most common breast cancer
subtype, accounting for approximately 70% of all breast cancers.1
Despite being classified as HER2-negative, many of these tumors
still carry some level of HER2 expression.2 It is estimated that
60-65% of HR-positive, HER2-negative breast cancers are HER2-low
and an additional 25% may be HER2-ultralow.3,4
Endocrine therapies are widely used in the early lines of
treatment for HR-positive metastatic breast cancer; however, after
two lines of treatment, further efficacy from endocrine therapy is
often limited.8 The current standard of care following endocrine
therapy is chemotherapy, which is associated with poor response
rates and outcomes.8-11
Prior to the approval of ENHERTU in HER2-low metastatic breast
cancer post chemotherapy based on the DESTINY-Breast04 trial, there
were no targeted therapies approved specifically for patients with
HER2-low expression. There are no targeted therapies specifically
approved for patients with HER2-low expression prior to
chemotherapy or for patients with HER2-ultralow expression.12
DESTINY-Breast06
DESTINY-Breast06 is a global, randomized, open-label, Phase III
trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg)
versus investigator’s choice of chemotherapy (capecitabine,
paclitaxel or nab-paclitaxel) in patients with HR-positive,
HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (defined as IHC 0
with membrane staining) advanced or metastatic breast cancer.
Patients in the trial had no prior chemotherapy for advanced or
metastatic disease and received at least two lines of prior
endocrine therapy in the metastatic setting. Patients were also
eligible if they had received one prior line of endocrine therapy
combined with a CDK4/6 inhibitor in the metastatic setting and
experienced disease progression within six months of starting
1st-line treatment or received endocrine therapy as an adjuvant
treatment and experienced disease recurrence within 24 months.
HER2 status in the trial was confirmed by central laboratory and
was performed on an archival tumor sample obtained at the time of
initial metastatic diagnosis or later. If archival tissue was not
available, a fresh tissue sample was required.
The primary endpoint is PFS in the HR-positive, HER2-low patient
population as measured by BICR. Key secondary endpoints include PFS
by BICR in the overall trial population (HER2-low and
HER2-ultralow), OS in the HER2-low patient population and OS in the
overall trial population. Other secondary endpoints include ORR,
DOR, time to first subsequent treatment or death, time to second
subsequent treatment or death and safety.
DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and
n=153 for HER2-ultralow) randomized at multiple sites in Asia,
Europe, Australia, North America and South America. For more
information about the trial, visit ClinicalTrials.gov.
ENHERTU (fam-trastuzumab deruxtecan-nxki)
ENHERTU (fam-trastuzumab deruxtecan-nxki) 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 number of topoisomerase I inhibitor payloads (an
exatecan derivative, DXd) via tetrapeptide-based cleavable
linkers.
ENHERTU (5.4mg/kg) is approved in more than 65 countries
worldwide for the treatment of adult patients with unresectable or
metastatic HER2-positive (immunohistochemistry [IHC] 3+ or in-situ
hybridization [ISH]+) 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 based
on the results from the DESTINY-Breast03 trial.
ENHERTU (5.4mg/kg) is approved in more than 65 countries
worldwide 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 systemic therapy 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 (5.4mg/kg) is approved in more than 45 countries
worldwide for the treatment of adult patients with unresectable or
metastatic NSCLC whose tumors have activating HER2 (ERBB2)
mutations, as detected by a locally or regionally approved test,
and who have received a prior systemic therapy based on the results
from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued
approval in the US for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial.
ENHERTU (6.4mg/kg) is approved in more than 45 countries
worldwide for the treatment of adult patients with locally advanced
or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or
gastroesophageal junction (GEJ) adenocarcinoma who have received a
prior trastuzumab-based regimen based on the results from the
DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06
trials. Full approval in China for this indication will depend on
whether a randomized controlled confirmatory clinical trial can
demonstrate clinical benefit in this population.
ENHERTU (5.4mg/kg) is approved in the US for the treatment of
adult patients with unresectable or metastatic HER2-positive (IHC
3+) solid tumors who have received prior systemic treatment and
have no satisfactory alternative treatment options based on
efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and
DESTINY-CRC02 trials. Continued approval for this indication in the
US may be contingent upon verification and description of clinical
benefit in a confirmatory trial.
ENHERTU development program
A comprehensive global clinical development program is underway
evaluating the efficacy and safety of ENHERTU monotherapy across
multiple HER2-targetable cancers. Trials in combination with other
anti-cancer treatments, such as immunotherapy, also are
underway.
Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global
collaboration to jointly develop and commercialize ENHERTU in March
2019 and datopotamab deruxtecan in July 2020, except in Japan where
Daiichi Sankyo maintains exclusive rights for each ADC. 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 starting to challenge, and redefine, the current
clinical paradigm for how breast cancer is classified and treated
to deliver even more effective 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.
With ENHERTU (fam-trastuzumab deruxtecan-nxki), a HER2-directed
antibody drug conjugate (ADC), AstraZeneca and Daiichi Sankyo are
aiming to improve outcomes in previously treated HER2-positive and
HER2-low metastatic breast cancer and are exploring its potential
in earlier lines of treatment and in new breast cancer
settings.
In HR-positive breast cancer, AstraZeneca continues to improve
outcomes with foundational medicines goserelin and aims to reshape
the HR-positive space with first-in-class AKT inhibitor,
capivasertib, and next-generation SERD and potential new medicine
camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo
to explore the potential of TROP2-directed ADC, datopotamab
deruxtecan, in this setting.
PARP inhibitor olaparib is a targeted treatment option that has
been studied in early and metastatic breast cancer patients with an
inherited BRCA mutation. AstraZeneca with MSD (Merck & Co.,
Inc. in the US and Canada) continue to research olaparib in these
settings and to explore its potential in earlier disease.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is evaluating the potential of datopotamab deruxtecan
alone and in combination with immunotherapy durvalumab,
capivasertib in combination with chemotherapy, and durvalumab in
combination with other oncology medicines, including olaparib and
ENHERTU.
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 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 125 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
social media @AstraZeneca.
References
- National Cancer Institute. Surveillance, Epidemiology and End
Results Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed September 2024.
- Sajjadi E, et al. Improving HER2 testing reproducibility in
HER2-low breast cancer. Cancer Drug Resist. 2022;5(4):882-888.
- 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.
Lancet Oncol. 2021 Aug;22(8):1151-1161.
- Chen Z, et al. Is HER2 ultra-low breast cancer different from
HER2 null or HER2 low breast cancer? A study of 1363 patients.
Breast Cancer Res Treat. 2023 Nov;202(2):313-323.
- Bray F, et al. Global cancer statistics 2022: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA Cancer J Clin. 2024 Apr 4. doi:
10.3322/caac.21834.
- Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2)
in Cancers: Overexpression and Therapeutic Implications. Mol Biol
Int. 2014;852748.
- Ahn S, et al. HER2 status in breast cancer: changes in
guidelines and complicating factors for interpretation. J Pathol
Transl Med. 2020;54(1):34-44.
- Manohar P, et al. Updates in endocrine therapy for metastatic
breast cancer. Cancer Biol Med. 2022 Feb 15; 19(2):202–212.
- Cortes J, et al. Eribulin monotherapy versus treatment of
physician’s choice in patients with metastatic breast cancer
(EMBRACE): a phase 3 open-label randomised study. Lancet.
2011;377:914-923.
- Yuan P, et al. Eribulin mesilate versus vinorelbine in women
with locally recurrent or metastatic breast cancer: A randomised
clinical trial. Eur J Cancer. 2019;112:57–65.
- Jerusalem G, et al. Everolimus Plus Exemestane vs Everolimus or
Capecitabine Monotherapy for Estrogen Receptor–Positive,
HER2-Negative Advanced Breast Cancer. JAMA Oncol.
2018;4(10):1367–1374.
- Modi S, et al. Trastuzumab Deruxtecan in Previously Treated
HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387:9-20.
US- 93544 | Last Updated 9/2024
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