AstraZeneca and Daiichi Sankyo’s ENHERTU
also improved progression-free survival by 22 months vs. T-DM1 in
patients previously treated with HER2-directed therapy in the
DESTINY-Breast03 Phase III trial
ENHERTU showed significant progression-free
and overall survival improvements vs. chemotherapy in later-line
HER2-positive setting in the DESTINY-Breast02 Phase III
trial
Updated results from the DESTINY-Breast03 Phase III trial showed
that ENHERTU® (fam-trastuzumab deruxtecan-nxki) demonstrated a
statistically significant and clinically meaningful improvement in
overall survival (OS) compared to trastuzumab emtansine (T-DM1) in
patients with HER2-positive unresectable and/or metastatic breast
cancer previously treated with trastuzumab and a taxane. These
results and primary results from the DESTINY-Breast02 Phase III
trial will be presented today at the 2022 San Antonio Breast Cancer
Symposium (SABCS), with the updated results from DESTINY-Breast03
simultaneously published in The Lancet.
ENHERTU is a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialized by
AstraZeneca and Daiichi Sankyo.
In the key secondary endpoint analysis of OS for
DESTINY-Breast03, ENHERTU demonstrated a 36% reduction in risk of
death versus T-DM1 (based on a hazard ratio [HR] 0.64; 95%
confidence interval [CI] 0.47-0.87; p=0.0037). In both treatment
arms, median OS was not yet reached (ENHERTU [40.5-NE] versus T-DM1
[34.0-NE]) after a median duration of follow-up of 28.4 months for
ENHERTU and 26.5 months for T-DM1. An estimated 77.4% of patients
were alive in the ENHERTU arm at two years compared to 69.9% of
patients treated with T-DM1. The observed survival benefit was
consistent across all analyzed subgroups, including patients with
or without baseline brain metastases, with or without baseline
visceral disease, those who were hormone receptor (HR)-positive or
HR-negative, and regardless of prior pertuzumab or lines of
systemic therapy.
Sara Hurvitz, MD, Medical Oncologist, Professor of Medicine, and
Director of the Breast Cancer Clinical Trials Program in the
Division of Hematology-Oncology at the David Geffen School of
Medicine at UCLA, and Medical Director for the Clinical Research
Unit at the UCLA Jonsson Comprehensive Cancer Center in Santa
Monica, CA, said: “The main goals of therapy for advanced breast
cancer are to control the disease and improve survival, and it is
therefore critical to continue to improve upon existing treatment
options, particularly in the metastatic setting. For patients with
HER2-positive breast cancer who experience disease progression
following initial treatment in the metastatic setting, ENHERTU has
shown significant improvement in survival compared to T-DM1,
further confirming this medicine as the new standard of care.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “The updated results for DESTINY-Breast03
showing that ENHERTU extends patients’ lives and also delays
progression by nearly two years reinforces our belief that this
medicine has the potential to set a new standard of care for
patients with HER2-positive metastatic breast cancer treated in the
second-line setting. Complemented by DESTINY-Breast02, we now have
two Phase III trials in HER2-positive metastatic breast cancer
showing patients in these trials have more disease-free time and
live longer when they receive ENHERTU versus the previous standard
of care.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “The
overall survival benefits shown in both the DESTINY-Breast03 and
DESTINY-Breast02 trials further validate the role of ENHERTU in
potentially extending the lives of patients with previously treated
HER2-positive breast cancer. Additionally, median progression-free
survival was four times longer with one in five patients showing no
detectable signs of disease when treated with ENHERTU compared to
T-DM1 in DESTINY-Breast03, which is particularly impressive in the
metastatic setting of HER2-positive breast cancer.”
With the additional follow-up in DESTINY-Breast03, ENHERTU also
continued to demonstrate a clinically meaningful improvement in
progression-free survival (PFS) with a 22 month improvement in
median PFS over T-DM1, reaffirming the statistically significant
finding at the previous interim analysis. The updated exploratory
analysis was not tested for statistical significance and not
powered to show differences between treatment arms. In this
exploratory post-hoc analysis, the median PFS for patients in the
ENHERTU arm was 28.8 months compared to 6.8 months for T-DM1, as
assessed by blinded independent central review (BICR). Confirmed
objective response rate (ORR) was 78.5% in the ENHERTU arm with
21.1% of patients demonstrating a complete response (CR) versus an
ORR of 35.0% in the T-DM1 arm, where 9.5% of patients achieved a
CR. The median duration of response (DoR) was 36.6 months in the
ENHERTU arm and 23.8 months in the T-DM1 arm.
Summary of updated results: DESTINY-Breast03
Efficacy Measure
ENHERTU (5.4mg/kg)
n=261
T-DM1 (3.6mg/kg)
n=263
OS
Median OS (months) (95% CI)
Not reached (40.5-NE)
Not reached (34.0-NE)
Hazard ratio (95% CI)
0.64 (0.47-0.87)
p-value
p=0.0037i
OS rate (%) (95% CI)
12 months
94.1 (90.4-96.4)
86.0 (81.1-89.8)
24 months
77.4 (71.7-82.1)
69.9 (63.7-75.2)
PFS by BICR
Median PFS (months) (95% CI)
28.8 (22.4-37.9)
6.8 (5.6-8.2)
Hazard ratio (95% CI)
0.33 (0.26-0.43)
p-value
p<0.000001i,ii
Median PFS2 by investigatoriii
Median PFS2 (months) (95% CI)
40.5 (40.5-NE)
25.7 (18.5-34.0)
Hazard ratio (95% CI)
0.47 (0.35-0.62)
Confirmed ORR (%) (95% CI)
78.5 (73.1-83.4)
35.0 (29.2-41.1)
p-value
p<0.0001i,ii
Complete Response (%)
21.1%
9.5%
Partial Response (%)
57.5%
25.5%
Stable Disease (%)
18.0%
41.8%
Progressive Disease (%)
1.1%
17.9%
Median DoR (months) (95% CI)iv
36.6 (22.4-NE)
23.8 (12.6-34.7)
OS, overall survival; CI, confidence
interval; PFS, progression-free survival; PFS2, second
progression-free survival; BICR, blinded independent central
review; ORR, objective response rate; DoR, duration of response i
Two-sided ii Nominal p value. Updated exploratory analysis was not
tested for statistical significance and not powered to show
differences between treatment arms iii From the time of
randomization to second progression iv Based on BICR
The safety profile observed with ENHERTU in DESTINY-Breast03 was
consistent with previous clinical trials, with no new safety
concerns identified. The most common Grade 3 or higher
treatment-related treatment-emergent adverse events (TEAEs) in the
ENHERTU arm were decreased neutrophil count (16.0%), anemia (9.3%),
decreased platelet count (7.8%) and nausea (7.0%). There were 39
cases (15.2%) of treatment-related interstitial lung disease (ILD)
or pneumonitis reported, as determined by an independent
adjudication committee. The majority (14.4%) were low grade (Grade
1 or Grade 2) with two Grade 3 (0.8%) events. No Grade 4 or Grade 5
ILD or pneumonitis events occurred.
DESTINY-Breast02 full results show significant improvements
in PFS and OS versus chemotherapy in later-line HER2-positive
metastatic breast cancer setting In primary results from the
DESTINY-Breast02 Phase III trial, ENHERTU demonstrated a 64%
reduction in the risk of disease progression or death in patients
with HER2-positive unresectable and/or metastatic breast cancer
previously treated with T-DM1 versus physician’s choice of
treatment (trastuzumab plus capecitabine or lapatinib plus
capecitabine) [HR=0.36; 95% CI 0.28-0.45; p<0.000001]. The
median PFS for patients in the ENHERTU arm was 17.8 months versus
6.9 months for those in the physician’s choice of treatment arm, as
assessed by BICR. ENHERTU also showed a 34% reduction in the risk
of death compared to physician’s choice of treatment (HR=0.66; 95%
CI 0.50-0.86; p=0.0021) with a median OS of 39.2 months versus 26.5
months.
The data from DESTINY-Breast02 confirms the data seen in the
DESTINY-Breast01 Phase II trial which supported the first approvals
of ENHERTU in patients with HER2-positive metastatic breast cancer
who have received two or more prior anti-HER2-based regimens.
The safety profile of ENHERTU in DESTINY-Breast02 was consistent
with previous clinical trials with no new safety concerns
identified. The most common Grade 3 or higher treatment-related
TEAEs in the ENHERTU arm were decreased neutrophil count (10.6%),
anemia (7.9%), neutropenia (7.7%) and nausea (6.7%). There were 42
cases (10.4%) of treatment-related ILD or pneumonitis reported, as
determined by an independent adjudication committee. The majority
(9.1%) were low grade (Grade 1 or Grade 2) with three Grade 3
(0.7%) events, no Grade 4 events and two (0.5%) Grade 5 ILD or
pneumonitis events occurring.
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 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 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. 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.
Metastatic Breast Cancer and HER2-Mutant
NSCLC (5.4 mg/kg) In patients with metastatic breast cancer
and HER2-mutant NSCLC 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).
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
NSCLC (5.4 mg/kg) In patients with metastatic breast cancer
and HER2-mutant NSCLC 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
NSCLC (5.4 mg/kg) In patients with metastatic breast cancer
and HER2-mutant NSCLC 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 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 Metastatic Breast
Cancer and HER2-Mutant NSCLC (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
DESTINY-Lung02. 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%).
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 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%).
Unresectable or Metastatic HER2-Mutant
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
unresectable or metastatic HER2-mutant NSCLC who received ENHERTU
5.4 mg/kg intravenously every three weeks 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, hypokalemia, 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%).
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 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 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 101 patients with unresectable or
metastatic HER2-mutant 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 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 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.
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
most common cancer and is one of the leading causes of
cancer-related deaths worldwide.1 More than two million patients
were diagnosed with breast cancer in 2020, with nearly 685,000
deaths globally.1 Approximately one in five cases of breast cancer
are considered HER2-positive.2
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.3 HER2 protein overexpression
may occur as a result of HER2 gene amplification and is often
associated with aggressive disease and poor prognosis in breast
cancer.4
Despite initial treatment with trastuzumab and a taxane,
patients with HER2-positive metastatic breast cancer will often
experience disease progression.5,6
DESTINY-Breast03 DESTINY-Breast03 is a global,
head-to-head, randomized, open-label, registrational Phase III
trial evaluating the efficacy and safety of ENHERTU (5.4mg/kg)
versus T-DM1 in patients with HER2-positive unresectable and/or
metastatic breast cancer previously treated with trastuzumab and a
taxane.
The primary efficacy endpoint of DESTINY-Breast03 is PFS based
on BICR. Overall survival is a key secondary efficacy outcome
measure. Other secondary efficacy endpoints include ORR, DoR, PFS
based on investigator assessment and safety.
DESTINY-Breast03 enrolled 524 patients at multiple sites in
Asia, Europe, North America, Oceania and South America. Primary
results from DESTINY-Breast03 were published in The New England
Journal of Medicine.7 For more information about the trial, visit
ClinicalTrials.gov.
DESTINY-Breast02 DESTINY-Breast02 is a global,
randomized, open-label, Phase III trial evaluating the efficacy and
safety of ENHERTU (5.4mg/kg) versus physician’s choice of treatment
(trastuzumab/capecitabine or lapatinib/capecitabine) in patients
with HER2-positive unresectable and/or metastatic breast cancer
previously treated with T-DM1. Patients were randomized 2:1 to
receive either ENHERTU or physician’s choice of treatment.
The primary endpoint of DESTINY-Breast02 is PFS based on BICR.
The key secondary endpoint is OS. Other secondary endpoints include
ORR based on BICR and investigator assessment, DoR based on BICR,
PFS based on investigator assessment and safety.
DESTINY-Breast02 enrolled approximately 600 patients at multiple
sites in Asia, Europe, North America, Oceania, and South 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 35 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 is also
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 Brazil and the US for the
treatment of adult patients with unresectable or metastatic
HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ
hybridization [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 under accelerated approval in the
US for the treatment of adult patients with unresectable or
metastatic NSCLC whose tumors have activating HER2 (ERBB2)
mutations, as detected by an FDA-approved test, and who have
received a prior systemic therapy based on the results from the
DESTINY-Lung02 trial. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
a confirmatory 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 (GEJ)
adenocarcinoma who have received a prior trastuzumab-based regimen
based on the results from the DESTINY-Gastric01 trial.
ENHERTU development program A comprehensive global
development program is underway 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, non-small cell
lung and gastric cancer are currently under review in several
countries.
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 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, a HER2-directed 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 fulvestrant and goserelin and
aims to reshape the HR-positive space with ngSERD and potential new
medicine camizestrant as well as a potential first-in-class AKT
kinase inhibitor, capivasertib. 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 with an
inherited BRCA mutation. AstraZeneca with MSD (Merck & Co.,
Inc. in the US and Canada) continue to research olaparib in these
settings and are exploring new opportunities to treat these
patients earlier in their disease.
To bring much-needed treatment options to patients with TNBC, 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 (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
- 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.
- 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.
- Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2)
in Cancers: Overexpression and Therapeutic Implications. Mol Biol
Int. 2014; 852748.
- Pillai R, et al. HER2 mutations in lung adenocarcinomas: A
report from the Lung Cancer Mutation Consortium. Cancer.
2017;1;123(21):4099-4105.
- Barok M, et al. Trastuzumab emtansine: mechanism of action and
drug resistance. Breast Cancer Res. 2014; 16(2):209.
- Nader-Marta G, et al. How we treat patients with metastatic
HER2-positive breast cancer. ESMO Open. 2022; 7:1.
- Cortes J, et al. Trastuzumab Deruxtecan versus Trastuzumab
Emtansine for Breast Cancer. N Engl J Med. 2022;
386:1143-1154.
US-71589 Last Updated 12/22
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version on businesswire.com: https://www.businesswire.com/news/home/20221207005239/en/
Media Inquiries Brendan McEvoy +1 302 885 2677 Chelsea
Ford +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
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