AstraZeneca and Daiichi Sankyo’s ENHERTU
achieved 61.6% progression-free survival rate at one year in
patients with active or stable brain metastases in
DESTINY-Breast12
Largest prospective trial of ENHERTU in this
patient population
Results from the DESTINY-Breast12 Phase IIIb/IV trial showed
that ENHERTU® (fam-trastuzumab deruxtecan-nxki) demonstrated
substantial overall and intracranial clinical activity in a large
cohort of patients with HER2-positive metastatic breast cancer who
have brain metastases and received no more than two prior lines of
therapy in the metastatic setting. Results will be presented today
as a late-breaking presentation (abstract #LBA18) at the European
Society for Medical Oncology (#ESMO24) and simultaneously published
in Nature Medicine.
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.
In patients with brain metastases at baseline, the primary
endpoint of progression-free survival (PFS) by independent central
review showed a 12-month PFS rate of 61.6%. Additionally, patients
with brain metastases showed a central nervous system (CNS)
12-month PFS rate of 58.9%. Results were consistent in patients
with stable and active brain metastases. Patients with stable brain
metastases had a 12-month PFS rate of 62.9% and a 12-month CNS PFS
rate of 57.8%. Patients with active brain metastases had a 12-month
PFS rate of 59.6% and a 12-month CNS PFS rate of 60.1%.
In patients without brain metastases at baseline, the primary
endpoint of confirmed objective response rate (ORR) by independent
central review showed an ORR of 62.7% with 23 complete responses
(CR) and 128 partial responses (PR).
Nancy Lin, MD, Associate Chief, Division of Breast Oncology,
Dana-Farber Cancer Institute, Boston, MA, US and principal
investigator for the trial, said: “Up to fifty percent of patients
with HER2-positive metastatic breast cancer experience the spread
of disease to the brain during the course of their illness, which
significantly impacts quality of life and outcomes. These data help
further characterize the clinical benefit and safety profile of
ENHERTU in these patients, which will help guide treatment
decisions.”
Sunil Verma, Global Head Oncology Franchise, AstraZeneca, said
“The results from DESTINY-Breast12 show substantial clinical
activity for patients whose disease has spread to the brain. The
data as well as the results in patients without brain metastases
further build confidence in the clinical profile of ENHERTU for the
second-line treatment of HER2-positive metastatic breast
cancer.”
Mark Rutstein, Global Head, Oncology Development, Daiichi
Sankyo, said, “Treating brain metastases in patients with breast
cancer is challenging as there are few effective treatment options.
Building on previous studies, these results show ENHERTU can
provide strong overall and intracranial clinical activity and
support its potential role in treating patients with active or
stable brain metastases.”
Summary of results: DESTINY-Breast12 primary analysis
Efficacy measure
Baseline brain metastases
(cohort 2)
No baseline brain metastases
(cohort 1)
Overall population
(n=263)
Stable brain metastasesi
(n=157)
Active brain metastasesii
(n=106)
Overall population
(n=241)iii
12-month PFS rate (%)
(95% CI)iv
61.6
(54.9-67.6)
62.9
(54.0-70.5)
59.6
(49.0-68.7)
--
12-month CNS PFS rate (%) (95%
CI)v
58.9
(51.9-65.3)
57.8
(48.2-66.1)
60.1
(49.2-69.4)
--
12 month OS rate (%) (95%
CI)
90.3
(85.9-93.4)
--
--
90.6
(86.0-93.8)
Confirmed ORR (%)vi, vii
(95% CI)
51.7
(45.7-57.8)
49.7
(41.9-57.5)
54.7
(45.2-64.2)
62.7
(56.5-68.8)
CR % (n)
4.2 (11)
--
--
9.5 (23)
PR % (n)
47.5 (125)
--
--
53.1 (128)viii
Confirmed CNS ORR (%) (95%
CI)ix
71.7
(64.2-79.3)
N=138
79.2
(70.2-88.3)
N=77
62.3
(50.1-74.5)
N=61
--
PFS, progression-free survival; CI,
confidence interval; CNS, central nervous system; OS, overall
survival; ORR, objective response rate; CR, complete response; PR,
partial response
i Stable brain metastases (previously
treated)
ii Active brain metastases (untreated or
previously treated / progressing [not requiring immediate local
therapy])
iii Includes 26 patients with no
measurable disease at baseline
iv Primary endpoint for baseline brain
metastases (cohort 2) was median PFS with 42.2% data maturity at
time of data cutoff (8 February 2024); post-hoc analysis showed
median PFS of 17.3 months (95% CI 13.7-22.1)
v Patients who had systemic progression,
but no CNS progression, were censored at the time of the
progression assessment; the analysis did not account for systemic
progression as a competing event
vi Primary endpoint for no baseline brain
metastases cohort (cohort 1)
vii ORR is (CR + PR)
viii One patient with no measurable
disease at baseline was assigned PR by independent central
review
ix Analysis of CNS ORR was in patients
with measurable CNS disease at baseline
A post-hoc analysis in patients with active brain metastases
showed the CNS ORR was 82.6% (n=19/23) for patients who had not
received prior local CNS therapy and 50.0% (n=19/38) in patients
who had progressed following prior local CNS therapy.
The safety profile of ENHERTU in DESTINY-Breast12 was consistent
with previous breast cancer clinical trials with no new safety
concerns identified. The safety profile of ENHERTU in the trial was
also generally consistent between patients with brain metastases
and patients without brain metastases.
Interstitial lung disease (ILD) or pneumonitis occurred in 12.9%
of patients in cohort without brain metastases and 16.0% in the
cohort of patients with brain metastases as determined by the
investigator. The majority of ILD events were low grade (Grade 1 or
2). In patients without brain metastases, there were 22 Grade 1 ILD
events, six Grade 2 events, zero Grade 3 and 4 events, and three
(1.2%) Grade 5 events. In patients with brain metastases, there
were 26 Grade 1 ILD events, eight Grade 2 events, one Grade 3
event, one Grade 4 event and six (2.3%) Grade 5 events. Five ILD or
pneumonitis events in the brain metastases cohort were reported by
the investigator as co-occurring with opportunistic infection (one
Grade 4 and four Grade 5).
ENHERTU is approved in more than 65 countries for the treatment
of unresectable or metastatic HER2-positive breast cancer who have
received a prior anti-HER2-based regimen.
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.
WARNING: INTERSTITIAL LUNG DISEASE and
EMBRYO-FETAL TOXICITY
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, HER2 expression and brain metastases
Breast cancer is the second most common cancer and one of the
leading causes of cancer-related deaths worldwide.1 More than two
million breast cancer cases were diagnosed in 2022 with more than
665,000 deaths globally.1 While survival rates are high for those
diagnosed with early breast cancer, only about 30% of patients
diagnosed with or who progress to metastatic disease are expected
to live five years following diagnosis.2
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors, including breast
cancer.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 Approximately one in five
cases of breast cancer are considered HER2-positive.5
Brain metastases occur when cancer cells spread from their
original location to the brain. An estimated 10% to 15% of patients
diagnosed with metastatic breast cancer will develop brain
metastases.6 The risk is higher for those with HER2-positive or
triple-negative metastatic breast cancer, with brain metastases
occurring in 30% to 50% of these patients.7
The median overall survival for patients with breast cancer who
have developed brain metastases is eight months; however, this
varies based on subtype and the availability of effective
treatments.8 Current guidelines do not recommend screening patients
with breast cancer for brain metastases. As a result, when brain
metastases are eventually diagnosed, patients may already present
with advanced disease.7
DESTINY-Breast12 DESTINY-Breast12 is an open-label,
multicenter, Phase IIIb/4 2-cohort, non-comparative clinical trial
designed to evaluate the efficacy and safety of ENHERTU (5.4 mg/kg)
in patients with previously treated advanced/metastatic
HER2-positive breast cancer. The study includes patients without
brain metastases (cohort 1) or with brain metastases (cohort 2) who
have experienced disease progression following prior
anti-HER2-based regimens and have received no more than two lines
of therapy in the metastatic setting. Patients were enrolled into
one of two cohorts according to the presence or absence of brain
metastases at baseline.
The primary endpoint of cohort 1 was ORR as assessed by
independent review (non-brain metastases cohort) and the primary
endpoint of cohort 2 (brain metastases cohort) was PFS. (Additional
endpoints included CNS PFS, CNS ORR, ORR in the brain metastases
cohort and safety.)
DESTINY-Breast12 enrolled 504 patients across multiple sites in
Asia, Europe, North America and Oceania. For more information about
the trial, visit ClinicalTrials.gov.
ENHERTU 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 (5.4 mg/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 (5.4 mg/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 (5.4 mg/kg) is approved in more than 35 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 (6.4 mg/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 (5.4 mg/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, 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
- 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.
- National Cancer Institute. Surveillance, Epidemiology and End
Results Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed September 2024.
- 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 Nov
1;123(21):4099-4105.
- 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.
- Simsek M, et al. Breast Cancer Patients with Brain Metastases:
A Cross-Sectional Study. Breast J. 2022; 19;2022:5763810.
- Kuksis M, et al. The incidence of brain metastases among
patients with metastatic breast cancer: a systematic review and
meta-analysis. Neuro Oncol. 2021 Jun 1;23(6):894-904.
- Bailleux C, et al. Treatment strategies for breast cancer brain
metastases. Br J Cancer. 2021 Jan;124(1):142-155.
US-93549 Last Updated 9/24
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