INDICATION
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate
indicated for:
-
HER2-Low and HER2-Ultralow Metastatic Breast
Cancer
-
As monotherapy for the treatment of adult patients with unresectable or
metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC
2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer,
as determined by an FDA-authorized test, that has progressed on one or
more endocrine therapies in the metastatic setting
-
As monotherapy for the treatment of adult patients with unresectable or
metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined
by an FDA-authorized test, who have received a prior chemotherapy in the
metastatic setting or developed disease recurrence during or within 6
months of completing adjuvant chemotherapy
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 1
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 Other Solid Tumors (5.4
mg/kg)
In patients 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 0.9% of patients treated with
ENHERTU.
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 1 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 1 level.
Metastatic Breast Cancer and Other Solid Tumors (5.4
mg/kg)
In patients treated with ENHERTU 5.4 mg/kg, a decrease in
neutrophil count was reported in 65% of patients. Nineteen 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.
Left Ventricular
Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular
dysfunction. Left ventricular dysfunction (LVD) has been observed with
anti-HER2 therapies, including ENHERTU. Assess left ventricular ejection fraction
(LVEF) prior to initiation of ENHERTU and
at regular intervals during treatment as clinically indicated. Manage LVD
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 Other Solid Tumors (5.4
mg/kg)
In patients treated with ENHERTU
5.4 mg/kg, LVD was reported in 4.6% of patients,
of which 0.6% were Grade 3 or 4.
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 1 level.
Adverse Reactions
Metastatic Breast Cancer and Other Solid Tumors (5.4
mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4
mg/kg intravenously every 3 weeks in 2233 patients in Study DS8201-A-J101
(NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04,
DESTINY-Breast06, and other clinical trials. Among these patients, 67% 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 decreased
white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased
neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased
platelet count (48%), increased aspartate aminotransferase (46%), increased alanine
aminotransferase (43%), increased blood alkaline phosphatase (39%), vomiting (38%),
alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite
(31%), diarrhea (30%), and musculoskeletal pain (24%).
HER2-Low and HER2-Ultralow Metastatic Breast Cancer
DESTINY-Breast06
The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic
HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast
cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in
DESTINY-Breast06. The median duration of treatment was 11 months (range: 0.4 to 39.6)
for patients who received ENHERTU.
Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse
reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, COVID-19,
febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in
2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial
meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general
physical health deterioration (0.2% each).
ENHERTU was permanently discontinued in 14% of patients. The most frequent adverse
reaction (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose
interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose interruption were
COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood
cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose reduction were nausea,
fatigue, decreased platelet count, and decreased neutrophil count.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were
decreased white blood cell count (86%), decreased neutrophil count (75%), nausea (70%),
decreased hemoglobin (69%), decreased lymphocyte count (66%), fatigue (53%), decreased
platelet count (48%), alopecia (48%), increased alanine aminotransferase (44%),
increased blood alkaline phosphatase (43%), increased aspartate aminotransferase (41%),
decreased blood potassium (35%), diarrhea (34%), vomiting (34%), constipation (32%),
decreased appetite (26%), COVID-19 (26%), and musculoskeletal pain (24%).
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%).
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 2233 patients treated with ENHERTU 5.4 mg/kg, 28% were ≥65 years and 6% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (56%) as compared to younger patients (49%).
-
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, monitor for increased adverse reactions 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
click here for
full Prescribing Information,
including Boxed WARNINGS, and
click here for
Medication
Guide.
