INDICATION
ENHERTU is a
HER2-directed
antibody and
topoisomerase inhibitor conjugate indicated for:
-
HER2-Positive Early Breast Cancer
-
As neoadjuvant treatment of adult patients with
HER2-positive (IHC 3+ or ISH+) Stage II or III breast
cancer, as determined by an FDA-authorized test followed by
a taxane, trastuzumab, and pertuzumab (THP)
-
As adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment
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. In the adjuvant HER2+ breast cancer setting, if drug-induced ILD is suspected, rule out radiotherapy-related pneumonitis. If only radiotherapy-related pneumonitis is suspected, consider interruption of ENHERTU for Grade 2 and permanently discontinue ENHERTU for Grade ≥3.
HER2-Positive Breast Cancer
and Other Solid Tumors (5.4 mg/kg)
ENHERTU followed by THP
In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11,
ILD occurred in 4.4% of patients. Median time to first onset was 2.7 months
(range: 1.1 to 6.0). Fatal outcomes due to ILD and/or pneumonitis occurred in 1
patient (0.3%) treated with ENHERTU followed by THP.
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.
HER2-Positive Breast Cancer
and Other Solid Tumors (5.4 mg/kg)
ENHERTU followed by THP
In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, a
decrease in neutrophil count was reported in 58% of patients. Seventeen percent
had Grade 3 or 4 decreased neutrophil count. Median time to first onset of
decreased neutrophil count was 42 days (range: 11 to 165). Febrile neutropenia
was reported in 0.9% 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.
HER2-Positive Breast Cancer
and Other Solid Tumors (5.4 mg/kg)
ENHERTU followed by THP
In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11,
LVD was reported in 1.3% of patients, of which 0.3% were Grade 3.
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
HER2-Positive Early Breast Cancer
DESTINY-Breast11
The safety of ENHERTU followed by THP was evaluated in 320 patients with HER2-positive (IHC 3+ or ISH+) early breast cancer who received at least 1 dose of ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11. ENHERTU was administered by intravenous infusion once every three weeks for 4 cycles followed by THP for 4 cycles. The median duration of treatment was 5.6 months (range: 0.7 to 9.1) for patients who received ENHERTU followed by THP.
Serious adverse reactions occurred in 11% of patients receiving ENHERTU followed by THP, including COVID-19 (0.9%) and ILD/pneumonitis (0.6%). Fatal adverse reactions occurred in 0.6% of patients, including ILD/pneumonitis and death not otherwise specified (1 patient each).
In patients treated with ENHERTU followed by THP, the permanent discontinuation of ENHERTU due to adverse reactions occurred in 1.3%, of which ILD/pneumonitis accounted for 0.6%. Dose interruptions of ENHERTU due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count and COVID-19. Dose reductions of ENHERTU occurred in 2.5% of patients treated with ENHERTU.
The most common (≥20%) adverse reactions in patients treated with ENHERTU followed by THP, including laboratory abnormalities, were decreased hemoglobin (83%), increased alanine aminotransferase (79%), increased aspartate aminotransferase (74%), decreased white blood cell count (67%), nausea (65%), peripheral neuropathy (59%), diarrhea (59%), decreased neutrophil count (58%), alopecia (48%), fatigue (41%), decreased lymphocyte count (40%), rash (31%), musculoskeletal pain (30%), decreased blood potassium (29%), constipation (29%), vomiting (29%), stomatitis (23%), and decreased appetite (20%).
DESTINY-Breast05
The safety of ENHERTU was evaluated in 806 patients with HER2-positive breast cancer with residual invasive disease following neoadjuvant HER2-targeted therapy who then received at least one dose of ENHERTU 5.4 mg/kg. ENHERTU was administered by intravenous infusion once every three weeks for 14 cycles. The median duration of treatment was 10 months (range: 0.7 to 16) for patients who received ENHERTU.
Serious adverse reactions occurred in 17% of patients receiving ENHERTU. Serious adverse reactions in ≥1% of patients who received ENHERTU were ILD/pneumonitis, radiation pneumonitis, pneumonia, and platelet count decreased. Fatal adverse reactions occurred in 0.4% of patients including ILD/pneumonitis (2 patients) and respiratory tract infection (1 patient).
Permanent discontinuation of ENHERTU due to an adverse reaction occurred in 18% of patients. The adverse reaction which resulted in permanent discontinuation of ENHERTU >2% included ILD/pneumonitis. Dose interruptions of ENHERTU due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruptions in >2% included radiation pneumonitis, neutrophil count decreased, COVID-19, white blood cell count decreased, ILD/pneumonitis, platelet count decreased, upper respiratory tract infection, fatigue, cough, and pyrexia. Dose reductions of ENHERTU due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reductions in >2% of patients included nausea, fatigue, platelet count decreased, ILD/pneumonitis, and neutrophil count decreased.
The most common (≥20%) adverse reactions, including laboratory abnormalities, in patients receiving ENHERTU were decreased white blood cell count (80%), decreased lymphocyte count (72%), decreased neutrophil count (72%), nausea (71%), decreased hemoglobin (61%), increased aspartate aminotransferase (60%), fatigue (54%), increased alanine aminotransferase (53%), decreased platelet count (46%), increased blood alkaline phosphatase (39%), constipation (32%), vomiting (31%), decreased blood potassium (27%), diarrhea (23%), musculoskeletal pain (23%), and decreased appetite (20%).
ILD was reported in 17% of patients receiving ENHERTU, which included COVID-19 pneumonia, interstitial lung disease, lung opacity, organizing pneumonia, pneumocystis jirovecii pneumonia, pneumonia, and pneumonitis which was adjudicated as ILD (irrespective of causality). Adjudicated drug-related ILD for ENHERTU was 10% for all Grades and 0.9% for Grades 3 or 4.
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: ENHERTU followed by THP: Of the 320 patients with HER2-positive early breast cancer treated with ENHERTU 5.4 mg/kg followed by THP, 12% were ≥65 years and 1.6% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients ≥65 years (38%) as compared to younger patients (30%).
- 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.
