INDICATION
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for:
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HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer (NSCLC)
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.
HER2-Mutant NSCLC 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.
HER2-Mutant NSCLC 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.
HER2-Mutant NSCLC 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
HER2-Mutant NSCLC 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 DESTINY-Lung02 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-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg)
DESTINY-Lung02 evaluated 2 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 3 weeks until disease progression or unacceptable toxicity in DESTINY‑Lung02. The
median duration of treatment was 8 months (range: 0.7 to 28) for patients who received
ENHERTU.
Serious adverse reactions occurred in 40% of patients receiving ENHERTU. Serious adverse
reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pleural effusion,
thrombocytopenia, dyspnea, nausea, pneumonia, vomiting, myocarditis, pulmonary embolism, and
increased troponin I. Fatalities due to adverse reactions occurred in 3% of patients
including ILD/pneumonitis, cerebrovascular accident, and pneumococcal sepsis (1 patient
each).
ENHERTU was permanently discontinued in 17% of patients. Adverse reactions which resulted in
permanent discontinuation of ENHERTU were ILD/pneumonitis, pneumonia, blood bilirubin
increased, hypokalemia, metastases to meninges, and myocarditis. Dose interruptions of
ENHERTU due to adverse reactions occurred in 50% of patients. Adverse reactions which
required dose interruption (>2%) included neutropenia, COVID-19, ILD/pneumonitis,
fatigue, anemia, and pneumonia. Dose reductions due to an adverse reaction occurred in 20%
of patients. The most frequent adverse reactions (>2%) associated with dose reduction were
neutropenia, fatigue, and decreased appetite.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were
decreased hemoglobin (68%), nausea (67%), decreased white blood cell count (66%), decreased
neutrophil count (59%), decreased lymphocyte count (56%), increased aspartate
aminotransferase (51%), decreased albumin (50%), decreased platelet count (49%), fatigue
(48%), increased alanine aminotransferase (41%), decreased appetite (41%), constipation
(38%), increased alkaline phosphatase (37%), vomiting (32%), decreased blood potassium
(29%), diarrhea (24%), alopecia (22%), and musculoskeletal pain (21%).
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
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Guide.
