INDICATION
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with 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.
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.
Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)
In patients with 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.
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.
Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)
In patients with 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.
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.
Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)
In patients with 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.
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
Solid Tumors (IHC3+) 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 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 (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 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.
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.
