INDICATION
ENHERTU is a HER2-directed antibody and
topoisomerase inhibitor conjugate indicated for the treatment of
adult patients with 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.
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-Mutant NSCLC and Other Solid Tumors
(5.4 mg/kg)
In patients with 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.
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-Mutant NSCLC and Other Solid Tumors
(5.4 mg/kg)
In patients with 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.
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-Mutant NSCLC and Other Solid Tumors
(5.4 mg/kg)
In patients with 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.
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-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 1799 patients in DESTINY-Lung02 and other clinical trials. 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-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%).
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 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.
-
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
click here for full Prescribing Information,
including Boxed WARNINGS, and
click here for Medication
Guide.
