INDICATIONS
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
-
HER2-Positive Metastatic Breast
Cancer
-
In combination with pertuzumab as first-line
treatment
of adult
patients with unresectable or metastatic
HER2-positive
(IHC 3+
or ISH+) breast cancer, as determined by an
FDA-authorized
test
-
As monotherapy for the treatment of adult patients
with
unresectable or metastatic HER2-positive (IHC 3+ or
ISH+) breast
cancer who have received a prior anti-HER2-based
regimen
either
in the metastatic setting, or, in the neoadjuvant or
adjuvant
setting and have developed disease recurrence during
or
within
six months of completing therapy
-
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
-
HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung
Cancer
(NSCLC)
-
As monotherapy for the treatment of adult patients
with
unresectable or metastatic NSCLC whose tumors have
activating
HER2 (ERBB2) mutations, as detected by an
FDA-authorized
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.
-
HER2-Positive Locally Advanced or Metastatic Gastric Cancer
-
HER2-Positive (IHC 3+) Unresectable or Metastatic Solid
Tumors
-
As monotherapy for the treatment of adult patients
with
unresectable or metastatic HER2-positive (IHC 3+)
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 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, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors
(Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
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.
ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with
pertuzumab (N=431), ILD occurred in 12% of patients. Median time to
first onset was 8.0 months (range: 0.6 to 33.8). Fatal outcomes due to
ILD and/or pneumonitis occurred in 0.5% of patients treated with ENHERTU
in combination with pertuzumab.
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.
HER2-Positive Locally Advanced or
Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or
GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10%
of patients. Median time to first onset was 2.8 months (range: 1.2 to
21).
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, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors
(Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
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.
ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with
pertuzumab (N=431), decreased neutrophil count occurred in 79% of
patients. Median time to first onset was 22 days (range: 5 to 994).
Twenty-nine percent had Grade 3 or 4 decreased neutrophil count. Febrile
neutropenia was reported in 2.6% of patients.
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.
HER2-Positive Locally Advanced or
Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or
GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in
neutrophil count was reported in 72% of patients. Fifty-one percent had
Grade 3 or 4 decreased neutrophil count. Median time to first onset of
decreased neutrophil count was 16 days (range: 4 to 187). Febrile
neutropenia was reported in 4.8% 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, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors
(Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
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.
ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with
pertuzumab (N=431), LVEF decrease was reported in 11% of patients, of
which 2.1% were Grade 3 or 4.
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.
HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or
GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse
events of heart failure were reported; however, on echocardiography, 8%
were found to have asymptomatic Grade 2 decrease in LVEF.
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, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors
(Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
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, DESTINY-Lung01, DESTINY-Lung02,
DESTINY-CRC02, and DESTINY-PanTumor02. 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%).
ENHERTU in Combination with Pertuzumab
The pooled safety population reflects exposure
to
ENHERTU 5.4 mg/kg in
combination with pertuzumab intravenously every 3 weeks in 431 patients
in DESTINY-Breast07 (n=50), and DESTINY-Breast09 (n=381). Among these
patients, 86% were exposed for >6 months and 73% 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 (86%), decreased hemoglobin (80%), decreased neutrophil
count (79%), nausea (74%), increased alanine aminotransferase (65%),
diarrhea (64%), increased aspartate aminotransferase (63%), decreased
lymphocyte count (61%), decreased platelet count (55%), increased blood
alkaline phosphatase (54%), decreased blood potassium (54%), fatigue
(53%), alopecia (48%), vomiting (46%), upper respiratory tract infection
(32%), constipation (31%), decreased appetite (31%), decreased weight
(28%), musculoskeletal pain (23%), increased blood bilirubin (23%), and abdominal pain (22%).
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.
HER2-Positive Metastatic Breast
Cancer
DESTINY-Breast09
The safety of ENHERTU 5.4 mg/kg in combination
with
pertuzumab was
evaluated in DESTINY-Breast09, a randomized, three-arm, multicenter
study including 763 patients with HER2-positive (IHC 3+ or ISH+)
unresectable or metastatic breast cancer. Three hundred eighty-one
patients received ENHERTU in combination with pertuzumab and 382
patients received THP (taxane [docetaxel or paclitaxel], trastuzumab,
and pertuzumab). Among patients who received ENHERTU in combination with
pertuzumab, the median duration of treatment was 22 months (range: 0.3
months to 44.5 months).
Serious adverse reactions occurred in 27% of
patients receiving ENHERTU
in combination with pertuzumab. Serious adverse reactions in >1% of
patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia,
vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to adverse
reactions occurred in 3.4% of patients including pneumonia (n=3), ILD
(n=2), sepsis (n=2), pulmonary embolism, septic shock, acute kidney
injury, dyspnea, febrile neutropenia, and intestinal ischemia (1
patient each).
ENHERTU was discontinued for adverse reactions
in
21% of patients. The most frequent adverse reaction (>2%) associated
with permanent discontinuation was ILD/pneumonitis (6%). Dose
interruptions due to adverse reactions occurred in 69% of patients. The
most frequent adverse reactions (>2%) associated with dose interruption
were COVID-19, neutropenia, upper respiratory tract infection, fatigue,
anemia, hypokalemia, ILD/pneumonitis, thrombocytopenia, pneumonia,
diarrhea, transaminase increased, leukopenia, cough, pyrexia, decreased
appetite, and blood bilirubin increased. Dose reductions occurred in 46%
of patients treated with ENHERTU in combination with pertuzumab. The
most frequent adverse reactions (>2%) associated with dose reduction
were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis,
thrombocytopenia, vomiting, transaminases increased, decreased weight,
febrile neutropenia, and hypokalemia.
The most common (≥20%) adverse reactions,
including
laboratory abnormalities, were decreased white blood cell count (87%),
decreased hemoglobin (80%), decreased neutrophil count (78%), nausea
(75%), increased alanine aminotransferase (66%), diarrhea (64%),
increased aspartate aminotransferase (62%), decreased lymphocyte count
(62%), decreased platelet count (56%), increased blood alkaline
phosphatase (55%), decreased blood potassium (54%), fatigue (53%),
alopecia (48%), vomiting (46%), upper respiratory tract infection (33%),
constipation (33%), decreased appetite (32%), decreased weight (30%),
COVID-19 (28%), musculoskeletal pain (24%), increased blood bilirubin
(23%), and abdominal pain (23%).
DESTINY-Breast03
The safety of ENHERTU was evaluated in 257
patients
with unresectable or metastatic HER2-positive breast cancer who received
at least 1 dose of ENHERTU 5.4 mg/kg intravenously once every 3 weeks in
DESTINY-Breast03. The median duration of treatment was 14 months (range:
0.7 to 30) for patients who received ENHERTU.
Serious adverse reactions occurred in 19% of
patients receiving ENHERTU. Serious adverse reactions in >1% of patients
who received ENHERTU were vomiting, ILD, pneumonia, pyrexia, and urinary
tract infection. Fatalities due to adverse reactions occurred in 0.8% of
patients including COVID-19 and sudden death (1 patient each).
ENHERTU was permanently discontinued in 14% of
patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions
due to adverse reactions occurred in 44% of patients treated with
ENHERTU. The most frequent adverse reactions (>2%) associated with dose
interruption were neutropenia, leukopenia, anemia, thrombocytopenia,
pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions
occurred in 21% of patients treated with ENHERTU. The most frequent
adverse reactions (>2%) associated with dose reduction were nausea,
neutropenia, and fatigue.
The most common (≥20%) adverse reactions,
including
laboratory abnormalities, were nausea (76%), decreased white blood cell
count (74%), decreased neutrophil count (70%), increased aspartate
aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte
count (55%), increased alanine aminotransferase (53%), decreased
platelet count (52%), fatigue (49%), vomiting (49%), increased blood
alkaline phosphatase (49%), alopecia (37%), decreased blood potassium
(35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%),
decreased appetite (29%), headache (22%), respiratory infection (22%),
abdominal pain (21%), increased blood bilirubin (20%), and stomatitis
(20%).
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%).
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%).
HER2-Positive Locally
Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
The safety of ENHERTU was evaluated in 187
patients
with locally advanced or metastatic HER2-positive gastric or GEJ
adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at
least 1 dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either
irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly
for 3 weeks. The median duration of treatment was 4.6 months (range:
0.7 to 22.3) for patients who received ENHERTU.
Serious adverse reactions occurred in 44% of
patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2%
of patients who received ENHERTU were decreased appetite, ILD, anemia,
dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor
hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of
patients: disseminated intravascular coagulation, large intestine
perforation, and pneumonia occurred in 1 patient each (0.8%).
ENHERTU was permanently discontinued in 15% of
patients, of which ILD accounted for 6%. Dose interruptions due to
adverse reactions occurred in 62% of patients treated with ENHERTU. The
most frequent adverse reactions (>2%) associated with dose interruption
were neutropenia, anemia, decreased appetite, leukopenia, fatigue,
thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract
infection, diarrhea, and decreased blood potassium. Dose reductions
occurred in 32% of patients treated with ENHERTU. The most frequent
adverse reactions (>2%) associated with dose reduction were neutropenia,
decreased appetite, fatigue, nausea, and febrile neutropenia.
The most common (≥20%) adverse reactions,
including
laboratory abnormalities, were decreased hemoglobin (75%), decreased
white blood cell count (74%), decreased neutrophil count (72%),
decreased lymphocyte count (70%), decreased platelet count (68%), nausea
(63%), decreased appetite (60%), increased aspartate aminotransferase
(58%), fatigue (55%), increased blood alkaline phosphatase (54%),
increased alanine aminotransferase (47%), diarrhea (32%), decreased
blood potassium (30%), vomiting (26%), constipation (24%), increased
blood bilirubin (24%), pyrexia (24%), and alopecia (22%).
HER2-Positive (IHC 3+)
Unresectable or Metastatic Solid Tumors
The safety of ENHERTU was evaluated in 347
adult
patients with unresectable or metastatic HER2-positive (IHC 3+) 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 1
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:
ENHERTU as Monotherapy: 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%). Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
ENHERTU in Combination with Pertuzumab: In patients with HER2-positive unresectable or metastatic breast cancer treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), 17% were ≥65 years and 3% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years compared to younger patients.
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.
All Indications
