Based on three Phase II trials of
AstraZeneca and Daiichi Sankyo’s ENHERTU which showed clinically
meaningful responses across a broad range of tumors
ENHERTU now has five approved indications
with the latest in HER2-expressing (IHC 3+) metastatic
cancers
AstraZeneca and Daiichi Sankyo's ENHERTU® (fam-trastuzumab
deruxtecan-nxki) has been approved in the US 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 (ORR) and duration of response (DoR).
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial.
ENHERTU is a specifically engineered HER2-directed antibody drug
conjugate (ADC) discovered by Daiichi Sankyo and being jointly
developed and commercialized by AstraZeneca and Daiichi Sankyo.
The first tumor-agnostic approval of a HER2-directed therapy and
ADC by the Food and Drug Administration (FDA) was based on results
from the subgroup of patients with HER2-positive IHC 3+ tumors in
each of the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02
Phase II trials.
Funda Meric-Bernstam, MD, Chair of Investigational Cancer
Therapeutics at The University of Texas MD Anderson Cancer Center,
US, said: “Until the approval of fam-trastuzumab deruxtecan-nxki,
patients with metastatic HER2-positive solid tumors have had
limited treatment options. Based on the clinically meaningful
response rates seen across clinical trials, this tumor-agnostic
approval means that patients may now be treated with a
HER2-directed medicine.”
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca, said: “As the first antibody drug conjugate to
be granted a tumor-agnostic indication, ENHERTU is truly delivering
on its potential across metastatic HER2-targetable tumors. The
approval also elevates the importance of testing for biomarkers,
including HER2, across a broad range of tumors to ensure these
patients with advanced cancer who have few options know whether a
targeted medicine might be right for them.”
Ken Keller, Global Head of Oncology Business, and President and
CEO, Daiichi Sankyo, Inc., said: “This fifth indication in the US
is a significant milestone as eligible patients with previously
treated metastatic HER2-positive solid tumors may now be treated
with ENHERTU. The accelerated approval by the FDA for this
tumor-agnostic indication is based on the clinically meaningful
efficacy seen with ENHERTU across numerous types of metastatic
cancers.”
In the DESTINY-PanTumor02 Phase II trial, patients with
centrally or locally assessed HER2-positive (IHC 3+) solid tumors
including either biliary tract, bladder, cervical, endometrial,
ovarian, pancreatic or other tumors treated with ENHERTU showed a
confirmed ORR of 51.4% (95% confidence interval [CI]: 41.7-61.0)
and a median DoR range of 19.4 months (range: 1.3-27.9+ [+ denotes
ongoing responses at data cutoff]). In DESTINY-Lung01, patients
with centrally confirmed HER2-positive (IHC 3+) non-small cell lung
cancer (NSCLC) treated with ENHERTU showed a confirmed ORR of 52.9%
(95% CI: 27.8-77.0) and median DoR range of 6.9 months (range:
4.0-11.7+). A confirmed ORR of 46.9% (95% CI: 34.3-59.8) and median
DoR range of 5.5 months (range: 1.3+-9.7+) was seen in patients
with centrally confirmed HER2-positive (IHC 3+) colorectal cancer
in the DESTINY-CRC02 trial.
The safety of ENHERTU was evaluated in 347 patients with
unresectable or metastatic HER2-positive (IHC 3+) solid tumors in
the DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01 and
DESTINY-CRC02 trials. The safety profile observed across the trials
was consistent with previous clinical trials of ENHERTU with no new
safety concerns identified.
Based on these results, fam-trastuzumab deruxtecan-nxki
(ENHERTU) has been included in the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) as a treatment option for
multiple metastatic tumors. See NCCN Guidelines® for detailed
recommendations.1
This approval was granted under the FDA’s Real-Time Oncology
Review program after securing Priority Review and Breakthrough
Therapy Designation for ENHERTU in the US in this setting.
The US regulatory submission was reviewed under Project Orbis,
which provides a framework for concurrent submission and review of
oncology medicines among participating international partners. As
part of Project Orbis, ENHERTU is also under regulatory review for
the same indication by regulatory authorities in Australia, Brazil
and Singapore.
Important Safety Information
Indications ENHERTU is a HER2-directed antibody and
topoisomerase inhibitor conjugate indicated for the treatment of
adult patients with:
- Unresectable or metastatic HER2-positive (IHC 3+ or ISH
positive) 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
- Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-)
breast cancer, as determined by an FDA-approved test, who have
received a prior chemotherapy in the metastatic setting or
developed disease recurrence during or within 6 months of
completing adjuvant chemotherapy
- 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.
- Locally advanced or metastatic HER2-positive (IHC 3+ or IHC
2+/ISH positive) gastric or gastroesophageal junction (GEJ)
adenocarcinoma who have received a prior trastuzumab-based
regimen
- 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.
WARNING: INTERSTITIAL LUNG DISEASE and
EMBRYO-FETAL TOXICITY
- Interstitial lung disease (ILD) and pneumonitis, including
fatal cases, have been reported with ENHERTU. Monitor for and
promptly investigate signs and symptoms including cough, dyspnea,
fever, and other new or worsening respiratory symptoms. Permanently
discontinue ENHERTU in all patients with Grade 2 or higher
ILD/pneumonitis. Advise patients of the risk and to immediately
report symptoms.
- Exposure to ENHERTU during pregnancy can cause embryo-fetal
harm. Advise patients of these risks and the need for effective
contraception.
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-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg) In patients with metastatic breast cancer,
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.
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 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-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg) In patients with metastatic breast cancer,
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.
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 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-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg) In patients with metastatic breast cancer,
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.
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 one
level.
Adverse Reactions HER2-Positive and
HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid
Tumors (Including IHC 3+) (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 Metastatic Breast
Cancer DESTINY-Breast03 The safety of ENHERTU was evaluated
in 257 patients with unresectable or metastatic HER2-positive
breast cancer who received at least one dose of ENHERTU 5.4 mg/kg
intravenously once every three weeks in DESTINY-Breast03. The
median duration of treatment was 14 months (range: 0.7 to 30).
Serious adverse reactions occurred in 19% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were vomiting, interstitial lung disease,
pneumonia, pyrexia, and urinary tract infection. Fatalities due to
adverse reactions occurred in 0.8% of patients including COVID-19
and sudden death (one 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 Metastatic Breast Cancer
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 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%).
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 one 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 one 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 (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 1287 patients with HER2-positive
or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg, 22% were
≥65 years and 3.8% were ≥75 years. No overall differences in
efficacy within clinical studies were observed between patients ≥65
years of age compared to younger patients. There was a higher
incidence of Grade 3-4 adverse reactions observed in patients aged
≥65 years (59%) as compared to younger patients (49%). 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. 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. 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.
Please see accompanying full Prescribing
Information, including Boxed WARNINGS, and Medication
Guide.
Notes
Financial considerations Sales of ENHERTU in the US are
recognized by Daiichi Sankyo. AstraZeneca reports its share of
gross profit margin from ENHERTU sales in the US as alliance
revenue in the Company’s financial statements.
Further details on the financial arrangements were set out in
the March 2019 announcement of the collaboration.
HER2 expression in solid tumors HER2 is a tyrosine kinase
receptor growth-promoting protein expressed on the surface of
various tissue cells throughout the body and is involved in normal
cell growth.2,3 In some cancers, HER2 expression is amplified or
the cells have activating mutations.2,4 HER2 protein overexpression
may occur as a result of HER2 gene amplification and is often
associated with aggressive disease and poor prognosis.5
HER2-directed therapies have been used to treat breast, gastric,
lung and colorectal cancers for a number of years.3,6,7 Although
HER2 is expressed in solid tumor types including biliary tract,
bladder, cervical, endometrial, ovarian and pancreatic cancers,
testing is not routinely performed in these additional tumor types
and as a result, available literature is limited.4 In these solid
tumors, HER2-positive expression, classified as
immunohistochemistry (IHC) 3+, has been observed at rates from 1%
to 28%.8,9 Approximately 1% to 5% of patients with NSCLC have
tumors with HER2 overexpression (IHC 3+), however, the levels of
protein expression reported vary in the literature.8,10
Approximately 1% to 4% of patients with metastatic colorectal
cancer have tumors which are HER2 overexpressing (IHC
3+).8,11,12
DESTINY-PanTumor02 DESTINY-PanTumor02 is a global,
multicenter, multi-cohort, open-label Phase II trial evaluating the
efficacy and safety of ENHERTU (5.4mg/kg) for the treatment of
previously treated HER2-expressing tumors, including biliary tract
cancer, bladder cancer, cervical cancer, endometrial cancer,
ovarian cancer, pancreatic cancer or other tumors.
The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed
ORR as assessed by investigator. Secondary endpoints include DoR,
disease control rate (DCR), progression-free survival (PFS),
overall survival (OS), safety, tolerability and
pharmacokinetics.
DESTINY-PanTumor02 has enrolled 267 patients, including 111
HER2-positive (IHC 3+) adult patients, at multiple sites in Asia,
Europe and North America, and is to be expanded to recruit more
patients with metastatic HER2-postive IHC 1+, IHC 2+ and IHC 3+
tumors. For more information about the trial, visit
ClinicalTrials.gov.
DESTINY-Lung01 DESTINY-Lung01 is a global Phase II,
open-label, two-cohort trial evaluating the efficacy and safety of
ENHERTU (5.4mg/kg or 6.4mg/kg) in patients with HER2-mutant (cohort
2, n=91) or HER2-overexpressing (defined as IHC 3+ or IHC 2+)
[cohort 1 and 1a, n=90]) unresectable or metastatic non-squamous
NSCLC who had progressed after one or more systemic therapies.
The primary endpoint is confirmed ORR by independent central
review. Key secondary endpoints include DoR, DCR, PFS, OS and
safety.
DESTINY-Lung01 enrolled 181 patients, including 17 HER2-postive
(IHC 3+) adult patients, at multiple sites, including Asia, Europe
and North America. For more information about the trial, visit
ClinicalTrials.gov.
DESTINY-CRC02 DESTINY-CRC02 is a global, randomized, two
arm, parallel, multicenter Phase II trial evaluating the efficacy
and safety of two doses (5.4mg/kg or 6.4mg/kg) of ENHERTU in
patients with locally advanced, unresectable or metastatic
HER2-positive colorectal cancer of BRAF wild-type, RAS wild-type or
RAS mutant tumor types previously treated with standard
therapy.
The trial was conducted in two stages. In the first stage,
patients (n=80) were randomized 1:1 to receive either 5.4mg/kg or
6.4mg/kg of ENHERTU. In the second stage, additional patients
(n=42) were enrolled in the 5.4mg/kg arm.
The primary endpoint is confirmed ORR as assessed by blinded
independent central review. Secondary endpoints include DoR, DCR,
investigator-assessed confirmed ORR, clinical benefit ratio, PFS,
OS and safety.
DESTINY-CRC02 enrolled 122 patients, including 64 HER2-positive
(IHC 3+) adult patients, at multiple sites in Asia, Europe and
North America. For more information about the trial, visit
ClinicalTrials.gov.
DESTINY-Breast01 DESTINY-Breast01 is a global,
single-arm, open-label, two-part multicenter Phase II trial
evaluating the safety and efficacy of ENHERTU in patients with
HER2-positive unresectable and/or metastatic breast cancer
previously treated with trastuzumab emtansine (T-DM1).
The primary endpoint of the trial is ORR, as determined by
independent central review. Secondary objectives include DoR, DCR,
clinical benefit rate, PFS and OS.
DESTINY-Breast01 enrolled 253 patients at multiple sites in
Asia, Europe and North America. For more information about the
trial, visit ClinicalTrials.gov.
ENHERTU ENHERTU is a HER2-directed ADC. Designed using
Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the
lead ADC in the oncology portfolio of Daiichi Sankyo and the most
advanced program in AstraZeneca’s ADC scientific platform. ENHERTU
consists of a HER2 monoclonal antibody attached to a number of
topoisomerase I inhibitor payloads, (an exatecan derivative, DXd)
via tetrapeptide-based cleavable linkers.
ENHERTU (5.4mg/kg) is approved in more than 60 countries for the
treatment of adult patients with unresectable or metastatic
HER2-positive (IHC 3+ or in-situ hybridization [ISH]+) breast
cancer who have received a (or one or more) 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 based on the results from
the DESTINY-Breast03 trial.
ENHERTU (5.4mg/kg) is approved in more than 55 countries for the
treatment of adult patients with unresectable or metastatic
HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a
prior systemic therapy in the metastatic setting or developed
disease recurrence during or within six months of completing
adjuvant chemotherapy based on the results from the
DESTINY-Breast04 trial.
ENHERTU (5.4mg/kg) is approved in more than 35 countries
worldwide for the treatment of adult patients with unresectable or
metastatic non-small cell lung cancer whose tumors have activating
HER2 (ERBB2) mutations, as detected by a locally or
regionally-approved test, and who have received a prior systemic
therapy based on the results from the DESTINY-Lung02 trial.
Continued approval in the US for this indication may be contingent
upon verification and description of clinical benefit in a
confirmatory trial.
ENHERTU (6.4mg/kg) is approved in more than 45 countries for the
treatment of adult patients with locally advanced or metastatic
HER2-positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal
junction (GEJ) adenocarcinoma who have received a prior
trastuzumab-based regimen based on the results from the
DESTINY-Gastric01 trial and/or DESTINY-Gastric02 trial.
ENHERTU (5.4 mg/kg) is approved in the US 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 based on the
results from the DESTINY-PanTumor02, DESTINY-Lung01 and
DESTINY-CRC02 trials. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
a confirmatory trial.
ENHERTU development program A comprehensive clinical
development program is underway globally, evaluating the efficacy
and safety of ENHERTU monotherapy across multiple HER2-targetable
cancers. Trials in combination with other anticancer treatments,
such as immunotherapy, are also underway.
Daiichi Sankyo collaboration Daiichi Sankyo Company,
Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca
entered into a global collaboration to jointly develop and
commercialize ENHERTU (a HER2-directed ADC) in March 2019, and
datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July
2020, except in Japan where Daiichi Sankyo maintains exclusive
rights. Daiichi Sankyo is responsible for the manufacturing and
supply of ENHERTU and datopotamab deruxtecan.
AstraZeneca in oncology AstraZeneca is leading a
revolution in oncology with the ambition to provide cures for
cancer in every form, following the science to understand cancer
and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
About AstraZeneca AstraZeneca is a global, science-led
biopharmaceutical company that focuses on the discovery,
development and commercialization of prescription medicines in
Oncology, Rare Diseases and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over
100 countries, and its innovative medicines are used by millions of
patients worldwide. For more information, please visit
www.astrazeneca-us.com and follow us on social media
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References
- Referenced with permission from the NCCN Guidelines. © National
Comprehensive Cancer Network 2024. All rights reserved. Accessed
March 2024. To view the most recent and complete version of the
guidelines, go online to NCCN.org. NCCN makes no warranties of any
kind whatsoever regarding their content, use or application and
disclaims any responsibility for their application or use in any
way.
- ASCO. Breast Cancer. Available at:
https://www.cancer.net/sites/cancer.net/files/asco_answers_guide_breast.pdf.
Accessed April 2024.
- Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2)
in Cancers: Overexpression and Therapeutic Implications. Mol Biol
Int. 2014; 852748.
- Omar N, et al. HER2-an emerging biomarker in non-breast and
non-gastric cancers. Pathogenesis. 2015;2(3):1-9.
- Pillai R, et al. HER2 mutations in lung adenocarcinomas: A
report from the Lung Cancer Mutation Consortium. Cancer.
2017;1;123(21): 4099-4105.
- National Cancer Institute. Enhertu Marks First Targeted Therapy
for HER2-Mutant Lung Cancer. Available at:
https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-lung-cancer-enhertu-her2.
Accessed April 2024.
- Siena S, et al. Targeting the Human Epidermal Growth Factor
Receptor 2 (HER2) Oncogene in Colorectal Cancer. Ann Oncol. 2018
May; 29(5):1108-1119.
- Yan M, et al. HER2 expression status in diverse cancers: review
of results from 37,992 patients. Cancer Metastasis Rev. 2015
Mar;34(1):157-64.
- Buza N, et al. Toward standard HER2 testing of endometrial
serous carcinoma: 4-year experience at a large academic center and
recommendations for clinical practice. Modern Pathology. 2013
Dec;26(12):1605-12.
- Zinner R, et al. Trastuzumab in combination with cisplatin and
gemcitabine in patients with Her2-overexpressing, untreated,
advanced non-small cell lung cancer: report of a phase II trial and
findings regarding optimal identification of patients with
Her2-overexpressing disease. Lung Cancer. 2004;
Apr;44(1):99-110.
- Cecchi F, et al. The HORIZON III retrospective exploratory
analysis: HER2 expression amplification in colorectal cancer. J
Clin Oncol. 2023;Jan;41(4).
- Valtora E, et al. Assessment of a HER2 scoring system for
colorectal cancer: results from a validation study. Mod Pathol.
2015 Nov;28(11):1481-91.
ENHERTU® is a registered trademark of Daiichi Sankyo Company,
Limited ©2024 Daiichi Sankyo, Inc. and AstraZeneca. PP-US-EN-2483
04/24
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