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ENHERTU
® (
fam-trastuzumab deruxtecan-nxki
) approved in the US as first
tumor
-agnostic
HER2-directed
therapy for previously treated patients with metastatic
HER2-positive solid tumors
2024-04-06
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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
HER2-expressing
(IHC 3+) metastatic cancers WILMINGTON, Del.--(BUSINESS WIRE)--
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 pro 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-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-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-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-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
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
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
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 and follow us on social media @AstraZeneca. 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: . 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: . 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 View source version on businesswire.com: Contacts Media Inquiries Brendan McEvoy, +1 302 885 2677 Jillian Gonzales, +1 302 885 2677 US Media Mailbox: usmediateam@astrazeneca.com Source: AstraZeneca View this news release online at:
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机构
AstraZeneca PLC
Daiichi Sankyo Co., Ltd.
US Food & Drug Administration
[+2]
适应症
肿瘤
HER2阳性实体瘤
HER2表达癌症
[+79]
靶点
HER2
Alkaline phosphatase
转氨酶
[+6]
药物
德曲妥珠单抗
Second Generation Her2-Directed Antibody-Drug Conjugates(Genentech)
Topoisomerase inhibitor (Idorsia)
[+13]
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