If approved, AstraZeneca and Daiichi
Sankyo’s ENHERTU will potentially be the first HER2-directed
treatment and antibody drug conjugate to receive a tumor-agnostic
indication
Application based on results from
DESTINY-PanTumor02 trial and supported by additional ENHERTU
data
Submission to be reviewed under FDA
Real-Time Oncology Review and Project Orbis
AstraZeneca and Daiichi Sankyo's supplemental Biologics License
Application (sBLA) for ENHERTU® (fam-trastuzumab deruxtecan-nxki)
has been accepted and granted Priority Review in the US for the
treatment of adult patients with unresectable or metastatic
HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have
received prior treatment or who have no satisfactory alternative
treatment options.
The sBLA is based on data from the ongoing DESTINY-PanTumor02
Phase II trial where ENHERTU demonstrated clinically meaningful and
durable responses leading to a clinically meaningful survival
benefit in previously treated patients across HER2-expressing
metastatic solid tumors, including biliary tract, bladder,
cervical, endometrial, ovarian cancers, and other tumors. Data from
other supporting trials in patients with HER2-positive IHC3+ tumors
in the ENHERTU clinical development program, including
DESTINY-Lung01 and DESTINY-CRC02, were also included in the
submission.
ENHERTU is a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialized by
AstraZeneca and Daiichi Sankyo.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that, if approved, would offer
significant improvements over available options by demonstrating
safety or efficacy improvements, preventing serious conditions or
enhancing patient compliance.1 The Prescription Drug User Fee Act
date, the FDA action date for their regulatory decision, is during
the second quarter of 2024.
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “Today’s Priority Review for the first
tumor-agnostic submission for ENHERTU reflects the potential of
this medicine to redefine the treatment of HER2-expressing cancers.
Biomarkers for HER2 expression are already established in breast
and gastric cancers, but we must now define them across tumor
types. We will continue working closely with the FDA to bring this
potential first tumor-agnostic HER2-targeted medicine and biomarker
to patients as quickly as possible.”
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said:
“The clinical benefit seen across HER2-expressing metastatic solid
tumors in the DESTINY-PanTumor02 trial and ongoing data from the
ENHERTU clinical development program continues to demonstrate the
potential of this medicine beyond its approved indications. If
approved, ENHERTU could become the first HER2-directed therapy and
antibody drug conjugate with a tumor-agnostic indication, providing
patients with a potential new treatment option.”
The sBLA is being reviewed under the Real-Time Oncology Review
(RTOR) program and Project Orbis, two initiatives of the FDA which
are designed to bring safe and effective cancer treatments to
patients as early as possible. RTOR allows the FDA to review
components of an application before submission of the complete
application. Project Orbis provides a framework for concurrent
submission and review of oncology medicines among participating
international partners.
Results from DESTINY-PanTumor02 were presented at the 2023
European Society for Medical Oncology Congress and simultaneously
published in the Journal of Clinical Oncology.2
The safety profile observed across the trials was consistent
with previous clinical trials of ENHERTU with no new safety
concerns identified.
The Priority Review follows receipt of Breakthrough Therapy
Designation (BTD) in the US in August 2023 for ENHERTU in
metastatic HER2-positive solid tumors.
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 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 gastric or
gastroesophageal junction adenocarcinoma who have received a prior
trastuzumab-based regimen
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.
Metastatic Breast Cancer and HER2-Mutant
NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC
treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients.
Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of
patients treated with ENHERTU. Median time to first onset was 5
months (range: 0.9 to 23).
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.
Metastatic Breast Cancer and HER2-Mutant
NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC
treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was
reported in 65% of patients. Sixteen percent had Grade 3 or 4
decreased neutrophil count. Median time to first onset of decreased
neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia
was reported in 1.1% of patients.
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.
Metastatic Breast Cancer and HER2-Mutant
NSCLC (5.4 mg/kg)
In patients with metastatic breast cancer and HER2-mutant NSCLC
treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.6%
of patients, of which 0.4% were Grade 3.
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
Metastatic Breast Cancer and HER2-Mutant
NSCLC (5.4 mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4
mg/kg intravenously every 3 weeks in 984 patients in Study
DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03,
DESTINY-Breast04, and DESTINY-Lung02. Among these patients 65% 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 nausea (76%),
decreased white blood cell count (71%), decreased hemoglobin (66%),
decreased neutrophil count (65%), decreased lymphocyte count (55%),
fatigue (54%), decreased platelet count (47%), increased aspartate
aminotransferase (48%), vomiting (44%), increased alanine
aminotransferase (42%), alopecia (39%), increased blood alkaline
phosphatase (39%), constipation (34%), musculoskeletal pain (32%),
decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and
respiratory infection (24%).
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 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%),
hypokalemia (35%), constipation (34%), musculoskeletal pain (31%),
diarrhea (29%), decreased appetite (29%), respiratory infection
(22%), headache (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 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 hypokalemia
(25%).
Unresectable or Metastatic HER2-Mutant
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
unresectable or metastatic HER2-mutant NSCLC who received ENHERTU
5.4 mg/kg intravenously every three weeks 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, hypokalemia, 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%).
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 hypokalemia. 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%), hypokalemia (30%), vomiting (26%), constipation
(24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia
(22%).
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 883 patients with breast cancer
treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.6% 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 (60%) as compared to
younger patients (48%). Of the 101 patients with unresectable or
metastatic HER2-mutant 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 locally
advanced or metastatic HER2-positive 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.
- 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.
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
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.3,4 In some cancers,
HER2 expression is amplified or the cells have activating
mutations.3,5 HER2 protein overexpression may occur as a result of
HER2 gene amplification and is often associated with aggressive
disease and poor prognosis.6
While HER2-directed therapies have been used to treat breast,
gastric, lung and colorectal cancers, more research is needed
evaluating their potential role in treating other HER2-expressing
solid tumor types.4,7,8
HER2 is an emerging biomarker in solid tumor types including
biliary tract, bladder, cervical, endometrial, ovarian and
pancreatic cancers.5 Testing is not routinely performed in these
additional tumor types and as a result, available literature is
limited. In these solid tumors, HER2-positive expression,
classified as IHC 3+, has been observed at rates from 1% to
28%.9,10 There is an unmet need for effective therapies for certain
HER2-expressing solid tumors, particularly for those who have
progressed on or are refractory to standard of care therapies as
there are currently no approved HER2-directed therapies for these
cancers.4,11
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
objective response rate (ORR) as assessed by investigator.
Secondary endpoints include duration of response (DoR), disease
control rate (DCR), progression-free survival (PFS), overall
survival (OS), safety, tolerability and pharmacokinetics.
DESTINY-PanTumor02 has enrolled 267 patients at multiple sites
in Asia, Europe and North America. 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 non-small cell lung
cancer (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 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, or RAS wild-type and 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 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 55 countries for the
treatment of adult patients with unresectable or metastatic
HER2-positive 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 45 countries for the
treatment of adult patients with unresectable or metastatic
HER2-low (IHC 1+ or IHC 2+/in-situ hybridization [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 30 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 30 countries for the
treatment of adult patients with locally advanced or metastatic
HER2-positive 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 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.
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. Please visit
www.astrazeneca-us.com and follow the Company on Social Media
@AstraZeneca.
References
- FDA. Priority Review. Available at:
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review.
Accessed January 2024.
- Meric-Bernstam F, et al. Efficacy and Safety of Trastuzumab
Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary
Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol.
2023 Oct;42:47-58.
- ASCO. Breast Cancer. Available at:
https://www.cancer.net/sites/cancer.net/files/asco_answers_guide_breast.pdf.
Accessed January 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 January 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.
- Meric-Bernstam F, et al. Pertuzumab plus trastuzumab for
HER2-amplified metastatic colorectal cancer (MyPathway): an updated
report from a multicentere, open-label, phase 2a, multiple basket
study. Lancet Oncol. 2019 Apr;20(4):518-530.
US-84753 Last Updated 01/24
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Brendan McEvoy, +1 302 885 2677 Jillian Gonzales, +1 302 885
2677
US Media Mailbox: usmediateam@astrazeneca.com
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