AstraZeneca and Daiichi Sankyo’s ENHERTU
also improved median overall survival by more than 6 months vs.
chemotherapy in all patients evaluated in DESTINY-Breast04
ENHERTU met the primary endpoint of
progression-free survival in patients with HR-positive disease,
reducing the risk of disease progression or death by 49% vs.
chemotherapy
ENHERTU is the first HER2-directed therapy
to demonstrate a survival benefit in this population, potentially
redefining treatment for approximately half of all patients with
breast cancer
Detailed positive results from the pivotal DESTINY-Breast04
Phase III trial showed that ENHERTU® (fam-trastuzumab
deruxtecan-nxki) demonstrated superior and clinically meaningful
progression-free survival (PFS) and overall survival (OS) in
previously treated patients with HER2-low (immunohistochemistry
(IHC) 1+ or IHC 2+/in-situ hybridization (ISH)-negative)
unresectable and/or metastatic breast cancer with hormone receptor
(HR) positive or HR-negative disease versus standard of care
physician’s choice of chemotherapy. Results will be presented
during the Plenary Session today at the 2022 American Society of
Clinical Oncology (ASCO) Annual Meeting, and have been
simultaneously published in The New England Journal of
Medicine.
ENHERTU is a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialized by
AstraZeneca and Daiichi Sankyo.
In the primary endpoint analysis for DESTINY-Breast04, ENHERTU
demonstrated a 49% reduction in the risk of disease progression or
death versus physician’s choice of chemotherapy in patients with
HER2-low metastatic breast cancer with HR-positive disease (PFS
hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.40-0.64;
p<0.001). A median PFS of 10.1 months was seen in patients
treated with ENHERTU compared to 5.4 months with chemotherapy, as
assessed by blinded independent central review (BICR).
Results also showed a 36% reduction in the risk of death with
ENHERTU compared to chemotherapy in patients with HR-positive
disease (OS HR 0.64; 95% CI: 0.48-0.86; p=0.003) with a median OS
of 23.9 months with ENHERTU versus 17.5 months with chemotherapy,
meeting a key secondary endpoint of the trial.
Additionally, data showed consistent efficacy for ENHERTU in the
overall trial population of patients with HER2-low metastatic
breast cancer with HR-positive or HR-negative disease and across
levels of HER2 expression (IHC 1+ and IHC 2+/ISH-). In the key
secondary endpoint analysis of PFS by BICR in all patients, a
similar 50% reduction in the risk of disease progression or death
was observed between ENHERTU and chemotherapy (PFS HR 0.50; 95%
CI:0.40-0.63; p<0.001). Results also showed a 36% reduction in
the risk of death with ENHERTU compared to chemotherapy (OS HR
0.64; 95% CI: 0.49-0.84; p=0.001) with a median OS of 23.4 months
for ENHERTU versus 16.8 months with chemotherapy.
Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering
Cancer Center, US and Principal Investigator for the trial, said:
“The results of DESTINY-Breast04 show for the first time that a
HER2-directed therapy can provide a survival benefit to patients
with low HER2 expression, indicating we must reconsider the way we
categorize patients with metastatic breast cancer. The efficacy
seen with ENHERTU also reinforces the potential to establish a new
standard of care for more than half of all patients with breast
cancer currently categorized as having HER2-negative disease, but
who actually have tumors with low HER2 expression.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca said: “Today’s results represent a pivotal moment
demonstrating the potential for ENHERTU to redefine the treatment
of HER2-targetable cancers. DESTINY-Breast04 validates targeting
the lower end of the spectrum of HER2 expression, since ENHERTU
reduced the risk of disease progression or death across all types
of patients in the trial by half, and reduced the risk of death by
over a third. We must now evolve the way we classify and treat
metastatic breast cancer to ensure these patients are effectively
diagnosed and treated.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: “As
innovative research organizations, extending the survival for
patients is one of our primary goals as we seek to identify
potentially new treatment options for patients with metastatic
breast cancer. These potentially practice-changing data show that
DESTINY-Breast04 takes us one step closer to achieving this goal,
as ENHERTU is the first HER2-directed medicine to demonstrate a
survival benefit in patients with HER2-low metastatic breast
cancer. We are honored by the recognition these important findings
are receiving at one of the world’s most prominent oncology
meetings as well as in one of the leading medical journals.”
Summary of results: DESTINY-Breast04
Efficacy Measure
HR-Positive (n=494)i
All Patients (n=557)
HR-Negative (n=58)i
ENHERTU
(5.4 mg/kg)
(n=331)
Chemotherapy
(n=163)
ENHERTU
(5.4 mg/kg)
(n=373)
Chemotherapy
(n=184)
ENHERTU
(5.4 mg/kg)
(n=40)
Chemotherapy
(n=18)
PFS
Median PFS (months)ii
10.1
(9.5-11.5)
5.4
(4.4-7.1)
9.9
(9.0-11.3)
5.1
(4.2-6.8)
8.5
(4.3-11.7)
2.9
(1.4-5.1)
Hazard Ratio (95% CI)
0.51 (0.40-0.64)
0.50 (0.40-0.63)
0.46 (0.24-0.89)
p-value
p<0.001
p<0.001
OS
Median OS (months)
23.9
(20.8-24.8)
17.5
(15.2-22.4)
23.4
(20.0-24.8)
16.8
(14.5-20.0)
18.2
(13.6-NE)
8.3
(5.6-20.6)
Hazard Ratio (95% CI)
HR 0.64 (0.48-0.86)
HR 0.64 (0.49-0.84)
HR 0.48 (0.24-0.95)
p-value
p=0.003
p=0.001
Confirmed ORR (%) (95% CI)ii,iii
52.6%
(47.0-58.0)
16.3%
(11.0-22.8)
52.3%
(47.1-57.4)
16.3%
(11.3-22.5)
50.0%
(33.8-66.2)
16.7%
(3.6-41.4)
Complete Response (%)
3.6%
0.6%
3.5%
1.1%
2.5%
5.6%
Partial Response (%)
49.2%
15.7%
49.1%
15.2%
47.5%
11.1%
Stable Disease (%)
35.1%
50.0%
34.6%
49.5%
30.0%
44.4%
Progressive Disease (%) (95% CI)
7.8%
21.1%
8.3%
22.3%
12.5%
33.3%
Median DoR (months)ii
10.7
6.8
10.7
6.8
8.6
4.9
CBR (%)ii, iv
71.2%
34.3%
70.2%
33.7%
62.5%
27.8%
DCR (%)iv,v
88.0%
66.3%
87.1%
65.8%
80.0%
61.1%
CI, confidence interval; CBR, clinical
benefit rate; DCR, disease control rate; DoR, Duration of Response;
HR, hazard ratio; NE, not evaluable; ORR, overall response rate;
OS, overall survival; PFS, progression-free survival
i For the primary end point (PFS in the
HR-positive cohort) and key secondary end points (PFS among all
patients and OS in the HR-positive cohort and among all patients),
the HR status is based on data collected with the use of the
interactive Web-response and voice-response system at the time of
randomization, which includes patients who were mis-stratified. For
the other end points, HR status is based on data from the
electronic data capture that was corrected for
mis-stratification
ii As assessed by BICR
iii ORR is (Complete Response + Partial
Response)
iv CBR is Complete Response + Partial
Response + Stable Disease (≥ 6 months)
v DCR is (Complete Response + Partial
Response + Stable Disease)
In an exploratory analysis of patients with HR-negative disease
(n=58), median PFS was 8.5 months with ENHERTU versus 2.9 months
with chemotherapy (PFS HR 0.46; 95% CI: 0.24-0.89) and median OS
was 18.2 months with ENHERTU versus 8.3 months with chemotherapy
(OS HR 0.48; 95% CI: 0.24-0.95).
The safety profile of ENHERTU was consistent with previous
clinical trials with no new safety concerns identified. The most
common Grade 3 or higher treatment-emergent adverse events were
neutropenia (13.7%), anaemia (8.1%), fatigue (7.5%), leukopenia
(6.5%), thrombocytopenia (5.1%), and nausea (4.6%).
Interstitial lung disease (ILD) or pneumonitis rates were
consistent with that observed in late-line HER2-positive breast
cancer trials of ENHERTU with a lower rate of Grade 5 ILD observed,
as determined by an independent adjudication committee. The
majority (10%) were primarily low Grade (Grade 1 or 2) with five
Grade 3 (1.3%), no Grade 4 and three Grade 5 (0.8%) events
reported.
U.S. Important Safety Information for ENHERTU
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
- 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. 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
In clinical studies, of the 491 patients with unresectable or
metastatic HER2-positive breast cancer treated with ENHERTU 5.4
mg/kg, ILD occurred in 13% of patients. Fatal outcomes due to ILD
and/or pneumonitis occurred in 1.4% of patients treated with
ENHERTU. Median time to first onset was 5.5 months (range: 1.1 to
20.8).
Locally Advanced or Metastatic Gastric
Cancer
In DESTINY-Gastric01, of the 125 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 21.0).
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. Reduce
dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and
temperature >38.3ºC or a sustained temperature of ≥38ºC for more
than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one
level.
Metastatic Breast Cancer
In clinical studies, of the 491 patients with unresectable or
metastatic HER2-positive breast cancer who received ENHERTU 5.4
mg/kg, a decrease in neutrophil count was reported in 68% of
patients. Eighteen percent had Grade 3 or 4 decrease in neutrophil
count. Median time to first onset of decreased neutrophil count was
22 days (range: 6 to 664). Febrile neutropenia was reported in 1.2%
of patients.
Locally Advanced or Metastatic Gastric
Cancer
In DESTINY-Gastric01, of the 125 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
In the 491 patients with unresectable or metastatic
HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, 13
cases (2.6%) of asymptomatic LVEF decrease were reported.
Locally Advanced or Metastatic Gastric
Cancer
In DESTINY-Gastric01, of the 125 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 at least 7
months following the last dose of ENHERTU. Advise male patients
with female partners of reproductive potential to use effective
contraception during treatment with ENHERTU and for at least 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. Reduce dose by
one level.
Adverse Reactions
Metastatic Breast Cancer
The pooled safety population for patients with metastatic breast
cancer reflects exposure to ENHERTU at 5.4 mg/kg given as an
intravenous infusion once every 3 weeks (21-day cycle) in 491
patients in DESTINY-Breast03, DESTINY-Breast01, and Study
DS8201-A-J101. The median duration of treatment was 13 months
(range: 0.7 to 37). In this pooled safety population, the most
common (≥20%) adverse reactions, including laboratory
abnormalities, were nausea (78%), decreased white blood cell count
(74%), decreased hemoglobin (68%), decreased neutrophil count
(68%), increased aspartate aminotransferase (58%), fatigue (57%),
decreased lymphocyte count (56%), vomiting (50%), decreased
platelet count (49%), increased alanine aminotransferase (48%),
increased blood alkaline phosphatase (45%), alopecia (41%),
constipation (35%), hypokalemia (33%), decreased appetite (32%),
diarrhea (31%), musculoskeletal pain (28%), increased transaminases
(27%), respiratory infection (24%), headache (21%), and abdominal
pain (21%).
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 in DESTINY-Breast03. ENHERTU
was administered by intravenous infusion once every three weeks.
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%).
Locally Advanced or Metastatic Gastric
Cancer
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 once every three 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) in the ENHERTU group and 2.8 months
(range: 0.5 to 13.1) in the irinotecan/paclitaxel group.
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 following 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 at least 7
months following the last dose. Males: Advise male patients with
female partners of reproductive potential to use effective
contraception during treatment with ENHERTU and for at least 4
months following 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 491 patients with HER2-positive
breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years
and 4% 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 (49%). 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 or severe renal
impairment.
- Hepatic Impairment: In patients with moderate hepatic
impairment, due to potentially increased exposure, closely monitor
for increased toxicities related to the topoisomerase
inhibitor.
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
Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the
leading causes of cancer-related deaths worldwide.1 More than two
million cases of breast cancer were diagnosed in 2020 with nearly
685,000 deaths globally.1
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors including breast,
gastric, lung and colorectal cancers, and is one of many biomarkers
expressed in breast cancer tumors.2 HER2 expression is currently
defined as either positive or negative, and is determined by an IHC
test which measures the amount of HER2 protein on a cancer cell,
and/or an ISH test which counts the copies of the HER2 gene in
cancer cells.2,3 HER2-positive cancers are defined as IHC 3+ or IHC
2+/ISH+, and HER2-negative cancers are currently defined as IHC 0,
IHC 1+ or IHC 2+/ISH-.2
Approximately half of all patients with breast cancer have
tumors with a HER2 IHC score of 1+, or 2+ in combination with a
negative ISH test, a level of HER2 expression not currently
eligible for HER2-targeted therapy.4-7 Low HER2 expression occurs
in both HR-positive and HR-negative disease.8
HER2 testing is routinely used to determine appropriate
treatment options for patients with metastatic breast cancer.
Targeting the lower range of expression in the HER2 spectrum may
offer another approach to delay disease progression and extend
survival in patients with metastatic breast cancer.9 Currently,
patients with low HER2 expression with HR-positive tumors have
limited treatment options following progression on endocrine
(hormone) therapy.10 Few targeted options are available for those
who are HR-negative.11
DESTINY-Breast04
DESTINY-Breast04 is a global, randomized, open-label,
registrational Phase III trial evaluating the efficacy and safety
of ENHERTU (5.4mg/kg) versus physician’s choice of chemotherapy
(capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel)
in patients with HR-positive or HR-negative HER2-low unresectable
and/or metastatic breast cancer previously treated with one or two
prior lines of chemotherapy. Patients were randomized 2:1 to
receive either ENHERTU or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with
HR-positive disease based on blinded independent central review
(BICR). Key secondary endpoints include PFS based on BICR in all
randomized patients (HR-positive and HR-negative disease), OS in
patients with HR-positive disease and OS in all randomized patients
(HR-positive and HR-negative disease). Other secondary endpoints
include PFS based on investigator assessment, objective response
rate based on BICR and on investigator assessment, duration of
response based on BICR and safety.
DESTINY-Breast04 enrolled approximately 557 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 topoisomerase I inhibitor
payload, an exatecan derivative, via a stable tetrapeptide-based
cleavable linker.
ENHERTU (5.4mg/kg) is approved in the US and Israel 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, based
on results from the DESTINY-Breast03 trial.
ENHERTU (5.4mg/kg) is also approved in approximately 40
countries for the treatment of adult patients with unresectable or
metastatic HER2-positive breast cancer who have received two or
more prior anti-HER2-based regimens based on the results from the
DESTINY-Breast01 trial.
ENHERTU (6.4mg/kg) is approved in several 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.
ENHERTU development program
A comprehensive development program is underway globally,
evaluating the efficacy and safety of ENHERTU monotherapy across
multiple HER2-targetable cancers, including breast, gastric, lung
and colorectal cancers. Trials in combination with other anticancer
treatments, such as immunotherapy, are also underway.
Regulatory applications for ENHERTU are currently under review
in China, Europe, Japan and several other countries for the
treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer who have received a prior anti-HER2
based regimen based on the results from the DESTINY-Breast03
trial.
ENHERTU was granted Breakthrough Therapy Designation in the US
for the treatment of adult patients with unresectable or metastatic
HER2-low (IHC 1+ or IHC 2+/ISH-negative) 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 of the
DESTINY-Breast04 trial. Patients with hormone receptor (HR)
positive breast cancer should additionally have received or be
ineligible for endocrine therapy.
ENHERTU is also currently under review in the US for the
treatment of adult patients with unresectable or metastatic
non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2)
mutation and who have received a prior systemic therapy, based on
the DESTINY-Lung01 trial, and in Europe for the treatment of adult
patients with locally advanced or metastatic HER2-positive gastric
or GEJ adenocarcinoma who have received a prior anti-HER2-based
regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02
trials.
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 breast cancer
Driven by a growing understanding of breast cancer biology,
AstraZeneca is starting to challenge, and redefine, the current
clinical paradigm for how breast cancer is classified and treated
to deliver even more effective treatments to patients in need –
with the bold ambition to one day eliminate breast cancer as a
cause of death.
AstraZeneca has a comprehensive portfolio of approved and
promising compounds in development that leverage different
mechanisms of action to address the biologically diverse breast
cancer tumor environment.
AstraZeneca aims to continue to transform outcomes for
HR-positive breast cancer with foundational medicines fulvestrant
and goserelin and the next-generation oral selective oestrogen
receptor degrader (SERD) and potential new medicine
camizestrant.
PARP inhibitor olaparib is a targeted treatment option that has
been studied in HER2-negative early and metastatic breast cancer
patients with an inherited BRCA mutation. AstraZeneca with MSD
(Merck & Co., Inc. in the US and Canada) continue to research
olaparib in metastatic breast cancer patients with an inherited
BRCA mutation and are exploring new opportunities to treat these
patients earlier in their disease.
Building on the initial approvals of ENHERTU, a HER2-directed
ADC, in previously treated HER2-positive metastatic breast cancer,
AstraZeneca and Daiichi Sankyo are exploring its potential in
earlier lines of treatment and in new breast cancer settings.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is testing immunotherapy durvalumab in combination with
other oncology medicines, including olaparib and ENHERTU,
evaluating the potential of AKT kinase inhibitor, capivasertib, in
combination with chemotherapy, and collaborating with Daiichi
Sankyo to explore the potential of TROP2-directed ADC, 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 (LSE/STO/Nasdaq: AZN) 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 Twitter @AstraZenecaUS.
References
1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN
Estimates of Incidence and Mortality Worldwide for 36 Cancers in
185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660. 2. Iqbal
N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in
Cancers: Overexpression and Therapeutic Implications. Mol Biol Int.
2014;852748. 3. Wolff A, et al. Human Epidermal Growth Factor
Receptor 2 Testing in Breast Cancer: American Society of Clinical
Oncology/College of American Pathologists Clinical Practice
Guideline Focused Update. Arch Pathol Lab Med. 2018; 142 (11):
1364-1382. 4. Ahn S, et al. HER2 status in breast cancer: changes
in guidelines and complicating factors for interpretation. J Pathol
Transl Med. 2020; 54(1): 34-44. 5. Schalper K, et al. A
retrospective population-based comparison of HER2
immunohistochemistry and fluorescence in situ hybridization in
breast carcinomas. Arch Pathol Lab Med. 2014; 138:213-219. 6.
Schettini F, et al. Clinical, pathological, and PAM50 gene
expression features of HER2-low breast cancer. npj Breast Cancer.
2021; 7:1 ; https://doi.org/10.1038/s41523-020-00208-2. 7. Denkert
C, et al. Clinical and molecular characteristics of
HER2-low-positive breast cancer: pooled analysis of individual
patient data from four prospective, neoadjuvant clinical trials.
2021. Lancet Oncol; 22: 1151–61. 8. Miglietta F, et al. Evolution
of HER2-low expression from primary to recurrent breast cancer. NPJ
Breast Cancer. 2021; 7:137; 10.1038/s41523-021-00343-4. 9. Eiger D,
et al. The Exciting New Field of HER2-Low Breast Cancer Treatment.
Cancers. 2021; 10.3390/cancers13051015. 10. Matutino A, et al.
Hormone receptor–positive, HER2-negative metastatic breast cancer:
redrawing the lines. Current Oncology. 2018; 25(S1):S131-S141. 11.
American Cancer Society. Breast Cancer Hormone Receptor Status.
Available at:
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html.
Accessed June 2022.
Dr. Modi has financial interests related to AstraZeneca and
Daiichi Sankyo.
US- 65340 Last Updated 06/22
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