DESTINY-Breast06 results show AstraZeneca
and Daiichi Sankyo’s ENHERTU is the first HER2-directed medicine
and ADC to demonstrate clinically meaningful benefit for patients
in this setting
Additionally, data from DESTINY-Breast03 and
DESTINY-Breast07 trials in HER2-positive metastatic breast cancer
reinforce ENHERTU as standard of care in 2nd-line setting and
highlight potential in 1st-line setting
Detailed positive results from the DESTINY-Breast06 Phase III
trial showed that ENHERTU® (fam-trastuzumab deruxtecan-nxki)
demonstrated a statistically significant and clinically meaningful
improvement in progression-free survival (PFS) compared to
standard-of-care chemotherapy in patients with HR-positive,
HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer and the
overall trial population (patients with HR-positive, HER2-low and
HER2-ultralow [defined as IHC 0 with membrane staining] expression)
following one or more lines of endocrine therapy.
These results will be presented today as a late-breaking oral
presentation during the 2024 American Society of Clinical Oncology
(ASCO) Annual Meeting (abstract #LBA1000).
ENHERTU is a specifically engineered HER2-directed DXd antibody
drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly
developed and commercialized by AstraZeneca and Daiichi Sankyo.
In the primary analysis of DESTINY-Breast06, results showed
ENHERTU reduced the risk of disease progression or death by 38% by
blinded independent central review (BICR) versus chemotherapy in
patients with HER2-low expression (hazard ratio [HR] 0.62; 95%
confidence interval [CI]: 0.51-0.74; p<0.0001). Median PFS was
13.2 months in the ENHERTU arm compared to 8.1 months for
chemotherapy.
PFS results by BICR in the overall trial population were similar
and showed ENHERTU achieved a 37% reduction in the risk of disease
progression or death compared to chemotherapy, with a median PFS of
13.2 months with ENHERTU versus 8.1 months for chemotherapy (HR
0.63; 95% CI: 0.53-0.75; p<0.0001).
A prespecified exploratory analysis showed the clinically
meaningful improvement in PFS was consistent between patients with
HER2-low and HER2-ultralow expression. In patients with
HER2-ultralow expression, ENHERTU reduced the risk of disease
progression or death by 22% compared to chemotherapy with a median
PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95%
CI: 0.50-1.21).
Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at
the University of Milan and Head of the Division of Early Drug
Development at the European Institute of Oncology, IRCCS, Italy and
principal investigator for the trial, said: “Endocrine therapies
are widely used early in the treatment of HR-positive metastatic
breast cancer, but following one or more lines of treatment,
patients often derive limited efficacy from further endocrine-based
therapy. With a median progression-free survival of more than a
year, the results from DESTINY-Breast06 show that ENHERTU could
become a new standard of care for patients with HER2-low- and
HER2-ultralow-expressing tumors following endocrine therapy in the
metastatic setting.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “DESTINY-Breast06 represents another potential
paradigm shift in how we treat patients across the spectrum of
HR-positive metastatic breast cancer. The results reinforce the
potential for ENHERTU to improve outcomes earlier in the treatment
landscape and in a broader population of patients with
HER2-expressing breast cancer who have never before been eligible
for a HER2-directed therapy.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said:
“ENHERTU continues to deliver pioneering results for a
HER2-directed medicine across many different types of cancer. These
latest results from DESTINY-Breast06 demonstrate clinically
meaningful results with ENHERTU even in tumors with very low levels
of HER2 expression, suggesting that it may have an important role
in treating a wide range of HER2-expressing metastatic breast
cancer.”
In patients with HER2-low expression, confirmed objective
response rate (ORR) was 56.5% for ENHERTU versus 32.2% with
chemotherapy. In the overall trial population, confirmed ORR was
57.3% for ENHERTU versus 31.2% with chemotherapy and in patients
with HER2-ultralow expression the confirmed ORR was 61.8% versus
26.3%, respectively. Complete responses were seen in 13 patients
from the ENHERTU arm, including nine patients with HER2-low
expression. In the HER2-ultralow subgroup, four patients in the
ENHERTU arm had complete responses. No complete responses were seen
in the chemotherapy arm.
Summary of results: DESTINY-Breast06
HER2-low (IHC 1+ or IHC
2+/ISH-)i
Overall trial population
(HER2-low and HER2-ultralow)
HER2-ultralow (defined as IHC
0 with membrane staining)i
ENHERTU
(n=359)
Chemo
(n=354)
ENHERTU
(n=436)
Chemo
(n=430)
ENHERTU
(n=76)
Chemo
(n=76)
PFSii
Median PFS in months
13.2
8.1
13.2
8.1
13.2
8.3
HR (95% CI)
0.62 (0.51-0.74)
0.63 (0.53-0.75)
0.78 (0.50-1.21)
p-value
p<0.0001
p<0.0001
---
OSiii
HR (95% CI)
0.83 (0.66-1.05)
0.81 (0.65-1.00)
0.75 (0.43-1.29)
p-value
p=0.1181iv
Not testedv
---
12-month OS rate (%)
87.6
81.7
87.0
81.1
84.0
78.7
ORRii,vi
Confirmed ORR (%) (n)vii
56.5
(203)
32.2
(114)
57.3
(250)
31.2
(134)
61.8
(47)
26.3
(20)
CR (%) (n)
2.5 (9)
0
3.0 (13)
0
5.3 (4)
0
PR (%) (n)
54.0 (194)
32.2 (114)
54.4 (237)
31.2 (134)
56.6 (43)
26.3 (20)
SD (%) (n)
34.8 (125)
48.0 (170)
33.9 (148)
49.3 (212)
28.9 (22)
55.3 (42)
Median DOR in months
14.1
8.6
14.3
8.6
14.3
14.1
PFS, progression-free survival; HR, hazard
ratio; CI, confidence interval; OS, overall survival; ORR,
objective response rate; CR, complete response; PR, partial
response; SD, stable disease; DOR, duration of response i HER2-low
status determined per IRT data, and HER2-ultralow status determined
per central laboratory data ii As assessed by BICR iii Less than
40% maturity for interim OS analysis iv P-value of <0.0046
required for statistical significance v No test of significance was
performed in line with the multiple testing procedure vi ORR is (CR
+ PR); ORR based on RECIST v1.1 vii Response required confirmation
after 4 weeks
Patients in the trial received a median of two prior lines of
endocrine therapy in each treatment arm. In the overall trial
population, 14.9% of patients (n=65) in the ENHERTU arm and 19.2%
of patients (n=82) in the chemotherapy arm had received one prior
line of endocrine therapy. No patients in the trial had received
prior chemotherapy treatment in the metastatic setting. Median
duration of follow-up was 18.2 months. As of the data cut-off of
March 18, 2024, a total of 119 patients (14%) remained on
treatment, 89 patients receiving ENHERTU and 30 receiving
chemotherapy.
The safety profile of ENHERTU was consistent with previous
breast cancer clinical trials with no new safety concerns
identified. The most common Grade 3 or higher treatment-related
treatment-emergent adverse events occurring in 5% or more of
patients treated with ENHERTU were neutropenia (20.7%), leukopenia
(6.9%) and anemia (5.8%). Interstitial lung disease
(ILD)/pneumonitis, adjudicated as drug-related by an independent
committee, occurred in 11.3% of patients treated with ENHERTU. The
majority of ILD events were low Grade (Grade 1 [n=7; 1.6%]; Grade 2
[n=36; 8.3%]). There were three Grade 3 ILD events (0.7%), no Grade
4 events and three Grade 5 events (0.7%).
Additional ENHERTU data at
ASCO
DESTINY-Breast03 updated results Updated overall survival
(OS) results from the DESTINY-Breast03 Phase III trial showed
ENHERTU continued to demonstrate a clinically meaningful survival
improvement over trastuzumab emtansine (T-DM1) after more than
three years of follow up in patients with HER2-positive
unresectable and/or metastatic breast cancer previously treated
with trastuzumab.
Results showed median OS was 52.6 months in the ENHERTU arm
compared to 42.7 months for T-DM1 (HR 0.73; 95% CI: 0.56-0.94).
The safety profile of ENHERTU continues to be generally
manageable and no cumulative toxicities were observed with longer
follow-up. Results will be presented during the 2024 ASCO Annual
Meeting (abstract #1025).
DESTINY-Breast07 results Interim results from the
DESTINY-Breast07 Phase Ib/II trial of ENHERTU alone or in
combination with other anticancer therapies as a 1st-line treatment
for HER2-positive metastatic breast cancer demonstrated promising
clinical activity for ENHERTU as a monotherapy (n=75) and in
combination with pertuzumab (n=50). Results were presented as an
oral presentation at the 2024 ASCO Annual Meeting (abstract
#1009).
Results showed a confirmed ORR of 76.0% with ENHERTU and 84.0%
with ENHERTU in combination with pertuzumab. The 12-month PFS rate
was 80.8% with ENHERTU monotherapy and 89.4% with ENHERTU and
pertuzumab.
The safety of ENHERTU as a monotherapy and in combination with
pertuzumab was consistent with the known safety profiles of each
therapy. ILD/pneumonitis was reported in seven patients (9.3%) in
the ENHERTU monotherapy arm and seven patients (14.0%) in the
combination arm. All ILD events were Grade 3 or lower.
These are the first data presented for ENHERTU as a 1st-line
treatment in HER2-positive metastatic breast cancer. Analyses from
the ongoing DESTINY-Breast09 Phase III trial will provide further
insights regarding the efficacy and safety of ENHERTU in this
HER2-positive patient population.
Important Safety Information
Indications ENHERTU is a HER2-directed antibody and
topoisomerase inhibitor conjugate indicated for the treatment of
adult patients with:
- Unresectable or metastatic HER2-positive (IHC 3+ or ISH
positive) breast cancer who have received a prior anti-HER2-based
regimen either:
- In the metastatic setting, or
- In the neoadjuvant or adjuvant setting and have developed
disease recurrence during or within six months of completing
therapy
- Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-)
breast cancer, as determined by an FDA-approved test, who have
received a prior chemotherapy in the metastatic setting or
developed disease recurrence during or within 6 months of
completing adjuvant chemotherapy
- Unresectable or metastatic non-small cell lung cancer (NSCLC)
whose tumors have activating HER2 (ERBB2) mutations, as detected by
an FDA-approved test, and who have received a prior systemic
therapy This indication is approved under accelerated approval
based on objective response rate and duration of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial.
- Locally advanced or metastatic HER2-positive (IHC 3+ or IHC
2+/ISH positive) gastric or gastroesophageal junction (GEJ)
adenocarcinoma who have received a prior trastuzumab-based
regimen
- Unresectable or metastatic HER2-positive (IHC3+) solid tumors
who have received prior systemic treatment and have no satisfactory
alternative treatment options This indication is approved under
accelerated approval based on objective response rate and duration
of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
a confirmatory trial.
WARNING: INTERSTITIAL LUNG DISEASE and
EMBRYO-FETAL TOXICITY
- Interstitial lung disease (ILD) and pneumonitis, including
fatal cases, have been reported with ENHERTU. Monitor for and
promptly investigate signs and symptoms including cough, dyspnea,
fever, and other new or worsening respiratory symptoms. Permanently
discontinue ENHERTU in all patients with Grade 2 or higher
ILD/pneumonitis. Advise patients of the risk and to immediately
report symptoms.
- Exposure to ENHERTU during pregnancy can cause embryo-fetal
harm. Advise patients of these risks and the need for effective
contraception.
Contraindications None.
Warnings and Precautions Interstitial Lung Disease /
Pneumonitis Severe, life-threatening, or fatal interstitial
lung disease (ILD), including pneumonitis, can occur in patients
treated with ENHERTU. A higher incidence of Grade 1 and 2
ILD/pneumonitis has been observed in patients with moderate renal
impairment. Advise patients to immediately report cough, dyspnea,
fever, and/or any new or worsening respiratory symptoms. Monitor
patients for signs and symptoms of ILD. Promptly investigate
evidence of ILD. Evaluate patients with suspected ILD by
radiographic imaging. Consider consultation with a pulmonologist.
For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until
resolved to Grade 0, then if resolved in ≤28 days from date of
onset, maintain dose. If resolved in >28 days from date of
onset, reduce dose one level. Consider corticosteroid treatment as
soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day
prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade
2 or greater), permanently discontinue ENHERTU. Promptly initiate
systemic corticosteroid treatment as soon as ILD/pneumonitis is
suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and
continue for at least 14 days followed by gradual taper for at
least 4 weeks.
HER2-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg) In patients with metastatic breast cancer,
HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4
mg/kg, ILD occurred in 12% of patients. Median time to first onset
was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD
and/or pneumonitis occurred in 1.0% of patients treated with
ENHERTU.
HER2-Positive Locally Advanced or
Metastatic Gastric Cancer (6.4 mg/kg) In patients with
locally advanced or metastatic HER2-positive gastric or GEJ
adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10%
of patients. Median time to first onset was 2.8 months (range: 1.2
to 21).
Neutropenia Severe neutropenia, including febrile
neutropenia, can occur in patients treated with ENHERTU. Monitor
complete blood counts prior to initiation of ENHERTU and prior to
each dose, and as clinically indicated. For Grade 3 neutropenia
(Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt
ENHERTU until resolved to Grade 2 or less, then maintain dose. For
Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until
resolved to Grade 2 or less, then reduce dose by one level. For
febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º
C or a sustained temperature of ≥38º C for more than 1 hour),
interrupt ENHERTU until resolved, then reduce dose by one
level.
HER2-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg) In patients with metastatic breast cancer,
HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4
mg/kg, a decrease in neutrophil count was reported in 63% of
patients. Seventeen percent had Grade 3 or 4 decreased neutrophil
count. Median time to first onset of decreased neutrophil count was
22 days (range: 2 to 939). Febrile neutropenia was reported in 1%
of patients.
HER2-Positive Locally Advanced or
Metastatic Gastric Cancer (6.4 mg/kg) In patients with
locally advanced or metastatic HER2-positive gastric or GEJ
adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in
neutrophil count was reported in 72% of patients. Fifty-one percent
had Grade 3 or 4 decreased neutrophil count. Median time to first
onset of decreased neutrophil count was 16 days (range: 4 to 187).
Febrile neutropenia was reported in 4.8% of patients.
Left Ventricular Dysfunction Patients treated with
ENHERTU may be at increased risk of developing left ventricular
dysfunction. Left ventricular ejection fraction (LVEF) decrease has
been observed with anti-HER2 therapies, including ENHERTU. Assess
LVEF prior to initiation of ENHERTU and at regular intervals during
treatment as clinically indicated. Manage LVEF decrease through
treatment interruption. When LVEF is >45% and absolute decrease
from baseline is 10-20%, continue treatment with ENHERTU. When LVEF
is 40-45% and absolute decrease from baseline is <10%, continue
treatment with ENHERTU and repeat LVEF assessment within 3 weeks.
When LVEF is 40-45% and absolute decrease from baseline is 10-20%,
interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If
LVEF has not recovered to within 10% from baseline, permanently
discontinue ENHERTU. If LVEF recovers to within 10% from baseline,
resume treatment with ENHERTU at the same dose. When LVEF is
<40% or absolute decrease from baseline is >20%, interrupt
ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of
<40% or absolute decrease from baseline of >20% is confirmed,
permanently discontinue ENHERTU. Permanently discontinue ENHERTU in
patients with symptomatic congestive heart failure. Treatment with
ENHERTU has not been studied in patients with a history of
clinically significant cardiac disease or LVEF <50% prior to
initiation of treatment.
HER2-Positive or HER2-Low Metastatic
Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC
3+) (5.4 mg/kg) In patients with metastatic breast cancer,
HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4
mg/kg, LVEF decrease was reported in 3.8% of patients, of which
0.6% were Grade 3.
HER2-Positive Locally Advanced or
Metastatic Gastric Cancer (6.4 mg/kg) In patients with
locally advanced or metastatic HER2-positive gastric or GEJ
adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse
events of heart failure were reported; however, on
echocardiography, 8% were found to have asymptomatic Grade 2
decrease in LVEF.
Embryo-Fetal Toxicity ENHERTU can cause fetal harm when
administered to a pregnant woman. Advise patients of the potential
risks to a fetus. Verify the pregnancy status of females of
reproductive potential prior to the initiation of ENHERTU. Advise
females of reproductive potential to use effective contraception
during treatment and for 7 months after the last dose of ENHERTU.
Advise male patients with female partners of reproductive potential
to use effective contraception during treatment with ENHERTU and
for 4 months after the last dose of ENHERTU.
Additional Dose Modifications Thrombocytopenia For
Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt
ENHERTU until resolved to Grade 1 or less, then maintain dose. For
Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt
ENHERTU until resolved to Grade 1 or less, then reduce dose by one
level.
Adverse Reactions HER2-Positive and
HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid
Tumors (Including IHC 3+) (5.4 mg/kg) The pooled safety
population reflects exposure to ENHERTU 5.4 mg/kg intravenously
every 3 weeks in 1799 patients in Study DS8201-A-J101
(NCT02564900), DESTINY-Breast01, DESTINY-Breast02,
DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02,
DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65%
were exposed for >6 months and 38% were exposed for >1 year.
In this pooled safety population, the most common (≥20%) adverse
reactions, including laboratory abnormalities, were nausea (73%),
decreased white blood cell count (70%), decreased hemoglobin (66%),
decreased neutrophil count (63%), decreased lymphocyte count (58%),
fatigue (56%), decreased platelet count (48%), increased aspartate
aminotransferase (47%), increased alanine aminotransferase (43%),
vomiting (40%), increased blood alkaline phosphatase (38%),
alopecia (34%), constipation (33%), decreased appetite (32%),
decreased blood potassium (31%), diarrhea (29%), musculoskeletal
pain (24%), and abdominal pain (20%).
HER2-Positive Metastatic Breast
Cancer DESTINY-Breast03 The safety of ENHERTU was evaluated
in 257 patients with unresectable or metastatic HER2-positive
breast cancer who received at least one dose of ENHERTU 5.4 mg/kg
intravenously once every three weeks in DESTINY-Breast03. The
median duration of treatment was 14 months (range: 0.7 to 30).
Serious adverse reactions occurred in 19% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were vomiting, interstitial lung disease,
pneumonia, pyrexia, and urinary tract infection. Fatalities due to
adverse reactions occurred in 0.8% of patients including COVID-19
and sudden death (one patient each).
ENHERTU was permanently discontinued in 14% of patients, of
which ILD/pneumonitis accounted for 8%. Dose interruptions due to
adverse reactions occurred in 44% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose
interruption were neutropenia, leukopenia, anemia,
thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis.
Dose reductions occurred in 21% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose
reduction were nausea, neutropenia, and fatigue.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were nausea (76%), decreased white blood cell count
(74%), decreased neutrophil count (70%), increased aspartate
aminotransferase (67%), decreased hemoglobin (64%), decreased
lymphocyte count (55%), increased alanine aminotransferase (53%),
decreased platelet count (52%), fatigue (49%), vomiting (49%),
increased blood alkaline phosphatase (49%), alopecia (37%),
decreased blood potassium (35%), constipation (34%),
musculoskeletal pain (31%), diarrhea (29%), decreased appetite
(29%), headache (22%), respiratory infection (22%), abdominal pain
(21%), increased blood bilirubin (20%), and stomatitis (20%).
HER2-Low Metastatic Breast Cancer
DESTINY-Breast04 The safety of ENHERTU was evaluated in 371
patients with unresectable or metastatic HER2-low (IHC 1+ or IHC
2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously
once every 3 weeks in DESTINY-Breast04. The median duration of
treatment was 8 months (range: 0.2 to 33) for patients who received
ENHERTU.
Serious adverse reactions occurred in 28% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea,
musculoskeletal pain, sepsis, anemia, febrile neutropenia,
hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to
adverse reactions occurred in 4% of patients including
ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic
colitis, disseminated intravascular coagulation, dyspnea, febrile
neutropenia, general physical health deterioration, pleural
effusion, and respiratory failure (1 patient each).
ENHERTU was permanently discontinued in 16% of patients, of
which ILD/pneumonitis accounted for 8%. Dose interruptions due to
adverse reactions occurred in 39% of patients treated with ENHERTU.
The most frequent adverse reactions (>2%) associated with dose
interruption were neutropenia, fatigue, anemia, leukopenia,
COVID-19, ILD/pneumonitis, increased transaminases, and
hyperbilirubinemia. Dose reductions occurred in 23% of patients
treated with ENHERTU. The most frequent adverse reactions (>2%)
associated with dose reduction were fatigue, nausea,
thrombocytopenia, and neutropenia.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were nausea (76%), decreased white blood cell count
(70%), decreased hemoglobin (64%), decreased neutrophil count
(64%), decreased lymphocyte count (55%), fatigue (54%), decreased
platelet count (44%), alopecia (40%), vomiting (40%), increased
aspartate aminotransferase (38%), increased alanine
aminotransferase (36%), constipation (34%), increased blood
alkaline phosphatase (34%), decreased appetite (32%),
musculoskeletal pain (32%), diarrhea (27%), and decreased blood
potassium (25%).
HER2-Mutant Unresectable or Metastatic
NSCLC (5.4 mg/kg) DESTINY-Lung02 evaluated two dose levels
(5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results
for the recommended dose of 5.4 mg/kg intravenously every 3 weeks
are described below due to increased toxicity observed with the
higher dose in patients with NSCLC, including ILD/pneumonitis.
The safety of ENHERTU was evaluated in 101 patients with
HER2-mutant unresectable or metastatic NSCLC who received ENHERTU
5.4 mg/kg intravenously once every three weeks until disease
progression or unacceptable toxicity in DESTINY‑Lung02. Nineteen
percent of patients were exposed for >6 months.
Serious adverse reactions occurred in 30% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea,
nausea, pleural effusion, and increased troponin I. Fatality
occurred in 1 patient with suspected ILD/pneumonitis (1%).
ENHERTU was permanently discontinued in 8% of patients. Adverse
reactions which resulted in permanent discontinuation of ENHERTU
were ILD/pneumonitis, diarrhea, decreased blood potassium,
hypomagnesemia, myocarditis, and vomiting. Dose interruptions of
ENHERTU due to adverse reactions occurred in 23% of patients.
Adverse reactions which required dose interruption (>2%)
included neutropenia and ILD/pneumonitis. Dose reductions due to an
adverse reaction occurred in 11% of patients.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were nausea (61%), decreased white blood cell count
(60%), decreased hemoglobin (58%), decreased neutrophil count
(52%), decreased lymphocyte count (43%), decreased platelet count
(40%), decreased albumin (39%), increased aspartate
aminotransferase (35%), increased alanine aminotransferase (34%),
fatigue (32%), constipation (31%), decreased appetite (30%),
vomiting (26%), increased alkaline phosphatase (22%), and alopecia
(21%).
HER2-Positive Locally Advanced or
Metastatic Gastric Cancer (6.4 mg/kg) The safety of ENHERTU
was evaluated in 187 patients with locally advanced or metastatic
HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01.
Patients intravenously received at least one dose of either ENHERTU
(N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150
mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The
median duration of treatment was 4.6 months (range: 0.7 to 22.3)
for patients who received ENHERTU.
Serious adverse reactions occurred in 44% of patients receiving
ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients
who received ENHERTU were decreased appetite, ILD, anemia,
dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor
hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of
patients: disseminated intravascular coagulation, large intestine
perforation, and pneumonia occurred in one patient each (0.8%).
ENHERTU was permanently discontinued in 15% of patients, of
which ILD accounted for 6%. Dose interruptions due to adverse
reactions occurred in 62% of patients treated with ENHERTU. The
most frequent adverse reactions (>2%) associated with dose
interruption were neutropenia, anemia, decreased appetite,
leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia,
upper respiratory tract infection, diarrhea, and decreased blood
potassium. Dose reductions occurred in 32% of patients treated with
ENHERTU. The most frequent adverse reactions (>2%) associated
with dose reduction were neutropenia, decreased appetite, fatigue,
nausea, and febrile neutropenia.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were decreased hemoglobin (75%), decreased white
blood cell count (74%), decreased neutrophil count (72%), decreased
lymphocyte count (70%), decreased platelet count (68%), nausea
(63%), decreased appetite (60%), increased aspartate
aminotransferase (58%), fatigue (55%), increased blood alkaline
phosphatase (54%), increased alanine aminotransferase (47%),
diarrhea (32%), decreased blood potassium (30%), vomiting (26%),
constipation (24%), increased blood bilirubin (24%), pyrexia (24%),
and alopecia (22%).
HER2-Positive (IHC3+) Unresectable or
Metastatic Solid Tumors The safety of ENHERTU was evaluated
in 347 adult patients with unresectable or metastatic HER2-positive
(IHC3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously
once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02,
DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment
was 8.3 months (range 0.7 to 30.2).
Serious adverse reactions occurred in 34% of patients receiving
ENHERTU. Serious adverse reactions in >1% of patients who
received ENHERTU were sepsis, pneumonia, vomiting, urinary tract
infection, abdominal pain, nausea, pneumonitis, pleural effusion,
hemorrhage, COVID-19, fatigue, acute kidney injury, anemia,
cellulitis, and dyspnea. Fatalities due to adverse reactions
occurred in 6.3% of patients including ILD/pneumonitis (2.3%),
cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The
following events occurred in one patient each (0.3%): acute kidney
injury, cerebrovascular accident, general physical health
deterioration, pneumonia, and hemorrhagic shock.
ENHERTU was permanently discontinued in 15% of patients, of
which ILD/pneumonitis accounted for 10%. Dose interruptions due to
adverse reactions occurred in 48% of patients. The most frequent
adverse reactions (>2%) associated with dose interruption were
decreased neutrophil count, anemia, COVID-19, fatigue, decreased
white blood cell count, and ILD/pneumonitis. Dose reductions
occurred in 27% of patients treated with ENHERTU. The most frequent
adverse reactions (>2%) associated with dose reduction were
fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and
diarrhea.
The most common (≥20%) adverse reactions, including laboratory
abnormalities, were decreased white blood cell count (75%), nausea
(69%), decreased hemoglobin (67%), decreased neutrophil count
(66%), fatigue (59%), decreased lymphocyte count (58%), decreased
platelet count (51%), increased aspartate aminotransferase (45%),
increased alanine aminotransferase (44%), increased blood alkaline
phosphatase (36%), vomiting (35%), decreased appetite (34%),
alopecia (34%), diarrhea (31%), decreased blood potassium (29%),
constipation (28%), decreased sodium (22%), stomatitis (20%), and
upper respiratory tract infection (20%).
Use in Specific Populations
- Pregnancy: ENHERTU can cause fetal harm when
administered to a pregnant woman. Advise patients of the potential
risks to a fetus. There are clinical considerations if ENHERTU is
used in pregnant women, or if a patient becomes pregnant within 7
months after the last dose of ENHERTU.
- Lactation: There are no data regarding the presence of
ENHERTU in human milk, the effects on the breastfed child, or the
effects on milk production. Because of the potential for serious
adverse reactions in a breastfed child, advise women not to
breastfeed during treatment with ENHERTU and for 7 months after the
last dose.
- Females and Males of Reproductive Potential:
Pregnancy testing: Verify pregnancy
status of females of reproductive potential prior to initiation of
ENHERTU. Contraception: Females:
ENHERTU can cause fetal harm when administered to a pregnant woman.
Advise females of reproductive potential to use effective
contraception during treatment with ENHERTU and for 7 months after
the last dose. Males: Advise male patients with female partners of
reproductive potential to use effective contraception during
treatment with ENHERTU and for 4 months after the last dose.
Infertility: ENHERTU may impair male
reproductive function and fertility.
- Pediatric Use: Safety and effectiveness of ENHERTU have
not been established in pediatric patients.
- Geriatric Use: Of the 1287 patients with HER2-positive
or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg, 22% were
≥65 years and 3.8% were ≥75 years. No overall differences in
efficacy within clinical studies were observed between patients ≥65
years of age compared to younger patients. There was a higher
incidence of Grade 3-4 adverse reactions observed in patients aged
≥65 years (59%) as compared to younger patients (49%). Of the 101
patients with HER2-mutant unresectable or metastatic NSCLC treated
with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years.
No overall differences in efficacy or safety were observed between
patients ≥65 years of age compared to younger patients. Of the 125
patients with HER2-positive locally advanced or metastatic gastric
or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in
DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No
overall differences in efficacy or safety were observed between
patients ≥65 years of age compared to younger patients. Of the 192
patients with HER2-positive (IHC 3+) unresectable or metastatic
solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02,
DESTINY-Lung01, or DESTINY-CRC02, 39% were 65 years or older and 9%
were 75 years or older. No overall differences in efficacy or
safety were observed between patients ≥65 years of age compared to
younger patients.
- Renal Impairment: A higher incidence of Grade 1 and 2
ILD/pneumonitis has been observed in patients with moderate renal
impairment. Monitor patients with moderate renal impairment more
frequently. The recommended dosage of ENHERTU has not been
established for patients with severe renal impairment (CLcr <30
mL/min).
- Hepatic Impairment: In patients with moderate hepatic
impairment, due to potentially increased exposure, closely monitor
for increased toxicities related to the topoisomerase inhibitor,
DXd. The recommended dosage of ENHERTU has not been established for
patients with severe hepatic impairment (total bilirubin >3
times ULN and any AST).
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi
Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or
fda.gov/medwatch.
Please see accompanying full Prescribing
Information, including Boxed WARNINGS, and Medication
Guide.
Notes
Breast cancer and HER2 expression Breast cancer is the
second most common cancer and one of the leading causes of
cancer-related deaths worldwide.1 More than two million breast
cancer cases were diagnosed in 2022 with more than 665,000 deaths
globally.1 While survival rates are high for those diagnosed with
early breast cancer, only approximately 30% of patients who are
diagnosed with or who progress to metastatic disease are expected
to live five years after their diagnosis.2
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors, including breast
cancer.3 Patients with high levels of HER2 expression (IHC 3+ or
2+/ISH+) are classified as HER2-positive and treated with
HER2-directed therapies, representing approximately 15-20% of all
breast cancers.4 Historically, tumors that were not classified as
HER2-positive were classified as HER2-negative.5
HR-positive, HER2-negative is the most common breast cancer
subtype, accounting for approximately 70% of all breast cancers.2
Despite being classified as HER2-negative, many of these tumors
still carry some level of HER2 expression.5 It is estimated that
approximately 60-65% of HR-positive, HER2-negative breast cancers
are HER2-low and potentially an additional 25% may be
HER2-ultralow.6,7
Endocrine therapies are widely used in the early lines of
treatment for HR-positive metastatic breast cancer; however, after
two lines of treatment, further efficacy from endocrine therapy is
often limited.8 The current standard of care following endocrine
therapy is chemotherapy, which is associated with poor response
rates and outcomes.8-11
Prior to the approval of ENHERTU in HER2-low metastatic breast
cancer post chemotherapy based on the DESTINY-Breast04 trial, there
were no targeted therapies approved specifically for patients with
HER2-low expression. There are no targeted therapies specifically
approved for patients with HER2-low expression prior to
chemotherapy or for patients with HER2-ultralow expression.12
DESTINY-Breast06 DESTINY-Breast06 is a global,
randomized, open-label, Phase III trial evaluating the efficacy and
safety of ENHERTU (5.4 mg/kg) versus investigator’s choice of
chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in
patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or
HER2-ultralow (defined as IHC 0 with membrane staining) advanced or
metastatic breast cancer. Patients in the trial had no prior
chemotherapy for advanced or metastatic disease and received at
least two lines of prior endocrine therapy in the metastatic
setting. Patients were also eligible if they had received one prior
line of endocrine therapy combined with a CDK4/6 inhibitor in the
metastatic setting and experienced disease progression within six
months of starting 1st-line treatment or received endocrine therapy
as an adjuvant treatment and experienced disease recurrence within
24 months.
The primary endpoint is PFS in the HR-positive, HER2-low patient
population as measured by BICR. Key secondary endpoints include PFS
by BICR in the overall trial population (HER2-low and
HER2-ultralow), OS in the HER2-low patient population and OS in the
overall trial population. Other secondary endpoints include ORR,
DOR, time to first subsequent treatment or death, time to second
subsequent treatment or death and safety.
DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and
n=153 for HER2-ultralow) randomized at multiple sites in Asia,
Europe, Australia, North America and South America. For more
information about the trial, visit ClinicalTrials.gov.
DESTINY-Breast03 DESTINY-Breast03 is a global,
head-to-head, randomized, open-label, pivotal Phase III trial
evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus
T-DM1 in patients with HER2-positive unresectable and/or metastatic
breast cancer previously treated with trastuzumab and a taxane. The
primary efficacy endpoint of DESTINY-Breast03 is PFS based on BICR.
OS is the key secondary efficacy outcome measure. Other secondary
endpoints include ORR, DOR, PFS based on investigator assessment
and safety.
DESTINY-Breast03 enrolled 524 patients at multiple sites in
Asia, Europe, North America, Australia and South America. Primary
results from DESTINY-Breast03 were published in The New England
Journal of Medicine, with updated OS results published in The
Lancet. For more information about the trial, visit
ClinicalTrials.gov.
DESTINY-Breast07 DESTINY-Breast07 is a global,
randomized, open-label Phase Ib/II dose-finding and dose-expansion
trial to explore the safety, tolerability and anti-tumor activity
of ENHERTU alone or in combination with other anticancer agents in
patients with HER2-positive metastatic breast cancer.
The study consists of two phases: a dose escalation phase and a
dose expansion phase. The dose escalation phase enrolled patients
with locally assessed HER2-positive or advanced metastatic breast
cancer in 2nd-line or later treatment. The dose expansion phase
enrolled patients with previously untreated for HER2-positive
advanced or metastatic breast cancer.
The primary endpoints of DESTINY-Breast07 are safety and
tolerability. Secondary endpoints include ORR and PFS based on
investigator assessment.
DESTINY-Breast07 enrolled 244 patients at multiple sites in
Asia, Europe, North America and South 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 (5.4 mg/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 (5.4 mg/kg) is approved in more than 60 countries for
the treatment of adult patients with unresectable or metastatic
HER2-low (IHC 1+ or 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 (5.4 mg/kg) is approved in more than 35 countries for
the treatment of adult patients with unresectable or metastatic
NSCLC 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 (6.4 mg/kg) is approved in more than 40 countries for
the treatment of adult patients with locally advanced or metastatic
HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal
junction (GEJ) adenocarcinoma who have received a prior
trastuzumab-based regimen based on the results from the
DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.
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 who
have no satisfactory alternative treatment options based on results
from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02
trials.
ENHERTU development program A comprehensive global
clinical development program is underway evaluating the efficacy
and safety of ENHERTU monotherapy across multiple HER2-targetable
cancers. Trials in combination with other anti-cancer treatments,
such as immunotherapy, also are underway.
Daiichi Sankyo collaboration AstraZeneca and Daiichi
Sankyo entered into a global collaboration to jointly develop and
commercialize ENHERTU in March 2019 and datopotamab deruxtecan in
July 2020, except in Japan where Daiichi Sankyo maintains exclusive
rights for each ADC. 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.
With ENHERTU, a HER2-directed antibody drug conjugate (ADC),
AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in
previously treated HER2-positive and HER2-low metastatic breast
cancer and are exploring its potential in earlier lines of
treatment and in new breast cancer settings.
In HR-positive breast cancer, AstraZeneca continues to improve
outcomes with foundational medicines fulvestrant and goserelin and
aims to reshape the HR-positive space with first-in-class AKT
inhibitor, capivasertib, and next-generation SERD and potential new
medicine camizestrant. AstraZeneca is also collaborating with
Daiichi Sankyo to explore the potential of TROP2-directed ADC,
datopotamab deruxtecan, in this setting.
PARP inhibitor olaparib is a targeted treatment option that has
been studied in early and metastatic breast cancer patients with an
inherited BRCA mutation. AstraZeneca with Merck & Co., Inc.
(MSD outside the US and Canada) continue to research olaparib in
these settings and to explore its potential in earlier disease.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is evaluating the potential of datopotamab deruxtecan
alone and in combination with immunotherapy durvalumab,
capivasertib in combination with chemotherapy, and durvalumab in
combination with other oncology medicines, including olaparib and
ENHERTU.
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 astrazeneca-us.com and follow the
Company on social media @AstraZeneca.
References
- Bray F, et al. Global cancer statistics 2022: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA Cancer J Clin. 2024 Apr 4. doi:
10.3322/caac.21834.
- National Cancer Institute. Surveillance, Epidemiology and End
Results Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed May 2024.
- Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2)
in Cancers: Overexpression and Therapeutic Implications. Mol Biol
Int. 2014;852748.
- 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.
- Sajjadi E, et al. Improving HER2 testing reproducibility in
HER2-low breast cancer. Cancer Drug Resist. 2022;5(4):882-888.
- 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.
Lancet Oncol. 2021 Aug;22(8):1151-1161.
- Chen Z, et al. Is HER2 ultra‑low breast cancer different from
HER2 null or HER2 low breast cancer? A study of 1363 patients.
Breast Cancer Res Treat. 2023 Nov;202(2):313-323.
- Manohar P, et al. Updates in endocrine therapy for metastatic
breast cancer. Cancer Biol Med. 2022 Feb 15; 19(2):202–212.
- Cortes J, et al. Eribulin monotherapy versus treatment of
physician’s choice in patients with metastatic breast cancer
(EMBRACE): a phase 3 open-label randomised study. Lancet.
2011;377:914-923.
- Yuan P, et al. Eribulin mesilate versus vinorelbine in women
with locally recurrent or metastatic breast cancer: A randomised
clinical trial. Eur J Cancer. 2019;112:57–65.
- Jerusalem G, et al. Everolimus Plus Exemestane vs Everolimus or
Capecitabine Monotherapy for Estrogen Receptor–Positive,
HER2-Negative Advanced Breast Cancer. JAMA Oncol.
2018;4(10):1367–1374.
- Modi S, et al. Trastuzumab Deruxtecan in Previously Treated
HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387:9-20.
US-89863 Last Updated 6/24
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