AstraZeneca and Daiichi Sankyo’s ENHERTU
showed objective response rates of 49% and 56% with 5.4mg/kg and
6.4mg/kg doses respectively in primary analysis
ENHERTU provided a median progression-free
survival of 9.9 months at 5.4mg/kg dose and 15.4 months at 6.4mg/kg
dose with a median duration of response of 16.8 months seen at the
5.4mg/kg dose and not reached at the 6.4mg/kg dose
Favorable safety profile confirms 5.4mg/kg
as optimal dose in this tumor type and reinforces role of ENHERTU
in this setting
Results from the primary analysis of the DESTINY-Lung02 Phase II
trial showed ENHERTU® (fam-trastuzumab deruxtecan-nxki) continued
to demonstrate strong and durable tumor responses in previously
treated patients with HER2-mutant (HER2m) unresectable and/or
metastatic non-squamous non-small cell lung cancer (NSCLC).
These results, along with the first report on progression-free
survival (PFS) and overall survival (OS), were presented today at
the International Association for the Study of Lung Cancer (IASLC)
2023 World Conference on Lung Cancer (WCLC) (abstract #MA13.10) and
simultaneously published in the Journal of Clinical Oncology.
ENHERTU is a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialized by
AstraZeneca and Daiichi Sankyo.
At the primary analysis, a confirmed objective response rate
(ORR) of 49.0% and 56.0% was seen in the 5.4mg/kg arm and 6.4mg/kg
arm respectively, as assessed by blinded independent central review
(BICR). The safety profile for both doses was consistent with the
overall safety profile of ENHERTU, with the 5.4mg/kg dose
demonstrating a favorable safety profile in this patient
population.
Secondary endpoint data were also encouraging, with ENHERTU
demonstrating a median PFS of 9.9 months and 15.4 months in the
5.4mg/kg and 6.4mg/kg arms respectively, as assessed by BICR. A
median OS of 19.5 months was achieved in the 5.4mg/kg arm and not
reached in the 6.4mg/kg arm at time of analysis.
Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic
Oncology and Belfer Center for Applied Cancer Science, Dana-Farber
Cancer Institute, US, said: “The primary results from
DESTINY-Lung02 demonstrate that ENHERTU continues to show strong
and durable tumor responses for patients treated at either dose.
The favorable safety profile seen at the 5.4mg/kg dose continues to
support the use of ENHERTU in the treatment of patients with
HER2-mutant non-small cell lung cancer, a particularly aggressive
form of the disease where patients face a poor prognosis and have
historically had few options.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “These results from DESTINY-Lung02 highlight
that HER2 is an actionable target in lung cancer and reinforce the
importance of testing for predictive biomarkers, including HER2
alterations, at the time of diagnosis to accurately identify
patients who may be able to benefit from a targeted treatment. The
data also reaffirm our belief in ENHERTU as a potential new
targeted treatment option for patients who have historically had
limited options.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “The
disease control achieved by more than 90% of patients with
previously treated HER2-mutant non-small cell lung cancer in the
primary analysis of DESTINY-Lung02 reinforces the efficacy we have
already seen with ENHERTU in this hard-to-treat disease. These
results, along with encouraging progression-free survival and
overall survival findings reported for the first time, demonstrate
the potential role of ENHERTU as an important treatment option for
this patient population.”
Summary of results: DESTINY-Lung02 Primary analysis
Efficacy Measure
ENHERTU (5.4mg/kg)
n=102
ENHERTU (6.4mg/kg)
n=50
Confirmed ORR (%)
(95% CI)i
49.0% (39.0-59.1)
56.0% (41.3-70.0)
Complete Response (%)
1.0%
4.0%
Partial Response (%)
48.0%
52.0%
Stable Disease (%)
44.1%
36.0%
Progressive Disease (%)
3.9%
4.0%
Not Evaluable (%)ii
2.9%
4.0%
DCR (95% CI) iii
93.1% (86.4-97.2)
92.0% (80.8-97.8)
Median DoR (months)
(95% CI)iv,v
16.8 (6.4-NE)
NE (8.3-NE)
Median TTIR (months)
(95% CI)iv
1.8 (1.2-7.0)
1.6 (1.2-11.2)
Median PFS (months)
(95% CI)iv,vi
9.9 (7.4-NE)
15.4 (8.3-NE)
Median OS (months)
(95% CI)vii
19.5 (13.6-NE)
NE (12.1-NE)
CI, confidence interval; DCR, disease
control rate; DoR, duration of response; NE, not estimable; ORR,
objective response rate; OS, overall survival; PFS, progression
free survival; TTIR, time to initial response
Data cutoff: As of December 23, 2022
i Proportion of patients with confirmed CR
or PR assessed by BICR per RECIST v1.1
ii Three patients were NE at 5.4mg/kg (one
patient never received treatment due to COVID-19; two patients
discontinued before first tumor assessment); two patients were NE
at 6.4mg/kg (discontinued due to adverse event before first tumor
assessment).
iii Proportion of patients with confirmed
CR, PR, or SD assessed by BICR
iv Assessed by BICR
v 60.0% and 75.0% of patients in the
5.4mg/kg and 6.4mg/kg arms were censored
vi 56.9% and 60.0% of patients in the
5.4mg/kg and 6.4mg/kg arms were censored
vii 63.7% and 72.0% of patients in the
5.4mg/kg and 6.4mg/kg arms were censored
In DESTINY-Lung02, no new safety signals were observed at either
dose of ENHERTU. Grade 3 or higher treatment-related treatment
emergent adverse events (TEAEs) were lower with ENHERTU 5.4mg/kg
versus 6.4mg/kg, occurring in 38.6% and 58.0% of all patients,
respectively. The most common Grade 3 or higher TEAEs were
neutropenia (18.8% (5.4mg/kg); 36.0% (6.4mg/kg)) and anemia (10.9%
(5.4mg/kg); 16.0% (6.4mg/kg)).
There were 27 cases (12.9% in the 5.4mg/kg arm and 28% in the
6.4mg/kg arm) of treatment-related interstitial lung disease (ILD)
or pneumonitis reported as determined by an independent
adjudication committee. In the 5.4mg/kg arm, the majority of ILD
cases were low Grade (Grade 1 or 2) (10.9%) with one Grade 3 event
(1.0%), no Grade 4 events and one Grade 5 event (1.0%) observed. In
the 6.4mg/kg arm, the majority of ILD cases were also low Grade
(26.0%) with no Grade 3 or 4 events and one Grade 5 event (2.0%)
reported.
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
HER2m NSCLC
Lung cancer is the second most common form of cancer globally,
with more than two million patients diagnosed in 2020.1 Prognosis
is particularly poor for patients with metastatic NSCLC, as only
approximately 9% will live beyond five years after diagnosis.2
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors, including lung,
breast, gastric and colorectal cancers. Certain HER2 (ERBB2) gene
alterations (called HER2 mutations) have been identified in
patients with non-squamous NSCLC as a distinct molecular target,
and occur in approximately 2-4% of patients with this type of lung
cancer.3,4 While HER2 gene mutations can occur in a range of
patients, they are more commonly found in patients with NSCLC who
are younger, female and have never smoked.5 HER2 gene mutations
have been independently associated with cancer cell growth and poor
prognosis, with an increased incidence of brain metastases.6
Next-generation sequencing has been utilized in the identification
of HER2 (ERBB2) mutations.7,8
Although the role of anti-HER2 treatment is well established in
breast and gastric cancers, there were no approved HER2-directed
therapies in NSCLC prior to the approvals of ENHERTU by the Israel
Ministry of Health (MOH) Pharmaceutical Division, the Japan
Ministry of Health, Labor and Welfare and the accelerated US Food
and Drug Administration (FDA) approval of ENHERTU in unresectable
or metastatic HER2 mutant NSCLC.9
DESTINY-Lung02
DESTINY-Lung02 is a global, randomized Phase II trial evaluating
the safety and efficacy of ENHERTU in patients with HER2m
unresectable and/or metastatic NSCLC with disease recurrence or
progression during or after at least one regimen of prior
anticancer therapy that must have contained a platinum-based
chemotherapy. Patients were randomized 2:1 to receive ENHERTU
5.4mg/kg (n=102) or ENHERTU 6.4mg/kg (n=50).
The primary endpoint of the trial is confirmed ORR as assessed
by BICR. Secondary endpoints include confirmed DCR, DoR and PFS
assessed by investigator and BICR, OS and safety.
DESTINY-Lung02 enrolled 152 patients at multiple sites,
including 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 more than 50 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 40 countries
worldwide for the treatment of adult patients with unresectable or
metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have
received a prior systemic therapy in the metastatic setting or
developed disease recurrence during or within six months of
completing adjuvant chemotherapy based on the results from the
DESTINY-Breast04 trial.
ENHERTU (5.4mg/kg) is approved in Israel, Japan and under
accelerated approval in the US 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
for this indication in the US 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 and/or
DESTINY-Gastric02 trials.
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 (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 lung cancer
AstraZeneca is working to bring patients with lung cancer closer
to cure through the detection and treatment of early-stage disease,
while also pushing the boundaries of science to improve outcomes in
the resistant and advanced settings. By defining new therapeutic
targets and investigating innovative approaches, the Company aims
to match medicines to the patients who can benefit most.
The Company’s comprehensive portfolio includes leading lung
cancer medicines and the next wave of innovations, including
osimertinib and gefitinib; durvalumab and tremelimumab; ENHERTU
(fam-trastuzumab deruxtecan-nxki) and datopotamab deruxtecan in
collaboration with Daiichi Sankyo; savolitinib in collaboration
with HUTCHMED; as well as a pipeline of potential new medicines and
combinations across diverse mechanisms of action.
AstraZeneca is a founding member of the Lung Ambition Alliance,
a global coalition working to accelerate innovation and deliver
meaningful improvements for people with lung cancer, including and
beyond treatment.
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 astrazeneca-us.com and follow the
Company on Social Media @AstraZeneca.
References
- WHO. International Agency of Cancer Research. Cancer Today.
2020. Available at: https://gco.iarc.fr/today/home. Accessed
September 2023.
- American Cancer Society. Lung Cancer Survival Rates. Available
at:
https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html.
Accessed September 2023.
- Liu S, et al. Targeting HER2 Aberrations in Non–Small Cell Lung
Cancer with Osimertinib. Clin Cancer Res. 2018;
24(11);2594-2604.
- Riudavets M, et al. Targeting HER2 in non-small-cell lung
cancer (NSCLC): a glimpse of hope? An updated review on therapeutic
strategies in NSCLC harbouring HER2 alterations. ESMO Open. 2021;
6(5):100260.
- Pillai RN, et al. HER2 mutations in lung adenocarcinomas: A
report from the Lung Cancer Mutation Consortium. Cancer. 2017;
123:4099-105.
- Offin M, et al. Frequency and Outcomes of Brain Metastases in
Patients With HER2-Mutant Lung Cancers. Cancer. 2019;
125:4380-7.
- Hechtman, J, et al. The Past, Present, and Future of HER2
(ERBB2) in Cancer: Approaches to Molecular Testing and an Evolving
Role in Targeted Therapy. Cancer Cyto. 2019; 127(7):428-431.
- Gulilat M, et al. Targeted next generation sequencing as a tool
for precision medicine. BMC Medical Genomics. 2019;12(81).
- Zhou J, et al. Clinical outcomes of patients with HER2-mutant
advanced lung cancer: chemotherapies versus HER2-directed
therapies. Ther Adv Med Oncol. 2020; 12.
US-80078 Last Updated 09/23
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version on businesswire.com: https://www.businesswire.com/news/home/20230911597442/en/
Media Inquiries Brendan McEvoy +1 302 885 2677 Jillian
Gonzales +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
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