- Daiichi Sankyo and AstraZeneca’s ENHERTU also demonstrated a
clinically meaningful progression-free survival improvement in
patients with HER2 ultralow expression
- Plans for global regulatory submissions are underway
Positive topline results from the DESTINY-Breast06 phase 3 trial
showed that ENHERTU® (trastuzumab deruxtecan) demonstrated a
statistically significant and clinically meaningful improvement in
progression-free survival (PFS) compared to standard of care
chemotherapy in the primary trial population of patients with HR
positive, HER2 low (IHC 1+ or IHC 2+/ISH-) metastatic breast cancer
following one or more lines of endocrine therapy.
A statistically significant and clinically meaningful
improvement in PFS also was observed in the overall trial
population (patients with HER2 low and HER2 ultralow [defined as
IHC 0 with membrane staining; IHC >0 <1+] metastatic breast
cancer). A pre-specified subgroup analysis showed that the
clinically meaningful improvement was consistent between patients
with HER2 low and HER2 ultralow expression.
Overall survival (OS) data were not mature at the time of the
analysis. However, ENHERTU showed an early trend towards an OS
improvement versus standard of care chemotherapy in patients with
HER2 low metastatic breast cancer and in the overall trial
population. The trial will continue as planned to further assess OS
and other secondary endpoints.
ENHERTU is a specifically engineered HER2 directed DXd antibody
drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and
being jointly developed and commercialized by Daiichi Sankyo and
AstraZeneca (LSE/STO/Nasdaq: AZN).
It is estimated that approximately 60% to 65% of HR positive,
HER2 negative breast cancers are HER2 low and potentially an
additional 25% may be HER2 ultralow.1,2 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.3 The
current standard of care following endocrine therapy is
chemotherapy, which is associated with poor response rates and
outcomes.3,4,5,6
“The topline results from DESTINY-Breast06 highlight the
importance of continuing to challenge current treatment paradigms
and established breast cancer classifications to evolve how we
treat patients with HR positive, HER2 expressing metastatic breast
cancer," said Ken Takeshita, MD, Global Head, R&D, Daiichi
Sankyo. “Building on the practice-changing data seen in
DESTINY-Breast04, these results reinforce the potential for use of
ENHERTU earlier in the treatment landscape and in an even broader
patient population.”
“DESTINY-Breast06 shows that ENHERTU could become a new standard
of care for patients with HER2 low and HER2 ultralow metastatic
breast cancer following one or more lines of endocrine therapy,”
said Susan Galbraith, MBBChir, PhD, Executive Vice President,
Oncology R&D, AstraZeneca. “These data underscore the potential
for treatment with ENHERTU across the spectrum of HR positive
breast cancer, further redefining the treatment of metastatic
breast cancer.”
The safety profile of ENHERTU was consistent with previous
breast cancer clinical trials with no new safety signals
identified.
Data from DESTINY-Breast06 will be presented at an upcoming
medical meeting and shared with global regulatory authorities.
About DESTINY-Breast06 DESTINY-Breast06 is a global,
randomized, open-label, phase 3 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 IHC 2+/ISH-) or HER2
ultralow (defined as IHC 0 with membrane staining [IHC >0
<1+]) advanced or metastatic breast cancer. Patients in the
trial had no prior chemotherapy for advanced or metastatic disease
and either experienced disease progression within six months of
starting first-line treatment with an endocrine therapy combined
with a CDK4/6 inhibitor or received at least two previous lines of
endocrine therapy in the metastatic setting.
The primary endpoint is PFS in the HR positive, HER2 low patient
population as measured by blinded independent central review
(BICR). Key secondary endpoints include OS in patients with HER2
low expression and PFS by BICR and OS in the overall trial
population (HER2 low and HER2 ultralow). Other secondary endpoints
include objective response rate, duration of response, time to
first subsequent treatment or death, time to second subsequent
treatment or death and safety. Analysis of the HER2 ultralow
subgroup was not powered to demonstrate statistical
significance.
DESTINY-Breast06 enrolled 866 patients (n=713 for HER2 low and
n=153 for HER2 ultralow) at multiple sites in Asia, Europe, North
America and South America. For more information about the trial,
visit ClinicalTrials.gov.
About Breast Cancer and HER2 Expression Breast cancer is
the second most common cancer and one of the leading causes of
cancer-related deaths worldwide.7 More than two million breast
cancer cases were diagnosed in 2022 with more than 665,000 deaths
globally.7 While survival rates are high for those diagnosed with
early breast cancer, only approximately 30% of patients who are
diagnosed with or progress to metastatic disease are expected to
live five years after their diagnosis.8
HR positive, HER2 negative is the most common breast cancer
subtype, accounting for approximately 70% of all breast cancers.8
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumors, including breast
cancer.9 Patients with high levels of HER2 expression (IHC 3+ or
IHC2+/ISH+) are classified as HER2 positive and treated with HER2
targeted therapies, representing approximately 15 to 20% percent of
all breast cancers.10 Historically, tumors that were not classified
as HER2 positive were classified as HER2 negative; however, many of
these tumors still carry some level of HER2 expression.11 It is
estimated that approximately 60% to 65% of HR positive, HER2
negative breast cancers are HER2 low and potentially an additional
25% may be HER2 ultralow.1,2
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.12 There are no targeted therapies specifically
approved for patients with HER2 ultralow expression.13
About ENHERTU ENHERTU (trastuzumab deruxtecan;
fam-trastuzumab deruxtecan-nxki in the U.S. only) 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
worldwide for the treatment of adult patients with unresectable or
metastatic HER2 positive (IHC 3+ or IHC 2+/ in-situ hybridization
(ISH)+) 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 the results from
the DESTINY-Breast03 trial.
ENHERTU (5.4 mg/kg) is approved in more than 55 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 (5.4 mg/kg) is approved in more than 35 countries
worldwide 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 U.S. 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 45 countries
worldwide for the treatment of adult patients with locally advanced
or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or
gastroesophageal junction (GEJ) adenocarcinoma who have received a
prior trastuzumab-based regimen based on the results from the
DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.
ENHERTU (5.4 mg/kg) is approved in the U.S. for the treatment of
adult patients with unresectable or metastatic HER2 positive (IHC
3+) solid tumors who have received prior systemic treatment and
have no satisfactory alternative treatment options based on
efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and
DESTINY-CRC02 trials. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
a confirmatory trial.
About the ENHERTU Clinical 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
anticancer treatments, such as immunotherapy, also are
underway.
About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca 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.
About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC
portfolio of Daiichi Sankyo currently consists of six ADCs in
clinical development across multiple types of cancer. ENHERTU, a
HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2
directed ADC, are being jointly developed and commercialized
globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3
directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC,
and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being
jointly developed and commercialized globally with Merck & Co.,
Inc., Rahway, N.J. USA. DS-3939, a TA-MUC1 directed ADC, is being
developed by Daiichi Sankyo.
Designed using Daiichi Sankyo’s proprietary DXd ADC Technology
to target and deliver a cytotoxic payload inside cancer cells that
express a specific cell surface antigen, each ADC consists of a
monoclonal antibody attached to a number of topoisomerase I
inhibitor payloads (an exatecan derivative, DXd) via
tetrapeptide-based cleavable linkers.
Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab
deruxtecan, raludotatug deruxtecan and DS-3939 are investigational
medicines that have not been approved for any indication in any
country. Safety and efficacy have not been established.
ENHERTU U.S. 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.
About Daiichi Sankyo Daiichi Sankyo is an innovative
global healthcare company contributing to the sustainable
development of society that discovers, develops and delivers new
standards of care to enrich the quality of life around the world.
With more than 120 years of experience, Daiichi Sankyo leverages
its world-class science and technology to create new modalities and
innovative medicines for people with cancer, cardiovascular and
other diseases with high unmet medical need. For more information,
please visit www.daiichisankyo.com.
_____________________________ References
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Chen Z, et al. Breast Cancer Res Treat. 2023 Nov;202(2):313-323. 3
Manohar P, et al. Cancer Biol Med. 2022 Feb 15; 19(2):202–212. 4
Cortes J, et al. Lancet. 2011;377:914-923. 5 Yuan P, et al. Eur J
Cancer. 2019;112:57-65. 6 Jerusalem G, et al. JAMA Oncol.
2018;4(10):1367–1374. 7 Bray F, et al. CA Cancer J Clin. 2024;
10.3322/caac.21834. 8 National Cancer Institute. SEER Cancer Stat
Facts: Female Breast Cancer Subtypes. Accessed April 2024. 9 Iqbal
N, et al. Mol Biol Int. 2014;852748. 10 Ahn S, et al. J Pathol
Transl Med. 2020;54(1):34-44. 11 Sajjadi E, et al. Cancer Drug
Resist. 2022;5(4):882-888. 12 Modi S, et al. N Engl J Med.
2022;387:9-20. 13 Eiger D, et al. Cancers. 2021 Mar; 13(5):
1015.
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