Based on DESTINY-Lung02 results which showed
AstraZeneca and Daiichi Sankyo’s ENHERTU reported a confirmed
objective response rate of 57.7% in patients with HER2-mutant
disease
AstraZeneca and Daiichi Sankyo’s ENHERTU® (fam-trastuzumab
deruxtecan-nxki) has been approved in the US for the treatment of
adult patients with unresectable or metastatic non-small cell lung
cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations,
as detected by a Food and Drug Administration (FDA)-approved test,
and who have received a prior systemic therapy.
This indication is approved under accelerated approval based on
objective response rate (ORR) and duration of response (DoR).
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial.
ENHERTU is a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialized by
AstraZeneca and Daiichi Sankyo.
The accelerated approval by the FDA was based on the results
from the DESTINY-Lung02 Phase II trial. An interim efficacy
analysis in a pre-specified patient cohort showed ENHERTU
(5.4mg/kg) demonstrated a confirmed ORR of 57.7% (n=52; 95%
confidence interval [CI] 43.2-71.3), as assessed by blinded
independent central review (BICR), in patients with previously
treated unresectable or metastatic non-squamous HER2-mutant (HER2m)
NSCLC. Complete responses (CR) were seen in 1.9% of patients and
partial responses (PR) in 55.8% of patients with a median DoR of
8.7 months (95% CI 7.1-NE). Results from the DESTINY-Lung02 trial
will be presented at an upcoming medical meeting.
Bob T. Li, MD, PhD, MPH, Medical Oncologist and
Physician-Scientist, Memorial Sloan Kettering Cancer Center, US,
said: “The approval of trastuzumab deruxtecan in non-small cell
lung cancer is an important milestone for patients and the oncology
community. After two decades of research into the role of targeting
HER2 in lung cancer, the approval of the first HER2-directed
treatment option validates HER2 as an actionable target in lung
cancer and marks an important step forward for treating this
patient population with unmet medical needs.”
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca, said: “HER2-mutant non-small cell lung cancer is
an aggressive form of disease which commonly affects young patients
who have faced limited treatment options and a poor prognosis to
date. Today’s news provides these patients with the opportunity to
benefit from a targeted therapy and highlights the importance of
testing for predictive markers, including HER2 in lung cancer, at
the time of diagnosis to ensure patients receive the most
appropriate treatment for their specific disease.”
Ken Keller, Global Head of Oncology Business, and President and
CEO, Daiichi Sankyo, Inc, said: “We are excited that the FDA has
granted accelerated approval for ENHERTU for patients with
HER2-mutant metastatic non-small cell lung cancer. ENHERTU has now
been approved in three different tumor types, underscoring its
significant potential across several HER2-targetable tumors. We are
continuing to evaluate the efficacy and safety of ENHERTU versus
standard chemotherapy in our DESTINY clinical trials in lung
cancer.”
The safety of ENHERTU was evaluated in an analysis of 101
patients with unresectable or metastatic HER2m NSCLC who received
at least one dose of ENHERTU (5.4mg/kg) in the DESTINY-Lung02
trial. In the analysis, the safety profile of ENHERTU was
consistent with previous clinical trials with no new safety
concerns identified.
Concurrently with this approval, the FDA also approved companion
diagnostic tests to detect HER2 mutations in lung tumor tissue and
plasma. This is the third tumor type approved by the FDA for
ENHERTU in three years, following approval in breast and gastric
cancers. The approval follows the recently received Priority Review
in the US as well as the Breakthrough Therapy Designation granted
in 2020 by the FDA for this specific type of lung cancer based on
the results of the DESTINY-Lung01 trial.
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 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
Financial considerations Following US approval, an amount
of $125m is due from AstraZeneca to Daiichi Sankyo as a milestone
payment for the HER2-mutant metastatic NSCLC indication. The
milestone will be capitalized as an addition to the upfront payment
made by AstraZeneca to Daiichi Sankyo in 2019 and subsequent
capitalized milestones, and will be amortized through the profit
and loss statement.
Sales of ENHERTU in the US are recognized by Daiichi Sankyo.
AstraZeneca reports its share of gross profit margin from ENHERTU
sales in the US as collaboration revenue in the Company’s financial
statements.
Further details on the financial arrangements were set out in
the March 2019 announcement of the collaboration.
HER2m NSCLC Lung cancer is the second most common form of
cancer globally, with more than two million patients diagnosed in
2020.1 In the US, lung cancer is the second most commonly diagnosed
cancer, with more than 236,000 patients expected to be diagnosed in
2022.2 For patients with metastatic NSCLC, prognosis is
particularly poor, as only approximately 8% will live beyond five
years after diagnosis.3
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 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.4,5 Next-generation sequencing is used to identify HER2
(ERBB2) mutations.6
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.7 HER2 gene mutations have been
independently associated with cancer cell growth and poor
prognosis, with an increased incidence of brain metastases.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 accelerated approval of ENHERTU in
unresectable or metastatic NSCLC.8,9
DESTINY-Lung02 DESTINY-Lung02 is a global Phase II trial
evaluating the safety and efficacy of two doses (5.4mg/kg or
6.4mg/kg) of ENHERTU in patients with HER2m 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.
The primary endpoint of the trial is ORR as assessed by BICR.
Secondary endpoints include disease control rate (DCR), DoR,
progression-free survival (PFS), investigator-assessed ORR, overall
survival (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.
DESTINY-Lung01 DESTINY-Lung01 is a global Phase II,
open-label, two-cohort trial evaluating the safety and efficacy of
ENHERTU in patients with HER2m (6.4mg/kg) or HER2-overexpressing
(defined as IHC 3+ or IHC 2+) [6.4mg/kg and 5.4mg/kg] unresectable
and/or metastatic non-squamous NSCLC who had progressed after one
or more systemic therapies. The primary endpoint is confirmed ORR
by independent central review (ICR). Key secondary endpoints
include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181
patients at multiple sites, including Asia, Europe and North
America.
Data from the DESTINY-Lung01 Phase II trial was published in
The New England Journal of Medicine.10
Primary results from previously-treated patients with
HER2-mutations (cohort 2) of DESTINY-Lung01 demonstrated an ORR of
54.9% (95% CI 44.2-65.4) in patients treated with ENHERTU(6.4mg/kg)
as assessed by ICR. One (1.1%) CR and 49 (53.8%) PRs were observed.
A confirmed DCR of 92.3% was seen with a reduction in tumor size
observed in most patients. After a median follow-up of 13.1 months,
the median DoR for ENHERTU was 9.3 months. The median PFS was 8.2
months and the median OS was 17.8 months.
The safety profile of the most common adverse events with
ENHERTU in DESTINY-Lung01 was consistent with previous clinical
trials with no new safety concerns identified. 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 30 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 several countries for the
treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer who have received two or more prior
anti-HER2-based regimens based on the results from the
DESTINY-Breast01 trial.
ENHERTU (5.4mg/kg) is approved in the US 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 chemotherapy
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 the US for the treatment of
adult patients with unresectable or metastatic NSCLC whose tumors
have activating HER2 (ERBB2) mutations, as detected by an
FDA-approved test, and who have received a prior systemic therapy
based on the results from the DESTINY-Lung02 trial.
ENHERTU (6.4mg/kg) is approved in several countries for the
treatment of adult patients with locally advanced or metastatic
HER2-positive gastric or gastroesophageal junction (GEJ)
adenocarcinoma who have received a prior trastuzumab-based regimen
based on the results from the DESTINY-Gastric01 trial.
ENHERTU development program A comprehensive development
program is underway globally, evaluating the efficacy and safety of
ENHERTU monotherapy across multiple HER2-targetable cancers,
including breast, gastric, lung and colorectal cancers. Trials in
combination with other anticancer treatments, such as
immunotherapy, are also underway.
Regulatory applications for ENHERTU in breast and gastric cancer
are currently under review in several countries based on the
DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04,
DESTINY-Gastric01 and DESTINY-Gastric02 trials, respectively.
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
(trastuzumab deruxtecan) 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 Twitter @AstraZenecaUS.
References
- WHO. International Agency of Cancer Research. Cancer Today.
2020. Available at: https://gco.iarc.fr/today/home. Accessed August
2022.
- American Cancer Society. Key Statistics for Lung Cancer.
Available at:
https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.
Accessed August 2022.
- American Cancer Society. Lung Cancer Survival Rates. Available
at:
https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html.
Accessed August 2022.
- 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.
- 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.
- 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.
- 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.
- Li B T, et al. Trastuzumab Deruxtecan in HER2-Mutant
Non-Small-Cell Lung Cancer. NEJM. 2022; 386:241-251.
Dr. Li has provided uncompensated advisory services to
AstraZeneca and Daiichi Sankyo.
###
ENHERTU® is a registered trademark of Daiichi
Sankyo Company, Limited. PP-US-EN-1835 08/22
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Media Inquiries Brendan McEvoy + 302 885 2677 Jessica
McDuell + 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
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