REG - AstraZeneca PLC - Enhertu efficacy results in HER2-low breast cancer

AstraZenecaAnnouncement

06/06/2022 07:01

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RNS Number : 6843N  AstraZeneca PLC  06 June 2022

06 June 2022 07:00 BST

 

Enhertu reduced the risk of disease progression or death by 50% vs.
chemotherapy in patients with HER2-low metastatic breast cancer with
HR-positive and HR-negative disease

 

AstraZeneca and Daiichi Sankyo's Enhertu also improved median overall survival
by more than 6 months vs. chemotherapy in all patients evaluated in
DESTINY-Breast04

 

Enhertu met the primary endpoint of progression-free survival in patients with
HR-positive disease, reducing the risk of disease progression or death by 49%
vs. chemotherapy

 

Enhertu is the first HER2-directed therapy to demonstrate a survival benefit
in this population, potentially redefining treatment for approximately half of
all patients with breast cancer

 

Detailed positive results from the pivotal DESTINY-Breast04 Phase III trial
showed that Enhertu (trastuzumab deruxtecan) demonstrated superior and
clinically meaningful progression-free survival (PFS) and overall survival
(OS) in previously treated patients with HER2-low (immunohistochemistry (IHC)
1+ or IHC 2+/in-situ hybridisation (ISH)-negative) unresectable and/or
metastatic breast cancer with hormone receptor (HR) positive or HR-negative
disease versus standard of care physician's choice of chemotherapy. Results
will be presented during the Plenary Session today at the 2022 American
Society of Clinical Oncology (ASCO) Annual Meeting, and have been
simultaneously published in The
(https://www.nejm.org/doi/full/10.1056/NEJMoa2203690)
(https://www.nejm.org/doi/full/10.1056/NEJMoa2203690) New England Journal of
Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2203690) .

 

Enhertu is a specifically engineered HER2-directed antibody drug conjugate
(ADC) being jointly developed and commercialised by AstraZeneca and Daiichi
Sankyo.

 

In the primary endpoint analysis for DESTINY-Breast04, Enhertu demonstrated a
49% reduction in the risk of disease progression or death versus physician's
choice of chemotherapy in patients with HER2-low metastatic breast cancer with
HR-positive disease (PFS hazard ratio  HR  0.51; 95% confidence interval  CI :
0.40-0.64; p<0.001). A median PFS of 10.1 months was seen in patients
treated with Enhertu compared to 5.4 months with chemotherapy, as assessed by
blinded independent central review (BICR).

 

Results also showed a 36% reduction in the risk of death with Enhertu compared
to chemotherapy in patients with HR-positive disease (OS HR 0.64; 95% CI:
0.48-0.86; p=0.003) with a median OS of 23.9 months with Enhertu versus 17.5
months with chemotherapy, meeting a key secondary endpoint of the trial.

 

Additionally, data showed consistent efficacy for Enhertu in the overall trial
population of patients with HER2-low metastatic breast cancer with HR-positive
or HR-negative disease and across levels of HER2 expression (IHC 1+ and IHC
2+/ISH-). In the key secondary endpoint analysis of PFS by BICR in all
patients, a similar 50% reduction in the risk of disease progression or death
was observed between Enhertu and chemotherapy (PFS HR 0.50; 95% CI: 0.40-0.63;
p<0.001). Results also showed a 36% reduction in the risk of death with
Enhertu compared to chemotherapy (OS HR 0.64; 95% CI: 0.49-0.84; p=0.001) with
a median OS of 23.4 months for Enhertu versus 16.8 months with chemotherapy.

 

Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, US
and Principal Investigator for the trial, said: "The results of
DESTINY-Breast04 show for the first time that a HER2-directed therapy can
provide a survival benefit to patients with low HER2 expression, indicating we
must reconsider the way we categorise patients with metastatic breast cancer.
The efficacy seen with Enhertu also reinforces the potential to establish a
new standard of care for more than half of all patients with breast cancer
currently categorised as having HER2-negative disease, but who actually have
tumours with low HER2 expression."

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said:
"Today's results represent a pivotal moment demonstrating the potential for
Enhertu to redefine the treatment of HER2-targetable cancers. DESTINY-Breast04
validates targeting the lower end of the spectrum of HER2 expression, since
Enhertu reduced the risk of disease progression or death across all types of
patients in the trial by half, and reduced the risk of death by over a third.
We must now evolve the way we classify and treat metastatic breast cancer to
ensure these patients are effectively diagnosed and treated."

 

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "As innovative
research organisations, extending the survival for patients is one of our
primary goals as we seek to identify potentially new treatment options for
patients with metastatic breast cancer. These potentially practice-changing
data show that DESTINY-Breast04 takes us one step closer to achieving this
goal, as Enhertu is the first HER2-directed medicine to demonstrate a survival
benefit in patients with HER2-low metastatic breast cancer. We are honoured by
the recognition these important findings are receiving at one of the world's
most prominent oncology meetings as well as in one of the leading medical
journals."

 

Summary of results: DESTINY-Breast04

 

 Efficacy Measure         HR-Positive (n=494)(i)                             All Patients (n=557)                               HR-Negative (n=58)(i)
                          Enhertu (5.4 mg/kg) (n=331)  Chemotherapy (n=163)  Enhertu (5.4 mg/kg) (n=373)  Chemotherapy (n=184)  Enhertu (5.4 mg/kg) (n=40)  Chemotherapy (n=18)
 PFS
 Median PFS (months)(ii)  10.1                         5.4                   9.9                          5.1                   8.5                         2.9

                          (9.5-11.5)                   (4.4-7.1)             (9.0-11.3)                   (4.2-6.8)             (4.3-11.7)                  (1.4-5.1)
 Hazard Ratio  (95% CI)   0.51 (0.40-0.64)                                   0.50 (0.40-0.63)                                   0.46 (0.24-0.89)

 p-value                  p<0.001                                            p<0.001
 OS
 Median OS (months)       23.9 (20.8-24.8)             17.5                  23.4                         16.8                  18.2                        8.3

                                                       (15.2-22.4)           (20.0-24.8)                  (14.5-20.0)           (13.6-NE)                   (5.6-20.6)
 Hazard Ratio  (95% CI)   HR 0.64 (0.48-0.86)                                HR 0.64 (0.49-0.84)                                HR 0.48 (0.24-0.95)

 p-value                  p=0.003                                            p=0.001
 Confirmed ORR (%)        52.6% (47.0-58.0)            16.3%                 52.3%                        16.3%                 50.0%                       16.7%

 (95% CI)(ii,iii)                                      (11.0-22.8)           (47.1-57.4)                  (11.3-22.5)           (33.8-66.2)                 (3.6-41.4)
 Complete Response (%)    3.6%                         0.6%                  3.5%                         1.1%                  2.5%                        5.6%
 Partial Response (%)     49.2%                        15.7%                 49.1%                        15.2%                 47.5%                       11.1%
 Stable Disease (%)       35.1%                        50.0%                 34.6%                        49.5%                 30.0%                       44.4%
 Progressive Disease (%)  7.8%                         21.1%                 8.3%                         22.3%                 12.5%                       33.3%

 (95% CI)
 Median DoR (months)(ii)  10.7                         6.8                   10.7                         6.8                   8.6                         4.9
 CBR (%)(ii,iv)           71.2%                        34.3%                 70.2%                        33.7%                 62.5%                       27.8%
 DCR (%)(iv,v)            88.0%                        66.3%                 87.1%                        65.8%                 80.0%                       61.1%

CI, confidence interval; CBR, clinical benefit rate; DCR, disease control
rate; DoR, Duration of Response; HR, hazard ratio; NE, not evaluable; ORR,
overall response rate; OS, overall survival; PFS, progression-free survival

(i) For the primary end point (PFS in the HR-positive cohort) and key
secondary end points (PFS among all patients and OS in the HR-positive cohort
and among all patients), the HR status is based on data collected with the use
of the interactive web-response and voice-response system at the time of
randomisation, which includes patients who were mis-stratified. For the other
end points, HR status is based on data from the electronic data capture that
was corrected for mis-stratification

(ii) As assessed by BICR

(iii) ORR is (Complete Response + Partial Response)

(iv) CBR is Complete Response + Partial Response + Stable Disease (≥ 6
months)

(v) DCR is (Complete Response + Partial Response + Stable Disease)

 

In an exploratory analysis of patients with HR-negative disease (n=58), median
PFS was 8.5 months with Enhertu versus 2.9 months with chemotherapy (PFS HR
0.46; 95% CI: 0.24-0.89) and median OS was 18.2 months with Enhertu versus 8.3
months with chemotherapy (OS HR 0.48; 95% CI: 0.24-0.95).

 

The safety profile of Enhertu was consistent with previous clinical trials
with no new safety concerns identified. The most common Grade 3 or higher
treatment-emergent adverse events were neutropenia (13.7%), anaemia (8.1%),
fatigue (7.5%), leukopenia (6.5%), thrombocytopenia (5.1%), and nausea (4.6%).

 

Interstitial lung disease (ILD) or pneumonitis rates were consistent with that
observed in late-line HER2-positive breast cancer trials of Enhertu with a
lower rate of Grade 5 ILD observed, as determined by an independent
adjudication committee. The majority (10%) were primarily low Grade (Grade 1
or 2) with five Grade 3 (1.3%), no Grade 4 and three Grade 5 (0.8%) events
reported.

 

Notes

 

Breast cancer and HER2 expression

Breast cancer is the most common cancer and is one of the leading causes of
cancer-related deaths worldwide.(1) More than two million cases of breast
cancer were diagnosed in 2020 with nearly 685,000 deaths globally.(1)

 

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the
surface of many types of tumours including breast, gastric, lung and
colorectal cancers, and is one of many biomarkers expressed in breast cancer
tumours.(2) HER2 expression is currently defined as either positive or
negative, and is determined by an IHC test which measures the amount of HER2
protein on a cancer cell, and/or an ISH test which counts the copies of the
HER2 gene in cancer cells.(2,3) HER2-positive cancers are defined as IHC 3+ or
IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+
or IHC 2+/ISH-.(2)

 

Approximately half of all patients with breast cancer have tumours with a HER2
IHC score of 1+, or 2+ in combination with a negative ISH test, a level of
HER2 expression not currently eligible for HER2-targeted therapy.(4-7) Low
HER2 expression occurs in both HR-positive and HR-negative disease.(8)

( )

HER2 testing is routinely used to determine appropriate treatment options for
patients with metastatic breast cancer. Targeting the lower range of
expression in the HER2 spectrum may offer another approach to delay disease
progression and extend survival in patients with metastatic breast cancer.(9)
Currently, patients with low HER2 expression with HR-positive tumours have
limited treatment options following progression on endocrine (hormone)
therapy.(10) Few targeted options are available for those who are
HR-negative.(11)

( )

DESTINY-Breast04

DESTINY-Breast04 is a global, randomised, open-label, registrational Phase III
trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus
physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine,
paclitaxel or nab-paclitaxel) in patients with HR-positive or HR-negative
HER2-low unresectable and/or metastatic breast cancer previously treated with
one or two prior lines of chemotherapy. Patients were randomised 2:1 to
receive either Enhertu or chemotherapy.

 

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive
disease based on blinded independent central review (BICR). Key secondary
endpoints include PFS based on BICR in all randomised patients (HR-positive
and HR-negative disease), OS in patients with HR-positive disease and OS in
all randomised patients (HR-positive and HR-negative disease). Other secondary
endpoints include PFS based on investigator assessment, objective response
rate based on BICR and on investigator assessment, duration of response based
on BICR and safety.

 

DESTINY-Breast04 enrolled approximately 557 patients at multiple sites in
Asia, Europe and North America. For more information about the trial,
visit ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03734029) .

 

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 programme in AstraZeneca's ADC scientific
platform. Enhertu consists of a HER2 monoclonal antibody attached to a
topoisomerase I inhibitor payload, an exatecan derivative, via a stable
tetrapeptide-based cleavable linker.

 

Enhertu (5.4mg/kg) is approved in the US and Israel for the treatment of adult
patients with unresectable or metastatic HER2-positive breast cancer who have
received a prior anti-HER2-based regimen either in the metastatic setting, or
in the neoadjuvant or adjuvant setting and have developed disease recurrence
during or within six months of completing therapy, based on results from the
DESTINY-Breast03 trial.

 

Enhertu (5.4mg/kg) is also approved in approximately 40 countries for the
treatment of adult patients with unresectable or metastatic HER2-positive
breast cancer who have received two or more prior anti-HER2-based regimens
based on the results from the DESTINY-Breast01 trial.

 

Enhertu (6.4mg/kg) is approved in several countries for the treatment of
adult patients with locally advanced or metastatic HER2-positive gastric or
gastroesophageal junction (GEJ) adenocarcinoma who have received a prior
trastuzumab-based regimen based on the results from the DESTINY-Gastric01
trial.

 

Enhertu development programme

A comprehensive development programme is underway globally, evaluating the
efficacy and safety of Enhertu monotherapy across multiple HER2-targetable
cancers, including breast, gastric, lung and colorectal cancers. Trials in
combination with other anticancer treatments, such as immunotherapy, are also
underway.

 

Regulatory applications for Enhertu are currently under review in China,
Europe, Japan and several other countries for the treatment of adult patients
with unresectable or metastatic HER2-positive breast cancer who have received
a prior anti-HER2 based regimen based on the results from the DESTINY-Breast03
trial.

 

Enhertu was granted Breakthrough Therapy Designation in the US for the
treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+
or IHC 2+/ISH-negative) breast cancer who have received a prior systemic
therapy in the metastatic setting or developed disease recurrence during or
within six months of completing adjuvant chemotherapy, based on the results of
the DESTINY-Breast04 trial. Patients with hormone receptor (HR) positive
breast cancer should additionally have received or be ineligible for endocrine
therapy.

 

Enhertu is also currently under review in the US for the treatment of adult
patients with unresectable or metastatic non-small cell lung cancer (NSCLC)
whose tumours have a HER2 (ERBB2) mutation and who have received a prior
systemic therapy, based on the DESTINY-Lung01 trial, and in Europe for the
treatment of adult patients with locally advanced or metastatic HER2-positive
gastric or GEJ adenocarcinoma who have received a prior anti-HER2-based
regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

 

Daiichi Sankyo collaboration

Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo]
and AstraZeneca entered into a global collaboration to jointly develop and
commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab
deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where
Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for
the manufacturing and supply of Enhertu and datopotamab deruxtecan.

 

AstraZeneca in breast cancer

Driven by a growing understanding of breast cancer biology, AstraZeneca is
starting to challenge, and redefine, the current clinical paradigm for how
breast cancer is classified and treated to deliver even more effective
treatments to patients in need - with the bold ambition to one day eliminate
breast cancer as a cause of death.

 

AstraZeneca has a comprehensive portfolio of approved and promising compounds
in development that leverage different mechanisms of action to address the
biologically diverse breast cancer tumour environment.

 

AstraZeneca aims to continue to transform outcomes for HR-positive breast
cancer with foundational medicines Faslodex (fulvestrant)
and Zoladex (goserelin) and the next-generation oral selective oestrogen
receptor degrader (SERD) and potential new medicine camizestrant.

 

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has
been studied in HER2-negative early and metastatic breast cancer patients with
an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the
US and Canada) continue to research Lynparza in metastatic breast cancer
patients with an inherited BRCA mutation and are exploring new opportunities
to treat these patients earlier in their disease.

 

Building on the initial approvals of Enhertu, a HER2-directed ADC, in
previously treated HER2-positive metastatic breast cancer, AstraZeneca and
Daiichi Sankyo are exploring its potential in earlier lines of treatment and
in new breast cancer settings.

 

To bring much-needed treatment options to patients with triple-negative breast
cancer, an aggressive form of breast cancer, AstraZeneca is testing
immunotherapy Imfinzi (durvalumab) in combination with other oncology
medicines, including Lynparza and Enhertu, evaluating the potential of AKT
kinase inhibitor, capivasertib, in combination with chemotherapy, and
collaborating with Daiichi Sankyo to explore the potential of TROP2-directed
ADC, datopotamab deruxtecan.

 

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide
cures for cancer in every form, following the science to understand cancer and
all its complexities to discover, develop and deliver life-changing medicines
to patients.

 

The Company's focus is on some of the most challenging cancers. It is through
persistent innovation that AstraZeneca has built one of the most diverse
portfolios and pipelines in the industry, with the potential to catalyse
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 commercialisation 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.com (http://www.astrazeneca.com/)  and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts
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.

 

References

1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of
Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J
Clin. 2021; 10.3322/caac.21660.

2. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers:
Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.

3. Wolff A, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast
Cancer: American Society of Clinical Oncology/College of American Pathologists
Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018; 142
(11): 1364-1382.

4. Ahn S, et al. HER2 status in breast cancer: changes in guidelines and
complicating factors for interpretation. J Pathol Transl Med. 2020; 54(1):
34-44.

5. Schalper K, et al. A retrospective population-based comparison of HER2
immunohistochemistry and fluorescence in situ hybridization in breast
carcinomas. Arch Pathol Lab Med. 2014; 138:213-219.

6. Schettini F, et al. Clinical, pathological, and PAM50 gene expression
features of HER2-low breast cancer. npj Breast Cancer. 2021; 7:1 ;
https://doi.org/10.1038/s41523-020-00208-2.

7. Denkert C, et al. Clinical and molecular characteristics of
HER2-low-positive breast cancer: pooled analysis of individual patient data
from four prospective, neoadjuvant clinical trials. 2021. Lancet Oncol; 22:
1151-61.

8. Miglietta F, et al. Evolution of HER2-low expression from primary to
recurrent breast cancer. NPJ Breast Cancer. 2021; 7:137;
10.1038/s41523-021-00343-4.

9. Eiger D, et al. The Exciting New Field of HER2-Low Breast Cancer Treatment.
Cancers. 2021; 10.3390/cancers13051015.

10. Matutino A, et al. Hormone receptor-positive, HER2-negative metastatic
breast cancer: redrawing the lines. Current Oncology. 2018; 25(S1):S131-S141.

11. American Cancer Society. Breast Cancer Hormone Receptor Status. Available
at:
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html.
Accessed June 2022.

 

Dr. Modi has financial interests related to AstraZeneca and Daiichi Sankyo.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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