ENHERTU® (fam-trastuzumab deruxtecan-nxki) Achieved Statistically Significant Overall Survival, Reducing the Risk of Death by 36% Vs. Trastuzumab Emtansine (T-DM1) in Patients With HER2-positive Metastatic Breast cancer in DESTINY-Breast03

AstraZeneca and Daiichi Sankyo’s ENHERTU also improved progression-free survival by 22 months vs. T-DM1 in patients previously treated with HER2-directed therapy in the DESTINY-Breast03 Phase III trial

ENHERTU showed significant progression-free and overall survival improvements vs. chemotherapy in later-line HER2-positive setting in the DESTINY-Breast02 Phase III trial

WILMINGTON, DE, USA I December 07, 2022 I Updated results from the DESTINY-Breast03 Phase III trial showed that ENHERTU^® (fam-trastuzumab deruxtecan-nxki) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared to trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. These results and primary results from the DESTINY-Breast02 Phase III trial will be presented today at the 2022 San Antonio Breast Cancer Symposium (SABCS), with the updated results from DESTINY-Breast03 simultaneously published in The Lancet.

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

In the key secondary endpoint analysis of OS for DESTINY-Breast03, ENHERTU demonstrated a 36% reduction in risk of death versus T-DM1 (based on a hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.47-0.87; p=0.0037). In both treatment arms, median OS was not yet reached (ENHERTU [40.5-NE] versus T-DM1 [34.0-NE]) after a median duration of follow-up of 28.4 months for ENHERTU and 26.5 months for T-DM1. An estimated 77.4% of patients were alive in the ENHERTU arm at two years compared to 69.9% of patients treated with T-DM1. The observed survival benefit was consistent across all analyzed subgroups, including patients with or without baseline brain metastases, with or without baseline visceral disease, those who were hormone receptor (HR)-positive or HR-negative, and regardless of prior pertuzumab or lines of systemic therapy.

Sara Hurvitz, MD, Medical Oncologist, Professor of Medicine, and Director of the Breast Cancer Clinical Trials Program in the Division of Hematology-Oncology at the David Geffen School of Medicine at UCLA, and Medical Director for the Clinical Research Unit at the UCLA Jonsson Comprehensive Cancer Center in Santa Monica, CA, said: “The main goals of therapy for advanced breast cancer are to control the disease and improve survival, and it is therefore critical to continue to improve upon existing treatment options, particularly in the metastatic setting. For patients with HER2-positive breast cancer who experience disease progression following initial treatment in the metastatic setting, ENHERTU has shown significant improvement in survival compared to T-DM1, further confirming this medicine as the new standard of care.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “The updated results for DESTINY-Breast03 showing that ENHERTU extends patients’ lives and also delays progression by nearly two years reinforces our belief that this medicine has the potential to set a new standard of care for patients with HER2-positive metastatic breast cancer treated in the second-line setting. Complemented by DESTINY-Breast02, we now have two Phase III trials in HER2-positive metastatic breast cancer showing patients in these trials have more disease-free time and live longer when they receive ENHERTU versus the previous standard of care.”

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “The overall survival benefits shown in both the DESTINY-Breast03 and DESTINY-Breast02 trials further validate the role of ENHERTU in potentially extending the lives of patients with previously treated HER2-positive breast cancer. Additionally, median progression-free survival was four times longer with one in five patients showing no detectable signs of disease when treated with ENHERTU compared to T-DM1 in DESTINY-Breast03, which is particularly impressive in the metastatic setting of HER2-positive breast cancer.”

With the additional follow-up in DESTINY-Breast03, ENHERTU also continued to demonstrate a clinically meaningful improvement in progression-free survival (PFS) with a 22 month improvement in median PFS over T-DM1, reaffirming the statistically significant finding at the previous interim analysis. The updated exploratory analysis was not tested for statistical significance and not powered to show differences between treatment arms. In this exploratory post-hoc analysis, the median PFS for patients in the ENHERTU arm was 28.8 months compared to 6.8 months for T-DM1, as assessed by blinded independent central review (BICR). Confirmed objective response rate (ORR) was 78.5% in the ENHERTU arm with 21.1% of patients demonstrating a complete response (CR) versus an ORR of 35.0% in the T-DM1 arm, where 9.5% of patients achieved a CR. The median duration of response (DoR) was 36.6 months in the ENHERTU arm and 23.8 months in the T-DM1 arm.

Summary of updated results: DESTINY-Breast03

The safety profile observed with ENHERTU in DESTINY-Breast03 was consistent with previous clinical trials, with no new safety concerns identified. The most common Grade 3 or higher treatment-related treatment-emergent adverse events (TEAEs) in the ENHERTU arm were decreased neutrophil count (16.0%), anemia (9.3%), decreased platelet count (7.8%) and nausea (7.0%). There were 39 cases (15.2%) of treatment-related interstitial lung disease (ILD) or pneumonitis reported, as determined by an independent adjudication committee. The majority (14.4%) were low grade (Grade 1 or Grade 2) with two Grade 3 (0.8%) events. No Grade 4 or Grade 5 ILD or pneumonitis events occurred.

DESTINY-Breast02 full results show significant improvements in PFS and OS versus chemotherapy in later-line HER2-positive metastatic breast cancer setting
In primary results from the DESTINY-Breast02 Phase III trial, ENHERTU demonstrated a 64% reduction in the risk of disease progression or death in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with T-DM1 versus physician’s choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine) [HR=0.36; 95% CI 0.28-0.45; p<0.000001]. The median PFS for patients in the ENHERTU arm was 17.8 months versus 6.9 months for those in the physician’s choice of treatment arm, as assessed by BICR. ENHERTU also showed a 34% reduction in the risk of death compared to physician’s choice of treatment (HR=0.66; 95% CI 0.50-0.86; p=0.0021) with a median OS of 39.2 months versus 26.5 months.

The data from DESTINY-Breast02 confirms the data seen in the DESTINY-Breast01 Phase II trial which supported the first approvals of ENHERTU in patients with HER2-positive metastatic breast cancer who have received two or more prior anti-HER2-based regimens.

The safety profile of ENHERTU in DESTINY-Breast02 was consistent with previous clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-related TEAEs in the ENHERTU arm were decreased neutrophil count (10.6%), anemia (7.9%), neutropenia (7.7%) and nausea (6.7%). There were 42 cases (10.4%) of treatment-related ILD or pneumonitis reported, as determined by an independent adjudication committee. The majority (9.1%) were low grade (Grade 1 or Grade 2) with three Grade 3 (0.7%) events, no Grade 4 events and two (0.5%) Grade 5 ILD or pneumonitis events occurring.

Important Safety Information

Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either:
  • In the metastatic setting, or
  • In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy
• Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
• Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy
  This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

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 patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.¹ Approximately one in five cases of breast cancer are considered HER2-positive.²

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers.³ HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer.⁴

Despite initial treatment with trastuzumab and a taxane, patients with HER2-positive metastatic breast cancer will often experience disease progression.^5,6

DESTINY-Breast03
DESTINY-Breast03 is a global, head-to-head, randomized, open-label, registrational Phase III trial evaluating the efficacy and safety of ENHERTU (5.4mg/kg) versus T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

The primary efficacy endpoint of DESTINY-Breast03 is PFS based on BICR. Overall survival is a key secondary efficacy outcome measure. Other secondary efficacy endpoints include ORR, DoR, PFS based on investigator assessment and safety.

DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Oceania and South America. Primary results from DESTINY-Breast03 were published in The New England Journal of Medicine.⁷ For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Breast02
DESTINY-Breast02 is a global, randomized, open-label, Phase III trial evaluating the efficacy and safety of ENHERTU (5.4mg/kg) versus physician’s choice of treatment (trastuzumab/capecitabine or lapatinib/capecitabine) in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with T-DM1. Patients were randomized 2:1 to receive either ENHERTU or physician’s choice of treatment.

The primary endpoint of DESTINY-Breast02 is PFS based on BICR. The key secondary endpoint is OS. Other secondary endpoints include ORR based on BICR and investigator assessment, DoR based on BICR, PFS based on investigator assessment and safety.

DESTINY-Breast02 enrolled approximately 600 patients at multiple sites in Asia, Europe, North America, Oceania, and South America. For more information about the trial, visit ClinicalTrials.gov.

ENHERTU
ENHERTU is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4mg/kg) is approved in more than 35 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 is also 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 Brazil and the US for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridization [ISH]-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

ENHERTU (5.4mg/kg) is approved under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory 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.

ENHERTUdevelopment program
A comprehensive global development program is underway 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, non-small cell lung and gastric cancer are currently under review in several countries.

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 (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 tumor environment.

With ENHERTU, a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings.

In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines fulvestrant and goserelin and aims to reshape the HR-positive space with ngSERD and potential new medicine camizestrant as well as a potential first-in-class AKT kinase inhibitor, capivasertib. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting.

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

To bring much-needed treatment options to patients with TNBC, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy durvalumab, capivasertib in combination with chemotherapy, and durvalumab in combination with other oncology medicines, including olaparib and ENHERTU.

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

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (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

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3. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014; 852748.
4. Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21):4099-4105.
5. Barok M, et al. Trastuzumab emtansine: mechanism of action and drug resistance. Breast Cancer Res. 2014; 16(2):209.
6. Nader-Marta G, et al. How we treat patients with metastatic HER2-positive breast cancer. ESMO Open. 2022; 7:1.
7. Cortes J, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022; 386:1143-1154. 

SOURCE: AstraZeneca