AstraZeneca and Daiichi Sankyo’s Enhertu Receives Priority Review for HER2-Low and Ultralow Breast Cancer Patients Pre-Chemotherapy

(IN BRIEF) AstraZeneca and Daiichi Sankyo announced that their drug Enhertu (trastuzumab deruxtecan) has been granted Priority Review by the US FDA for treating patients with unresectable or metastatic HER2-low or HER2-ultralow breast cancer who have previously undergone endocrine therapy. The decision is based on the Phase III DESTINY-Breast06 trial, which showed significant improvements in progression-free survival for patients using Enhertu compared to chemotherapy. If approved, Enhertu will become the first HER2-directed therapy for this patient population before chemotherapy. It has also been granted Breakthrough Therapy Designation, further expediting the review process. This development underscores the potential of Enhertu to redefine treatment options for HER2-low and HER2-ultralow breast cancer, addressing a large unmet need in this area.

(PRESS RELEASE) CAMBRIDGE, 1-Oct-2024 — /EuropaWire/ — AstraZeneca and Daiichi Sankyo’s leading antibody-drug conjugate, Enhertu (trastuzumab deruxtecan), has been granted Priority Review by the U.S. Food and Drug Administration (FDA) for patients with unresectable or metastatic HER2-low or HER2-ultralow breast cancer. This development represents a significant potential shift in treatment options for individuals who have previously undergone at least one line of endocrine therapy in the metastatic setting.

The FDA’s decision follows the positive results from the pivotal DESTINY-Breast06 Phase III trial, where Enhertu demonstrated a substantial and meaningful improvement in progression-free survival (PFS) compared to chemotherapy. This trial marks the first time Enhertu could be made available as a targeted therapy for HER2-low and HER2-ultralow patients prior to chemotherapy, positioning it as a game-changing option for patients with advanced-stage breast cancer.

The FDA grants Priority Review to therapies that have the potential to significantly improve treatment options over existing approaches. If approved, Enhertu will become the first HER2-directed therapy available for this patient population prior to chemotherapy, further expanding its indications.

Enhertu was also recently granted Breakthrough Therapy Designation (BTD) in this specific treatment setting, which highlights the urgency of making the drug accessible to more patients in need. BTD expedites the regulatory process for medications intended to address serious conditions with significant unmet medical needs.

Revolutionizing HER2-Low Breast Cancer Treatment
HER2-low and HER2-ultralow breast cancer subtypes, which include tumors that were traditionally classified as HER2-negative but still exhibit some HER2 expression, account for a large portion of breast cancer diagnoses. Up to 85-90% of tumors previously considered HR-positive, HER2-negative, may actually fall into the HER2-low or HER2-ultralow categories. Currently, after endocrine therapy fails, chemotherapy is the standard next-line treatment, though it often comes with limited efficacy and poor outcomes.

“Endocrine therapies are often effective initially for HR-positive, metastatic breast cancer, but their benefit diminishes with each additional treatment line. The DESTINY-Breast06 results suggest that Enhertu could revolutionize the treatment landscape for patients by offering a targeted option even before chemotherapy,” said Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca.

“This Priority Review is an important milestone as it expands Enhertu’s reach into a broader patient population, including those with HER2-ultralow expression. We look forward to collaborating closely with the FDA to ensure this innovative therapy reaches patients as soon as possible,” added Ken Takeshita, Global Head, R&D, Daiichi Sankyo.

Positive Results from DESTINY-Breast06 Trial
The submission for Priority Review is based on the results of the DESTINY-Breast06 trial, which compared Enhertu to chemotherapy in patients with HR-positive, HER2-low or HER2-ultralow breast cancer. The trial showed that Enhertu reduced the risk of disease progression or death by 37% compared to chemotherapy. The median PFS was 13.2 months for Enhertu versus 8.1 months for chemotherapy, underscoring its potential to deliver longer-lasting benefits.

The trial’s findings were consistent for patients with both HER2-low and HER2-ultralow expression, marking a significant development for this underserved population.

A Potential Paradigm Shift
If approved, Enhertu will become the first targeted therapy specifically for HER2-low and HER2-ultralow metastatic breast cancer, providing patients with an alternative to chemotherapy that is both targeted and more effective.

As Enhertu continues to demonstrate strong efficacy and safety across multiple trials, its role in the treatment of HER2-related cancers continues to expand, offering hope to a broader spectrum of breast cancer patients.

About Enhertu
Enhertu is a HER2-directed DXd antibody drug conjugate (ADC) developed jointly by AstraZeneca and Daiichi Sankyo. It is designed to target and deliver a potent cytotoxic agent directly to cancer cells expressing HER2, reducing off-target effects and enhancing treatment precision. It is approved in more than 65 countries for HER2-positive and HER2-low metastatic breast cancer and continues to be investigated for various other cancer types.

Notes

Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.5 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.5 While survival rates are high for those diagnosed with early breast cancer, only approximately 30% of patients who are diagnosed with or who progress to metastatic disease are expected to live five years after their diagnosis.1

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.6 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15-20% of all breast cancers.7 Historically, tumours that were not classified as HER2-positive were classified as HER2-negative.2

HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.1 Despite being classified as HER2-negative, many of these tumours still carry some level of HER2 expression.2 It is estimated that 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow.3,4

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.8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.8-11

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. There are no targeted therapies specifically approved for patients with HER2-low expression prior to chemotherapy or for patients with HER2-ultralow expression.12

DESTINY-Breast06
DESTINY-Breast06 is a global, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

HER2 status in the trial was confirmed by central laboratory and was performed on an archival tumour sample obtained at the time of initial metastatic diagnosis or later. If archival tissue was not available, a fresh tissue sample was required.

The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by BICR. Key secondary endpoints include PFS by BICR in the overall trial population (HER2-low and HER2-ultralow), OS in the HER2-low patient population and OS in the overall trial population. Other secondary endpoints include ORR, DOR, time to first subsequent treatment or death, time to second subsequent treatment or death and safety.

DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) randomised at multiple sites in Asia, Europe, Australia, North America 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 programme 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 (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or in-situ hybridisation [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 (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours 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 and/or DESTINY-Lung05 trials.  Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/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 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Full approval in China for this indication will depend on whether a randomised controlled confirmatory clinical trial can demonstrate clinical benefit in this population.

Enhertu (5.4mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours 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 in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway.

Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise 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.

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.

With Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate (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 Faslodex and Zoladex (goserelin) and aims to reshape the HR-positive space with first-in-class AKT inhibitor, Truqap, and next-generation SERD and potential new medicine camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in 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 these settings and to explore its potential in earlier disease.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy Imfinzi (durvalumab), Truqap in combination with chemotherapy, and Imfinzi in combination with other oncology medicines, including Lynparza 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 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’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca

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9. Cortes J, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377:914-923.
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