AstraZeneca and Daiichi Sankyo's supplemental Biologics License Application (sBLA) for Enhertu (trastuzumab deruxtecan) has been accepted and granted Priority Review in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who have received at least one endocrine therapy in the metastatic setting based on the positive results from the DESTINY-Breast06 Phase III trial which compared Enhertu to chemotherapy.

The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is anticipated during the first quarter of 2025.

Enhertu was also recently granted Breakthrough Therapy Designation (BTD) by the FDA in this setting. BTD accelerates the development and regulatory review of potential new medicines intended to treat a serious condition and address a significant unmet medical need.

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 up to 85-90% of tumours historically classified as HR-positive, HER2-negative, may be HER2-low or HER2-ultralow.[3,4 ]

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "While endocrine therapies are widely used in the initial treatment of HR-positive metastatic breast cancer, most patients see limited benefit with additional lines of treatment, and subsequent chemotherapy is associated with poor response rates and outcomes. The results from DESTINY-Breast06 show that Enhertu has the potential to evolve the current HR-positive treatment landscape and become the first targeted treatment for patients with HER2-low or HER2-ultralow expression following endocrine therapy."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "This Priority Review highlights the potential to expand the existing indication of Enhertu in HER2-low metastatic breast cancer to include use in an earlier disease setting as well as in a broader patient population that includes HER2-ultralow. We look forward to working closely with the FDA with the goal of bringing Enhertu to more patients as quickly as possible."

The sBLA is based on data from the DESTINY-Breast06 Phase III trial (https://www.astrazeneca.com/media-centre/press-releases/2024/Enhertu-demonstrated-median-progression-free-survival-thirteen-months.html) presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and recently published in The New England Journal of Medicine (https://www.nejm.org/).

In the trial, Enhertu reduced the risk of disease progression or death by 37% by blinded independent central review (BICR) versus chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.53-0.75; p<0.0001) in the overall trial population. Median PFS was 13.2 months with Enhertu compared to 8.1 months with chemotherapy.

Results were consistent between patients with HER2-low expression and HER2-ultralow expression. In the primary endpoint analysis of patients with HER2-low expression, Enhertu showed a median PFS of 13.2 months compared to 8.1 months for chemotherapy (HR 0.62; 95% CI 0.51-0.74; p<0.0001). In a prespecified exploratory analysis of patients with HER2-ultralow expression, Enhertu showed a median PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95% CI 0.50-1.21).

The safety profile of Enhertu in DESTINY-Breast06 was consistent with previous clinical trials of Enhertu in breast cancer with no new safety concerns identified.

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

Enhertu is already approved in more than 65 countries, including the US, for patients with HER2-low metastatic 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.

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 (https://clinicaltrials.gov/study/NCT04494425).

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 (https://clinicaltrials.gov/ct2/show/NCT03529110) 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 (https://clinicaltrials.gov/ct2/show/NCT03734029) 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 (https://www.clinicaltrials.gov/study/NCT04644237?term=DESTINY-Lung02&rank=1) and/or DESTINY-Lung05 (https://clinicaltrials.gov/study/NCT05246514) 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 (https://clinicaltrials.gov/ct2/show/NCT03329690), DESTINY-Gastric02 (https://clinicaltrials.gov/ct2/show/NCT04014075) and/or DESTINY-Gastric06 (https://clinicaltrials.gov/study/NCT04989816) 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 (https://classic.clinicaltrials.gov/ct2/show/NCT04482309), DESTINY-Lung01 (https://clinicaltrials.gov/study/NCT03505710) and DESTINY-CRC02 (https://www.clinicaltrials.gov/study/NCT04744831?term=DESTINY-CRC02&rank=1) 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 (https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html) and datopotamab deruxtecan in July 2020 (https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html#!), 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 (https://www.astrazeneca.com/) and follow the Company on social media @AstraZeneca (https://www.linkedin.com/company/astrazeneca/). 

Contacts
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References

1. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed September 2024.
2. Sajjadi E, et al. Improving HER2 testing reproducibility in HER2-low breast cancer. Cancer Drug Resist. 2022;5(4):882-888.
3. 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. Lancet Oncol. 2021 Aug;22(8):1151-1161.
4. Chen Z, et al. Is HER2 ultra-low breast cancer different from HER2 null or HER2 low breast cancer? A study of 1363 patients. Breast Cancer Res Treat. 2023 Nov;202(2):313-323.
5. Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4. doi: 10.3322/caac.21834.
6. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.
7. 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.
8. Manohar P, et al. Updates in endocrine therapy for metastatic breast cancer. Cancer Biol Med. 2022 Feb 15; 19(2):202-212.
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.
10. Yuan P, et al. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019;112:57-65.
11. Jerusalem G, et al. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer. JAMA Oncol. 2018;4(10):1367-1374.
12. Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387:9-20.