Enhertu demonstrated a median progression-free survival of 13.2 months in HR-positive, HER2-low and HER2-ultralow metastatic breast cancer following one or more lines of endocrine therapy

DESTINY-Breast06 results show AstraZeneca and Daiichi Sankyo’s Enhertu is the first HER2-directed medicine and ADC to demonstrate clinically meaningful benefit for patients in this setting. Additionally, data from DESTINY-Breast03 and DESTINY-Breast07 trials in HER2-positive metastatic breast cancer reinforce Enhertu as standard of care in 2nd-line setting and highlight potential in 1st-line setting.

Detailed positive results from the DESTINY-Breast06 Phase III trial showed that Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemotherapy in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer and the overall trial population (patients with HR-positive, HER2-low and HER2-ultralow [defined as IHC 0 with membrane staining] expression) following one or more lines of endocrine therapy.

These results will be presented today as a late-breaking oral presentation during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA1000).

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.

In the primary analysis of DESTINY-Breast06, results showed Enhertu reduced the risk of disease progression or death by 38% by blinded independent central review (BICR) versus chemotherapy in patients with HER2-low expression (hazard ratio [HR] 0.62; 95% confidence interval [CI]: 0.51-0.74; p<0.0001). Median PFS was 13.2 months in the Enhertu arm compared to 8.1 months for chemotherapy.

PFS results by BICR in the overall trial population were similar and showed Enhertu achieved a 37% reduction in the risk of disease progression or death compared to chemotherapy, with a median PFS of 13.2 months with Enhertu versus 8.1 months for chemotherapy (HR 0.63; 95% CI: 0.53-0.75; p<0.0001).

A prespecified exploratory analysis showed the clinically meaningful improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, Enhertu reduced the risk of disease progression or death by 22% compared to chemotherapy with a median PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95% CI: 0.50-1.21).

Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of Milan and Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy and principal investigator for the trial, said: “Endocrine therapies are widely used early in the treatment of HR-positive metastatic breast cancer, but following one or more lines of treatment, patients often derive limited efficacy from further endocrine-based therapy. With a median progression-free survival of more than a year, the results from DESTINY-Breast06 show that Enhertu could become a new standard of care for patients with HER2-low- and HER2-ultralow-expressing tumours following endocrine therapy in the metastatic setting.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR-positive metastatic breast cancer. The results reinforce the potential for Enhertu to improve outcomes earlier in the treatment landscape and in a broader population of patients with HER2-expressing breast cancer who have never before been eligible for a HER2-directed therapy.”

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “Enhertu continues to deliver pioneering results for a HER2-directed medicine across many different types of cancer. These latest results from DESTINY-Breast06 demonstrate clinically meaningful results with Enhertu even in tumours with very low levels of HER2 expression, suggesting that it may have an important role in treating a wide range of HER2-expressing metastatic breast cancer.”

In patients with HER2-low expression, confirmed objective response rate (ORR) was 56.5% for Enhertu versus 32.2% with chemotherapy. In the overall trial population, confirmed ORR was 57.3% for Enhertu versus 31.2% with chemotherapy and in patients with HER2-ultralow expression the confirmed ORR was 61.8% versus 26.3%, respectively. Complete responses were seen in 13 patients from the Enhertu arm, including nine patients with HER2-low expression. In the HER2-ultralow subgroup, four patients in the Enhertu arm had complete responses. No complete responses were seen in the chemotherapy arm.

Summary of results: DESTINY-Breast06

	HER2-low (IHC 1+ or IHC 2+/ISH-)i		Overall trial population (HER2-low and HER2-ultralow)		HER2-ultralow (defined as IHC 0 with membrane staining)i
	Enhertu(n=359)	Chemo(n=354)	Enhertu(n=436)	Chemo(n=430)	Enhertu(n=76)	Chemo(n=76)
PFSii
Median PFS in months	13.2	8.1	13.2	8.1	13.2	8.3
HR (95% CI)	0.62 (0.51-0.74)		0.63 (0.53-0.75)		0.78 (0.50-1.21)
p-value	p<0.0001		p<0.0001		---
OSiii
HR (95% CI)	0.83 (0.66-1.05)		0.81 (0.65-1.00)		0.75 (0.43-1.29)
p-value	p=0.1181iv		Not testedv		---
12-month OS rate (%)	87.6	81.7	87.0	81.1	84.0	78.7
ORRii,vi
Confirmed ORR (%) (n)vii	56.5 (203)	32.2 (114)	57.3(250)	31.2(134)	61.8 (47)	26.3 (20)
CR (%) (n)	2.5 (9)	0	3.0 (13)	0	5.3 (4)	0
PR (%) (n)	54.0 (194)	32.2 (114)	54.4 (237)	31.2 (134)	56.6 (43)	26.3 (20)
SD (%) (n)	34.8 (125)	48.0 (170)	33.9 (148)	49.3 (212)	28.9 (22)	55.3 (42)
Median DOR in months	14.1	8.6	14.3	8.6	14.3	14.1

PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DOR, duration of response

ⁱ HER2-low status determined per IRT data, and HER2-ultralow status determined per central laboratory data

ⁱⁱ As assessed by BICR

ⁱⁱⁱ Less than 40% maturity for interim OS analysis

^iv P-value of <0.0046 required for statistical significance

^v No test of significance was performed in line with the multiple testing procedure

^vi ORR is (CR + PR); ORR based on RECIST v1.1

^vii Response required confirmation after 4 weeks

Patients in the trial received a median of two prior lines of endocrine therapy in each treatment arm. In the overall trial population, 14.9% of patients (n=65) in the Enhertu arm and 19.2% of patients (n=82) in the chemotherapy arm had received one prior line of endocrine therapy. No patients in the trial had received prior chemotherapy treatment in the metastatic setting. Median duration of follow-up was 18.2 months. As of the data cut-off of 18 March 2024, a total of 119 patients (14%) remained on treatment, 89 patients receiving Enhertu and 30 receiving chemotherapy.

The safety profile of Enhertu was consistent with previous breast cancer clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-related treatment-emergent adverse events occurring in 5% or more of patients treated with Enhertu were neutropenia (20.7%), leukopenia (6.9%) and anaemia (5.8%). Interstitial lung disease (ILD)/pneumonitis, adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with Enhertu. The majority of ILD events were low Grade (Grade 1 [n=7; 1.6%]; Grade 2 [n=36; 8.3%]). There were three Grade 3 ILD events (0.7%), no Grade 4 events and three Grade 5 events (0.7%).

Additional Enhertu data at ASCO

DESTINY-Breast03 updated results
Updated overall survival (OS) results from the DESTINY-Breast03 Phase III trial showed Enhertu continued to demonstrate a clinically meaningful survival improvement over trastuzumab emtansine (T-DM1) after more than three years of follow up in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab.

Results showed median OS was 52.6 months in the Enhertu arm compared to 42.7 months for T-DM1 (HR 0.73; 95% CI: 0.56-0.94).

The safety profile of Enhertu continues to be generally manageable and no cumulative toxicities were observed with longer follow-up. Results will be presented during the 2024 ASCO Annual Meeting (abstract #1025).

DESTINY-Breast07 results

Interim results from the DESTINY-Breast07 Phase Ib/II trial of Enhertu alone or in combination with other anticancer therapies as a 1st-line treatment for HER2-positive metastatic breast cancer demonstrated promising clinical activity for Enhertu as a monotherapy (n=75) and in combination with pertuzumab (n=50). Results were presented as an oral presentation at the 2024 ASCO Annual Meeting (abstract #1009).

Results showed a confirmed ORR of 76.0% with Enhertu and 84.0% with Enhertu in combination with pertuzumab. The 12-month PFS rate was 80.8% with Enhertu monotherapy and 89.4% with Enhertu and pertuzumab.

The safety of Enhertu as a monotherapy and in combination with pertuzumab was consistent with the known safety profiles of each therapy. ILD/pneumonitis was reported in seven patients (9.3%) in the Enhertu monotherapy arm and seven patients (14.0%) in the combination arm. All ILD events were Grade 3 or lower.

These are the first data presented for Enhertu as a 1st-line treatment in HER2-positive metastatic breast cancer. Analyses from the ongoing DESTINY-Breast09 Phase III trial will provide further insights regarding the efficacy and safety of Enhertu in this HER2-positive patient population.

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.¹ More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.¹ 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.²

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.³ 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.⁴ Historically, tumours that were not classified as HER2-positive were classified as HER2-negative.⁵

HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.² Despite being classified as HER2-negative, many of these tumours still carry some level of HER2 expression.⁵ It is estimated that approximately 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow.^6,7

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 (5.4 mg/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 (defined as 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.

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.

DESTINY-Breast03

DESTINY-Breast03 is a global, head-to-head, randomised, open-label, pivotal Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/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. OS is the key secondary efficacy outcome measure. Other secondary endpoints include ORR, DOR, PFS based on investigator assessment and safety.

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

DESTINY-Breast07

DESTINY-Breast07 is a global, randomised, open-label Phase Ib/II dose-finding and dose-expansion trial to explore the safety, tolerability and anti-tumour activity of Enhertu alone or in combination with other anticancer agents in patients with HER2-positive metastatic breast cancer.

The study consists of two phases: a dose escalation phase and a dose expansion phase. The dose escalation phase enrolled patients with locally assessed HER2-positive or advanced metastatic breast cancer in 2nd-line or later treatment. The dose expansion phase enrolled patients with previously untreated for HER2-positive advanced or metastatic breast cancer.

The primary endpoints of DESTINY-Breast07 are safety and tolerability. Secondary endpoints include ORR and PFS based on investigator assessment.

DESTINY-Breast07 enrolled 244 patients at multiple sites in Asia, Europe, 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 (5.4 mg/kg) is approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or in-situ hybridisation [ISH]+) 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 (5.4 mg/kg) is approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or 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 (5.4 mg/kg) is approved in more than 35 countries 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 trial. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4 mg/kg) is approved in more than 40 countries 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 and/or DESTINY-Gastric02 trials.

Enhertu (5.4 mg/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 who have no satisfactory alternative treatment options based on results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials.

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 operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca. 

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