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

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




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 Daiichi Sankyo and AstraZeneca’s ENHERTU is the first HER2 directed medicine and antibody drug conjugate 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 second-line setting and highlight potential in first-line setting

TOKYO & BASKING RIDGE, N.J.–(BUSINESS WIRE)–Detailed positive results from the DESTINY-Breast06 phase 3 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 IHC 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. Results will be presented today as a late-breaking oral presentation (LBA1000) at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting.


ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

In the primary endpoint analysis of patients with HR positive, HER2 low metastatic breast cancer, ENHERTU reduced the risk of disease progression or death by 38% versus chemotherapy (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 in the chemotherapy arm as assessed by blinded independent central review (BICR).

In the key secondary endpoint analysis of PFS by BICR in the overall trial population, ENHERTU achieved a similar 37% reduction in the risk of disease progression or death versus chemotherapy with a median PFS of 13.2 months in the ENHERTU arm versus 8.1 months with 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 showed a 22% reduction in the risk of disease progression or death compared to chemotherapy with a median PFS of 13.2 months with ENHERTU versus 8.3 months with chemotherapy (HR: 0.78; 95% CI: 0.50-1.21).

In patients with HER2 low expression, confirmed objective response rate (ORR) was 56.5% in the ENHERTU arm with nine complete responses (CRs) and 194 partial responses (PRs) versus 32.2% in the chemotherapy arm with zero CRs and 114 PRs. In the overall trial population, confirmed ORR in the ENHERTU arm was 57.3% with 13 CRs and 237 PRs versus 31.2% in the chemotherapy arm with zero CRs and 134 PRs. In patients with HER2 ultralow expression, the confirmed ORR in the ENHERTU arm was 61.8% with four CRs and 43 PRs versus 26.3% in the chemotherapy arm with zero CRs and 20 PRs.

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,” said Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of Milan and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy and Principal Investigator for the trial. “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 tumors following endocrine therapy in the metastatic setting.”

The safety profile of ENHERTU in DESTINY-Breast06 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 (TEAEs) occurring in 5% or more of patients treated with ENHERTU were neutropenia (20.7%), leukopenia (6.9%) and anemia (5.8%). Interstitial lung disease (ILD) or pneumonitis occurred in 11.3% of patients treated with ENHERTU. The majority of ILD or pneumonitis events were low grade (grade 1 [n=7; 1.6%] or grade 2 [n=36; 8.3%]). There were three grade 3 ILD events (0.7%), zero grade 4 events and three grade 5 events (0.7%) as determined by an independent adjudication committee.

ENHERTU continues to deliver pioneering results for a HER2 directed medicine across many different types of cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These latest results from DESTINY-Breast06 demonstrate clinically meaningful results with ENHERTU even in tumors 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.”

DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR positive metastatic breast cancer,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “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.”

Patients in the DESTINY-Breast06 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 had received one prior line of endocrine therapy and 67.8% (n=295) had received two prior lines 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 March 18, 2024, a total of 119 patients (14.0%) remained on study treatment, with 89 (20.5%) receiving ENHERTU and 30 (7.2%) receiving chemotherapy.

Summary of DESTINY-Breast06 Primary Analysis Results

Efficacy Measure

HER2 low (IHC 1+ and IHC 2+/ISH-)

Overall trial population (HER2 low and HER2 ultralow)

HER2 ultralow (defined as IHC 0 with membrane staining)i,ii

ENHERTU

(n=359)

Chemotherapy

(n=354)

ENHERTU

(n=436)

Chemotherapy

(n=430)

ENHERTU

(n=76)

Chemotherapy

(n=76)

PFS

Median PFSiii (months)

(95% CI)

13.2 months

8.1 months

13.2 months

8.1 months

13.2 months

8.3 months

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

OS

12 month OS Rate (%)

(95% CI)

87.6%

81.7%

87.0%

81.1%

84.0%

78.7%

HR (95% CI)

0.83 (0.66-1.05)

0.81 (0.65-1.00)v

0.75 (0.43-1.29)

p-value

p=0.1181vi

ORR

Confirmed ORRi,iii,vii (%) (n)

56.5% (203)

32.2% (114)

57.3% (250)

31.2% (134)

61.8% (47)

26.3% (20)

Best Overall Response

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 (months)

14.1 months

8.6 months

14.3 months

8.6 months

14.3 months

14.1 months

CI, confidence interval; CR, complete response; DOR, duration of response; HR, hazard ratio; NA, not available; PFS, progression-free survival; ORR, objective response rate; OS, overall survival; PR, partial response; SD, stable disease

i Descriptive analysis

ii Per central lab

iii As assessed by BICR

iv Less than 40% maturity for interim OS analysis (HER2 low)

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

vi P-value of 0.0046 required for statistical significance at this OS interim analysis

vii ORR is (CR + PR)

Additional ENHERTU Data at ASCO

DESTINY-Breast03 Updated Results

Updated overall survival (OS) results from the DESTINY-Breast03 phase 3 trial also presented as a poster show 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. In the updated analysis of OS, the key secondary endpoint of median OS has been reached in both treatment arms. Median OS was 52.6 months (95% CI: 48.7-NE) in the ENHERTU arm compared to 42.7 months (95% CI: 35.4-NE) in the T-DM1 arm (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. Grade 3 or higher treatment related TEAEs occurred in 48.6% of patients receiving ENHERTU. Since the prior data cut-off, there were four new ILD events (all grade 2).

DESTINY-Breast07 Results

Interim results from the DESTINY-Breast07 phase 1b/2 trial of ENHERTU alone or in combination with other anticancer therapies as a first-line treatment for HER2 positive metastatic breast cancer also were presented as an oral presentation. In the analysis, ENHERTU demonstrated promising activity as a monotherapy (n=75) and in combination with pertuzumab (n=50).

Confirmed ORR in the ENHERTU monotherapy arm was 76.0% (80% CI: 68.5-82.4) with six CRs and 51 PRs. In the ENHERTU plus pertuzumab combination arm, confirmed ORR was 84.0% (80% CI: 75.3-90.5) with 10 CRs and 32 PRs. The 12-month PFS rate was 80.8% (80% CI: 73.7-86.1) in the ENHERTU monotherapy arm and 89.4% (80% CI: 81.9-93.9) in the ENHERTU plus pertuzumab combination arm.

The safety of ENHERTU as a monotherapy and in combination with pertuzumab was consistent with known safety profiles of each therapy. Grade 3 or higher TEAEs occurred in 52.0% of patients in the ENHERTU monotherapy arm and 62.0% of patients in the ENHERTU plus pertuzumab combination arm. The most common grade 3 or higher TEAEs occurring in 5% or more of patients were neutropenia (27.0% in ENHERTU monotherapy arm; 24% in ENHERTU plus pertuzumab arm), anemia (4.0% in ENHERTU monotherapy arm; 14.0% in ENHERTU plus pertuzumab arm) and diarrhea (3.0% in ENHERTU monotherapy arm; 6.0% in ENHERTU plus pertuzumab arm). The majority of ILD or pneumonitis events were low grade (grade 1 or 2). In the ENHERTU monotherapy arm, there were two (2.7%) grade 1 events and five (6.7%) grade 2 events. There were no grade 3 or higher events observed in the ENHERTU monotherapy arm. In the ENHERTU plus pertuzumab combination arm, there were six (12.0%) grade 2 events and one (2.0%) grade 3 event. There were no grade 4 or 5 events observed in the ENHERTU plus pertuzumab combination arm.

This is the first dataset of ENHERTU as a first-line treatment of HER2 positive metastatic breast cancer. Analyses from the ongoing DESTINY-Breast09 phase 3 trial will provide further insights regarding the efficacy and safety of ENHERTU in this HER2 positive patient population.

About DESTINY-Breast06

DESTINY-Breast06 is a global, randomized, open-label, phase 3 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 IHC 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 also were 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 first-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 patients 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. Analysis of the HER2 ultralow subgroup was not powered to demonstrate statistical significance.

DESTINY-Breast06 enrolled 866 patients (n=713 for HER2 low and n=153 for HER2 ultralow) at multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov.

About DESTINY-Breast03

DESTINY-Breast03 is a global, head-to-head, randomized, open-label, pivotal phase 3 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, Oceania 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.

About DESTINY-Breast07

DESTINY-Breast07 is a global, randomized, open-label phase 1b/2 dose-finding and dose-expansion trial to explore the safety, tolerability and antitumor 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 second-line or later treatment. The dose expansion phase enrolled patients with locally assessed HER2 positive breast cancer previously untreated for advanced or metastatic disease.

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.

About 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 about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer.3 Patients with high levels of HER2 expression (IHC 3+ or IHC2+/ISH+) are classified as HER2 positive and treated with HER2 targeted therapies, representing approximately 15 to 20% percent of all breast cancers.4 Historically, tumors that were not classified as HER2 positive were classified as HER2 negative, despite the fact that many of these tumors still carry some level of HER2 expression.5 It is estimated that approximately 60% to 65% of HR positive breast cancers are HER2 low and potentially an additional 25% may be HER2 ultralow.6,7

Endocrine therapies are widely given consecutively in the early lines of treatment for HR positive metastatic breast cancer. However, following two lines of endocrine therapy, further efficacy with additional endocrine treatment is often limited. 8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes. 8,9,10,11

Prior to the approval of ENHERTU following chemotherapy in HER2 low metastatic breast cancer based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2 low expression.12 There are no targeted therapies specifically approved for patients with HER2 ultralow expression.13

About ENHERTU

ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) 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 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 worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+ or in-situ hybridization (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 (5.4 mg/kg) is approved in more than 60 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 (5.4 mg/kg) is approved in more than 35 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors 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 U.S. 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 45 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 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 U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors 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 may be contingent upon verification and description of clinical benefit in a confirmatory trial.

About the ENHERTU Clinical Development Program

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

About the Daiichi Sankyo and AstraZeneca Collaboration

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

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc., Rahway, N.J. USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

Designed using Daiichi Sankyo’s proprietary DXd ADC Technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

ENHERTU U.S. 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 (IHC 3+ or ISH 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 (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen

  • Unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options

    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.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
  • Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
  • Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU.

Contacts

Global/US:
Jennifer Brennan

Daiichi Sankyo, Inc.

jbrennan2@dsi.com
+1 908 900 3183 (mobile)

Japan:
Daiichi Sankyo Co., Ltd.

DS-PR@daiichisankyo.co.jp

Investor Relations Contact:
DaiichiSankyoIR@daiichisankyo.co.jp

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