ENHERTU® Showed Substantial Clinical Activity in Patients with HER2 Positive Metastatic Breast Cancer and Brain Metastases

• Daiichi Sankyo and AstraZeneca’s ENHERTU achieved a 61.6% progression-free survival rate at one year in patients with active or stable brain metastases in DESTINY-Breast12
• Largest prospective trial of ENHERTU in this patient population

TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)--Results from the DESTINY-Breast12 phase 3b/4 trial showed that ENHERTU^® (trastuzumab deruxtecan) demonstrated substantial overall and intracranial clinical activity in a large cohort of patients with HER2 positive metastatic breast cancer who have brain metastases and received no more than two prior lines of therapy in the metastatic setting. Results will be presented today as a late-breaking proffered paper presentation (LBA18) at the European Society for Medical Oncology (#ESMO24) and simultaneously published in Nature Medicine.

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 progression-free survival (PFS) assessed by independent central review in patients with brain metastases at baseline (n=263), ENHERTU achieved a 12-month PFS rate of 61.6% (95% confidence interval [CI]: 54.9-67.6). In an additional endpoint analysis in this patient population, ENHERTU demonstrated a central nervous system (CNS) 12-month PFS rate of 58.9% (95% CI: 51.9-65.3). Results were consistent in patients with stable and active brain metastases. Patients with stable brain metastases (n=157) had a 12-month PFS rate of 62.9% (95% CI: 54.0-70.5) and a 12-month CNS PFS rate of 57.8% (95% CI: 48.2-66.1). Patients with active brain metastases (n=106) had a 12-month PFS rate of 59.6% (95% CI: 49.0-68.7) and a 12-month CNS PFS rate of 60.1% (95% CI: 49.2-69.4).

In the primary endpoint analysis of confirmed objective response rate (ORR) assessed by independent central review in patients with no brain metastases at baseline (n=241), ENHERTU demonstrated an ORR of 62.7% (95% CI: 56.5-68.8) with 23 complete responses (CR) and 128 partial responses (PR).

An additional endpoint analysis of CNS ORR in patients with brain metastases at baseline showed ENHERTU demonstrated a CNS ORR of 62.3% (95% CI: 50.1-74.5; n=38/61) in patients with active brain metastases and 79.2% (95% CI: 70.2-88.3; n=61/77) in patients with stable brain metastases. A post-hoc analysis in patients with active brain metastases showed the CNS ORR was 82.6% (95% CI: 67.1-98.1; n=19/23) in untreated patients and 50.0% (95% CI: 34.1-65.9; n=19/38) in patients with treated/progressing brain metastases.

“Up to fifty percent of patients with HER2 positive metastatic breast cancer experience the spread of disease to the brain during the course of their illness, which significantly impacts quality of life and outcomes,” said Nancy Lin, MD, Associate Chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S. and Principal Investigator for the trial. “These data help further characterize the clinical benefit and safety profile of ENHERTU in these patients, which will help guide treatment decisions.”

The safety profile of ENHERTU in DESTINY-Breast12 was consistent with previous breast cancer clinical trials with no new safety concerns identified. The safety profile of DESTINY-Breast12 was generally consistent between the brain metastases and non-brain metastases cohorts. The most common grade 3 or higher adverse events occurring in 5% or more of patients in either cohort included neutropenia (16% in brain metastases and 18% in non-brain metastases), fatigue (9% in brain metastases and 10% in non-brain metastases), anemia (7% in brain metastases and 5% in non-brain metastases) and nausea (5% in brain metastases and 5% in non-brain metastases). Interstitial lung disease (ILD) or pneumonitis occurred in 16.0% of patients in the brain metastases cohort and 12.9% of patients in the non-brain metastases cohort as determined by the investigator. In the brain metastases cohort, there were 26 grade 1 events, eight grade 2 events, one grade 3 event, one grade 4 event and six grade 5 events as determined by the investigator. Five ILD or pneumonitis events in the brain metastases cohort were reported by the investigator as co-occurring with opportunistic infection (one grade 4 and four grade 5). In the non-brain metastases cohort, there were 22 grade 1 ILD events, six grade 2 events, zero grade 3 and 4 events, and three grade 5 events as determined by the investigator.

“Treating brain metastases in patients with breast cancer is challenging as there are few effective treatment options,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “Building on previous studies, these results show ENHERTU can provide strong overall and intracranial clinical activity and support its potential role in treating patients with active or stable brain metastases.”

“The results from DESTINY-Breast12 show substantial clinical activity for patients whose disease has spread to the brain,” said Sunil Verma, MD, Global Head, Oncology Franchise, AstraZeneca. “These data as well as the results in patients without brain metastases further build confidence in the clinical profile of ENHERTU for the second-line treatment of HER2 positive metastatic breast cancer.”

Patients in the DESTINY-Breast12 trial received no more than two prior lines of therapy in the metastatic setting. Median duration of follow-up was 15.4 months (range 0.1-30.0) in the brain metastases cohort and 16.1 months (range 0.8-28.4) in the non-brain metastases cohort. A total of 213 patients (118 in the brain metastases cohort and 95 in the non-brain metastases cohort) remained on treatment as of the data cut-off of February 8, 2024.

Summary of DESTINY-Breast12 Primary Analysis Results

About DESTINY-Breast12
DESTINY-Breast12 is an open-label, multicenter, phase 3b/4 clinical trial designed to evaluate the efficacy and safety of ENHERTU (5.4 mg/kg) in patients with previously treated advanced/metastatic HER2 positive breast cancer. The study includes patients with or without baseline brain metastases who have experienced disease progression following prior anti-HER2-based regimens and have received no more than two lines of therapy in the metastatic setting. Patients were enrolled into one of two cohorts according to the presence or absence of brain metastases at baseline.

The primary endpoints of DESTINY-Breast12 were PFS (brain metastases cohort; cohort 2) or ORR (non-brain metastases cohort; cohort 1) as assessed by independent central review. Additional endpoints included CNS PFS, CNS ORR, ORR in the brain metastases cohort and safety.

DESTINY-Breast12 enrolled 504 patients across multiple sites in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov.

About Breast Cancer, HER2 Expression and Brain Metastases
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, 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 Approximately one in five cases of breast cancer are considered HER2 positive.⁵

Brain metastases occur when cancer cells spread from their original location to the brain. An estimated 10% to 15% of patients diagnosed with metastatic breast cancer will develop brain metastases.⁶ The risk is higher for those with HER2 positive or triple negative metastatic breast cancer, with brain metastases occurring in 30% to 50% of these patients.⁷

The median overall survival for patients with breast cancer who have developed brain metastases is eight months; however, this varies based on subtype and the availability of effective treatments.⁸ Current guidelines do not recommend screening patients with breast cancer for brain metastases. As a result, when brain metastases are eventually diagnosed, patients may already present with advanced disease.⁷

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 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [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 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 (5.4 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, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Full approval in China for this indication will depend on whether a randomized controlled confirmatory clinical trial can demonstrate clinical benefit in this population.

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 in the U.S. 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 ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo.

The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where 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. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which 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. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 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.

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. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1% of patients.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.

Contacts

Media:

Global/US:
Jennifer Brennan
Daiichi Sankyo, Inc.
jennifer.brennan@daiichisankyo.com
+1 908 900 3183 (mobile)

Japan:
Daiichi Sankyo Co., Ltd.
DS-PR@daiichisankyo.co.jp

Investor Relations:
DaiichiSankyoIR@daiichisankyo.co.jp

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