On December 7, 2022 Updated results from the DESTINY-Breast03 phase 3 trial (Abstract #GS2-02) reported that ENHERTU (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared to trastuzumab emtansine (T-DM1) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane (Press release, AstraZeneca, DEC 7, 2022, View Source [SID1234624921]). These results and primary results from the DESTINY-Breast02 phase 3 trial (Abstract #GS2-01) will be presented today at the 2022 San Antonio Breast Cancer Symposium (#SABCS22), with the updated results from DESTINY-Breast03 simultaneously published in The Lancet.
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ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo (TSE:4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).
In the key secondary endpoint analysis of OS in DESTINY-Breast03, ENHERTU demonstrated a 36% reduction in risk of death versus T-DM1 (hazard ratio [HR] = 0.64; 95% confidence interval [CI] 0.47-0.87; p=0.0037). In both treatment arms, median OS was not yet reached (ENHERTU [40.5-NE] versus T-DM1 [34.0-NE]) after a median duration of follow-up of 28.4 months for ENHERTU and 26.5 months for T-DM1. In the ENHERTU arm, an estimated 77.4% of patients were alive at two years (95% CI: 71.7-81.2) compared to 69.9% of patients treated with T-DM1 (95% CI: 63.7-75.2). The observed survival benefit was consistent across all analyzed subgroups, including patients with or without baseline brain metastases, with or without baseline visceral disease, those who were hormone receptor (HR) positive or HR negative and patients regardless of prior pertuzumab or lines of systemic therapy.
"The main goals of therapy for advanced breast cancer are to control the disease and improve survival, and it is therefore critical to continue to improve upon existing treatment options, particularly in the metastatic setting," said Sara Hurvitz, MD, Medical Oncologist, Professor of Medicine and Director of the Breast Cancer Clinical Trials Program in the Division of Hematology-Oncology at the David Geffen School of Medicine at UCLA, and Medical Director for the Clinical Research Unit at the UCLA Jonsson Comprehensive Cancer Center in Santa Monica, CA. "For patients with HER2 positive breast cancer who experience disease progression following initial treatment in the metastatic setting, ENHERTU has shown significant improvement in survival compared to T-DM1, further confirming this medicine as the new standard of care."
With the additional follow-up in DESTINY-Breast03, ENHERTU also continued to demonstrate a clinically meaningful improvement in progression-free survival (PFS) with a 22 month improvement in median PFS over T-DM1, reaffirming the statistically significant finding at the previous interim analysis. The updated exploratory analysis was not tested for statistical significance and not powered to show differences between treatment arms. The median PFS for patients in the ENHERTU arm was 28.8 months (HR=0.33; 95% CI: 22.4-37.9) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review (BICR). Confirmed objective response rate (ORR) was 78.5% in the ENHERTU arm with 21.1% of patients demonstrating a complete response (CR) versus an ORR of 35.0% in the T-DM1 arm where 9.5% of patients achieved a CR. The median duration of response (DoR) was 36.6 months in the ENHERTU arm and 23.8 months in the T-DM1 arm.
The safety profile observed with ENHERTU in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. Grade 3 or higher treatment-related treatment emergent adverse events (TEAEs) occurred in 47.1% of patients receiving ENHERTU. The most common grade 3 or higher treatment-related TEAEs in the ENHERTU arm were decreased neutrophil count (16.0%), anemia (9.3%), decreased platelet count (7.8%), nausea (7.0%), decreased white blood cell count (6.2%) and fatigue (5.8%). In the ENHERTU arm, 15.2% of patients (n=39) experienced interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 or grade 2) with two grade 3 events and no grade 4 or grade 5 events observed in patients treated with ENHERTU.
"The overall survival benefits shown in both the DESTINY-Breast03 and DESTINY-Breast02 trials further validate the role of ENHERTU in potentially extending the lives of patients with previously treated HER2 positive breast cancer," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Additionally, median progression-free survival was four times longer with one in five patients showing no detectable signs of disease when treated with ENHERTU compared to T-DM1 in DESTINY-Breast03, which is particularly impressive in the metastatic setting of HER2 positive breast cancer."
"The updated results for DESTINY-Breast03 showing that ENHERTU extends patients’ lives and also delays progression by nearly two years reinforces our belief that this medicine has the potential to set a new standard of care for patients with HER2 positive metastatic breast cancer treated in the second-line setting," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "Complemented by DESTINY-Breast02, we now have two phase 3 trials in HER2 positive metastatic breast cancer showing patients in these trials have more disease-free time and live longer when they receive ENHERTU versus the previous standard of care."
All patients in DESTINY-Breast03 received at least one prior cancer therapy, including trastuzumab (ENHERTU = 99.6%; T-DM1 = 99.6%) or pertuzumab (ENHERTU = 62.1%; T-DM1 = 60.1%). In the ENHERTU arm, 41.4% of patients had received one prior line of therapy in the metastatic setting. At baseline, 16.5% of patients in the ENHERTU arm and 14.8% of patients in the T-DM1 arm had a history of brain metastases. As of data cut-off on July 25, 2022, 75 patients remained on treatment with ENHERTU and 18 patients on T-DM1.
Summary of Updated DESTINY-Breast03 Results
Efficacy Measure
ENHERTU (5.4 mg/kg)
n=261
Trastuzumab Emtansine
(T-DM1; 3.6 mg/kg)
n=263
Median OS, months (95% CI)
Not reached (40.5-NE)
Not reached (34.0-NE)
HR=0.64 (0.47-0.87) p=0.0037i
OS rate (%) (95% CI)
12 months
94.1% (90.4-96.4)
86.0% (81.1-89.8)
24 months
77.4 % (71.7-82.1)
69.9% (63.7-75.2)
Median PFS by BICR, months (95% CI)
28.8 months (22.4-37.9)
6.8 months (5.6-8.2)
HR=0.33 (0.26-0.43) p<000001i,ii
Median PFS2 by investigator, months (95% CI)iii
40.5 months (40.5-NE)
25.7 months (18.5-34.0)
HR=0.47 (0.35-0.62) p=0.000001i,ii
Confirmed ORR, % (95% CI)
78.5% (73.1-83.4)
35.0% (29.2-41.1)
p<0.0001i,ii
CR (%)
21.1% (n=55)
9.5% (n=25)
PR (%)
57.5% (n=150)
25.5% (n=67)
SD (%)
18.0% (n=47)
41.8% (n=110)
PD (%)
1.1% (n=3)
17.9% (n=47)
Median DoR, months (95% CI)iv
36.6 months (22.4-NE)
23.8 months (12.6-34.7)
BICR, blinded independent central review; CI, confidence interval; CR, complete response, DoR, duration of response; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PFS2, second progression-free survival; PR, partial response; SD, stable disease
i Two-sided
ii Nominal p value. Updated exploratory analysis was not tested for statistical significance and not powered to show differences between treatment arms
iii From the time of randomization to second progression
iv Based on BICR
DESTINY-Breast02 Primary Results
In the primary results from the DESTINY-Breast02 phase 3 trial, ENHERTU demonstrated a 64% reduction in the risk of disease progression or death in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with T-DM1 compared to physician’s choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine) (HR=0.36; 95% CI: 0.28-0.45; p<0.000001). The median PFS for patients in the ENHERTU arm was 17.8 months (95% CI: 14.3-20.8) compared to 6.9 months (95% CI: 5.5-8.4) for those treated with physician’s choice of therapy as assessed by BICR. Treatment with ENHERTU also showed a 34% reduction in the risk of death compared to physician’s choice of treatment (HR=0.66; 95% CI: 0.50-0.86; p=0.0021) with a median OS of 39.2 months with ENHERTU (95% CI: 32.7-NE) versus 26.5 months with physician’s choice of therapy (95% CI: 21.0-NE).
The data from DESTINY-Breast02 confirm the data seen in the DESTINY-Breast01 phase 2 trial, which supported the first approvals of ENHERTU in patients with HER2 positive metastatic breast cancer who received two or more prior anti-HER2-based regimens.
The safety profile observed with ENHERTU in DESTINY-Breast02 was consistent with previous clinical trials with no new safety concerns identified. Grade 3 or higher treatment-related TEAEs occurred in 41.3% of patients receiving ENHERTU. The most common grade 3 or higher treatment-related TEAEs in the ENHERTU arm were decreased neutrophil count (10.6%), anemia (7.9%), neutropenia (7.7%), nausea (6.7%) and asthenia (5.0%). In the ENHERTU arm, 10.4% of patients (n=42) experienced ILD or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 or grade 2), with three grade 3 events, no grade 4 events and two grade 5 events observed.
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 a 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-Breast02
DESTINY-Breast02 is a global, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus physician’s choice of treatment (trastuzumab/capecitabine or lapatinib/capecitabine) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with T-DM1. Patients were randomized 2:1 to receive either ENHERTU or physician’s choice of treatment. The primary endpoint of DESTINY-Breast02 is PFS based on BICR. The key secondary endpoint is OS. Other secondary endpoints include ORR based on BICR and investigator assessment, DoR based on BICR, PFS based on investigator assessment and safety. DESTINY-Breast02 enrolled approximately 600 patients at multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov.
About HER2 Positive Breast Cancer
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.1 More than two million breast cancer cases were diagnosed in 2020, with nearly 685,000 deaths globally.1 Approximately one in five cases of breast cancer are considered HER2 positive.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
Despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer will often experience disease progression.5,6
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 topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.
ENHERTU (5.4 mg/kg) is approved in more than 35 countries for the treatment of adult patients with unresectable or metastatic HER2 positive 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 also is approved in several countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.
ENHERTU (5.4 mg/kg) is approved in Brazil and the U.S. for the treatment of adult patients with unresectable or metastatic HER2 low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridization (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 under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval 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 several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.
ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.
About the ENHERTU Clinical Development Program
A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.
Regulatory applications for ENHERTU in breast and gastric cancer are currently under review in several countries.