ENHERTU® (fam-trastuzumab deruxtecan-nxki) 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® (fam-trastuzumab deruxtecan-nxki), developed by AstraZeneca and Daiichi Sankyo, has shown promising results in the DESTINY-Breast06 Phase III trial for HR-positive, HER2-low and HER2-ultralow metastatic breast cancer. The trial indicated a median progression-free survival (PFS) of 13.2 months versus 8.1 months for chemotherapy, reducing the risk of disease progression or death by 38% (HR 0.62; 95% CI: 0.51-0.74; p<0.0001). Data also confirmed a higher objective response rate of 57.3% for ENHERTU compared to 31.2% with chemotherapy. No new safety concerns emerged, but interstitial lung disease was noted in 11.3% of patients. Additional data from DESTINY-Breast03 and DESTINY-Breast07 reinforce ENHERTU's potential as a standard treatment in earlier lines for HER2-positive breast cancer.
- Median progression-free survival (PFS) of 13.2 months for ENHERTU vs. 8.1 months for chemotherapy.
- ENHERTU reduced the risk of disease progression or death by 38% (HR 0.62; 95% CI: 0.51-0.74; p<0.0001).
- Objective response rate (ORR) for ENHERTU was 57.3% compared to 31.2% with chemotherapy.
- Clinically meaningful benefit observed in both HER2-low and HER2-ultralow expression subgroups.
- No complete responses in chemotherapy arm, while ENHERTU had multiple complete responses.
- DESTINY-Breast07 showed promising results with 76% ORR for ENHERTU monotherapy and 84% in combination with pertuzumab.
- Interstitial lung disease (ILD) occurred in 11.3% of patients treated with ENHERTU.
- Grade 3 or higher treatment-related adverse events included neutropenia (20.7%), leukopenia (6.9%), and anemia (5.8%).
- Three Grade 5 ILD events (0.7%) were reported.
- A higher incidence of Grade 1 and 2 ILD/pneumonitis in patients with moderate renal impairment.
The latest results from the DESTINY-Breast06 Phase III trial show significant promise for ENHERTU in the treatment of HR-positive, HER2-low and HER2-ultralow metastatic breast cancer. The median progression-free survival (PFS) of 13.2 months compared to 8.1 months for standard chemotherapy represents a notable improvement. This is particularly important as these patients often have limited options following multiple lines of endocrine therapy. The data indicate that ENHERTU can be beneficial even at very low levels of HER2 expression. This suggests a broadening scope for HER2-directed therapies, traditionally limited to higher HER2 expression levels. It also opens up potential treatment avenues for a larger patient population. However, the incidence of interstitial lung disease (ILD) is a safety concern that needs to be managed carefully. Patients and oncologists must weigh the benefits against the potential risks. Overall, these results could redefine treatment standards for this patient group.
From a market perspective, the successful results of the DESTINY-Breast06 trial could significantly impact AstraZeneca and Daiichi Sankyo. The extension of ENHERTU’s efficacy to HER2-low and HER2-ultralow metastatic breast cancer patients represents a notable expansion of its market potential. With a confirmed objective response rate (ORR) of 56.5% in HER2-low and 61.8% in HER2-ultralow patients compared to chemotherapy, ENHERTU demonstrates substantial clinical value. This could drive higher adoption rates among oncologists, translating into increased sales and market share. Furthermore, the performance in the DESTINY-Breast03 and DESTINY-Breast07 trials reinforces ENHERTU’s standing as a standard of care, further solidifying its market position. However, investors should be mindful of the competitive landscape and potential regulatory hurdles related to safety profiles. Despite these factors, the overall outlook for ENHERTU in expanding its indications and market presence appears optimistic.
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
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 commercialized by AstraZeneca and Daiichi Sankyo.
In the primary analysis of DESTINY-Breast06, results showed ENHERTU reduced the risk of disease progression or death by
PFS results by BICR in the overall trial population were similar and showed ENHERTU achieved a
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
Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of
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 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.”
In patients with HER2-low expression, confirmed objective response rate (ORR) was
Summary of results: DESTINY-Breast06
HER2-low
|
Overall trial population
|
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 ( |
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 ( |
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
|
Patients in the trial received a median of two prior lines of endocrine therapy in each treatment arm. In the overall trial population,
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
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;
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
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 (
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.
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
|
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
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
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
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
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 >
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
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, no clinical adverse events of heart failure were reported; however, on echocardiography,
Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.
Additional Dose Modifications
Thrombocytopenia
For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.
Adverse Reactions
HER2-Positive and HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients,
HER2-Positive Metastatic Breast Cancer
DESTINY-Breast03
The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously once every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30).
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
HER2-Low Metastatic Breast Cancer
DESTINY-Breast04
The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg)
DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.
The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity in DESTINY‑Lung02. Nineteen percent of patients were exposed for >6 months.
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU.
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
HER2-Positive (IHC3+) Unresectable or Metastatic Solid Tumors
The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2).
Serious adverse reactions occurred in
ENHERTU was permanently discontinued in
The most common (≥
Use in Specific Populations
- Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
- Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
- Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
- Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
-
Geriatric Use: Of the 1287 patients with HER2-positive or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg,
22% were ≥65 years and3.8% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (59% ) as compared to younger patients (49% ). Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg,40% were ≥65 years and8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01,56% were ≥65 years and14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02,39% were 65 years or older and9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. - Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
- Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.
Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.
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
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 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15
HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately
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, randomized, 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) randomized at multiple sites in
DESTINY-Breast03
DESTINY-Breast03 is a global, head-to-head, randomized, 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
DESTINY-Breast07
DESTINY-Breast07 is a global, randomized, open-label Phase Ib/II dose-finding and dose-expansion trial to explore the safety, tolerability and anti-tumor 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
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 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 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 (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 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 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 tumors 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 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 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 commercialize ENHERTU in March 2019 and datopotamab deruxtecan in July 2020, except in
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 tumor environment.
With ENHERTU, 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 fulvestrant and goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, capivasertib, 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 olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with Merck & Co., Inc. (MSD outside the US and
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 durvalumab, capivasertib in combination with chemotherapy, and durvalumab in combination with other oncology medicines, including olaparib 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 catalyze 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 is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in
References
- 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.
- National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed May 2024.
- Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.
- 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.
- Sajjadi E, et al. Improving HER2 testing reproducibility in HER2-low breast cancer. Cancer Drug Resist. 2022;5(4):882-888.
- 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.
- 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.
- Manohar P, et al. Updates in endocrine therapy for metastatic breast cancer. Cancer Biol Med. 2022 Feb 15; 19(2):202–212.
- 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.
- 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.
- 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.
- Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387:9-20.
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Last Updated 6/24
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FAQ
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