ENHERTU® Reduced the Risk of Disease Progression or Death by 50% vs. Chemotherapy in Patients with HER2 Low Metastatic Breast Cancer with HR Positive and HR Negative Disease
Daiichi Sankyo and AstraZeneca's ENHERTU has shown promising results in the DESTINY-Breast04 trial, enhancing median overall survival by over 6 months compared to chemotherapy for patients with HER2 low metastatic breast cancer. Key findings include a 49% reduction in disease progression or death risk and a median progression-free survival of 10.1 months. The treatment demonstrated a confirmed overall response rate of 52.6%, significantly higher than chemotherapy's 16.3%. The safety profile remains consistent, with most adverse events being manageable.
- ENHERTU achieved a 49% reduction in risk of disease progression or death in HER2 low metastatic breast cancer (HR = 0.51; p<0.001).
- Median progression-free survival (PFS) with ENHERTU was 10.1 months compared to 5.4 months with chemotherapy.
- Overall survival (OS) increased to 23.9 months with ENHERTU versus 17.5 months with chemotherapy (HR = 0.64; p=0.003).
- Confirmed overall response rate (ORR) was 52.6% for ENHERTU, compared to 16.3% for chemotherapy.
- No significant new safety concerns were identified; however, the study reported treatment-emergent adverse events, including neutropenia (13.7%) and anemia (8.1%).
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Daiichi Sankyo and AstraZeneca’s ENHERTU also improved median overall survival by more than 6 months vs. chemotherapy in all patients evaluated in DESTINY-Breast04 -
ENHERTU met the primary endpoint of progression free survival in patients with HR positive disease, reducing the risk of disease progression or death by
49% vs. chemotherapy - ENHERTU is the first HER2 directed therapy to demonstrate a survival benefit in this population, potentially redefining treatment for approximately half of all patients with breast cancer
ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by
In the primary endpoint analysis for DESTINY-Breast04, ENHERTU demonstrated a
Results also showed a
“The results of DESTINY-Breast04 show for the first time that a HER2 directed therapy can provide a survival benefit to patients with low HER2 expression, indicating we must reconsider the way we categorize patients with metastatic breast cancer,” said
Additionally, data showed consistent efficacy for ENHERTU in the overall trial population of patients with HER2 low metastatic breast cancer with HR positive or HR negative disease and across levels of HER2 expression (both IHC1+ and IHC 2+/ISH-). In the key secondary endpoint analysis of PFS by BICR in all patients, a similar
In an exploratory analysis of patients with HR negative disease, median PFS was 8.5 months (4.3-11.7) with ENHERTU versus 2.9 months (1.4-5.1) with chemotherapy (HR=0.46;
The safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher treatment emergent adverse events were neutropenia (
“As innovative research organizations, extending the survival for patients is one of our primary goals as we seek to identify potentially new treatment options for patients with metastatic breast cancer,” said
“Today’s results represent a pivotal moment demonstrating the potential for ENHERTU to redefine the treatment of HER2 targetable cancers,” said
All patients in DESTINY-Breast04 received at least one prior cancer therapy, including targeted therapy (ENHERTU = 279; chemotherapy = 140), a CDK4/6 inhibitor (ENHERTU = 239; chemotherapy = 119), endocrine therapy (ENHERTU = 347; chemotherapy = 165), chemotherapy (ENHERTU = 373; chemotherapy = 183). The median lines of prior systemic therapies in the metastatic setting were three (range 1-9). A prior CDK4/6 inhibitor was received by
Summary of DESTINY-Breast04 Results
Efficacy Measure |
HR Positive (n=494) |
All Patients (n=557) |
HR Negative (n=58)i |
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ENHERTU (5.4 mg/kg) (n=331) |
Chemotherapy (n=163) |
ENHERTU (5.4 mg/kg) (n=373) |
Chemotherapy (n=184) |
ENHERTU (5.4 mg/kg) (n=40) |
Chemotherapy (n=18) |
Median PFS (months)
( |
10.1 months (9.5-11.5) |
5.4 months (4.4-7.1) |
9.9 months (9.0-11.3) |
5.1 months (4.2-6.8) |
8.5 months (4.3-11.7) |
2.9 months (1.4-5.1) |
HR=0.51 (0.40-0.64) p<0.001 |
HR=0.50 (0.40-0.63) p<0.001 |
HR=0.46 (0.24-0.89) |
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Median OS (months)
( |
23.9 months (20.8-24.8) |
17.5 months (15.2-22.4) |
23.4 months (20.0-24.8) |
16.8 months (14.5-20.0) |
18.2 months (13.6-NE) |
8.3 months (5.6-20.6) |
HR=0.64 (0.48-0.86) p=0.003 |
HR=0.64 (0.49-0.84) p=0.001 |
HR=0.48 (0.24-0.95) |
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Confirmed ORR (%)
( |
(47.0-58.0) |
(11.0-22.8) |
(47.1-57.4) |
(11.3-22.5) |
(33.8-66.2) |
(3.6-41.4) |
CR (%) |
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PR (%) |
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SD (%) |
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PD (%)
( |
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Median DoR (months)ii |
10.7 months |
6.8 months |
10.7 months |
6.8 months |
8.6 months |
4.9 months |
CBR (%)ii,iv |
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DCR (%)v |
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CI, confidence interval; CBR, clinical benefit rate; CR, complete response; DCR, disease control rate; DoR, duration of response; HR, hazard ratio; NE, not evaluable; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease |
i For the primary endpoint (PFS in the HR positive cohort) and key secondary endpoints (PFS among all patients and OS in the HR positive cohort and among all patients), the HR status is based on data collected with the use of the interactive Web response and voice response system at the time of randomization, which includes patients who were mis-stratified. For the other endpoints, HR status is based on data from the electronic data capture that was corrected for mis-stratification |
ii As assessed by BICR |
iii ORR is (CR + PR) |
iv CBR is CR + PR + SD (≥ 6 months) |
v DCR is (CR + PR + SD) |
About DESTINY-Breast04
DESTINY-Breast04 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 chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR positive or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with HR positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomized patients (HR positive and HR negative disease), OS in patients with HR positive disease and OS in all randomized patients (HR positive and HR negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.
DESTINY-Breast04 enrolled 557 patients at multiple sites in
About Breast Cancer and HER2 Expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.1 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.1
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, and is one of many biomarkers expressed in breast cancer tumors.2
HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein on a cancer cell, and/or an ISH test, which counts the copies of the HER2 gene in cancer cells.2,3 HER2 positive cancers are defined as IHC 3+, IHC 2+/ISH+.2 HER2 negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.2 Approximately half of all patients with breast cancer have tumors with a HER2 IHC score of 1+, or a HER2 IHC score of 2+ in combination with a negative ISH test, an expression level not currently eligible for HER2 targeted therapy.4,5,6,7 Low HER2 expression occurs in both HR positive and HR negative disease.8
HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer. Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.9 Currently, patients with low HER2 expression with HR positive tumors have limited treatment options following progression on endocrine (hormone) therapy.10 Few targeted options are available for those who are HR negative.11
About ENHERTU
ENHERTU® (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the
ENHERTU (5.4 mg/kg) is approved in the
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
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, are also underway.
Regulatory applications for ENHERTU are currently under review in
ENHERTU was granted Breakthrough Therapy Designation in the
ENHERTU also is currently under review in the
About the
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:
-
Unresectable or metastatic HER2-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
- Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen
| 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. 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.
Metastatic Breast Cancer
In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in
Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 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. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.
Metastatic Breast Cancer
In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in
Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 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 >
Metastatic Breast Cancer
In the 491 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, 13 cases (
Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 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 at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 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. Reduce dose by one level.
Adverse Reactions
Metastatic Breast Cancer
The pooled safety population for patients with metastatic breast cancer reflects exposure to ENHERTU at 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) in 491 patients in DESTINY-Breast03, DESTINY-Breast01, and Study DS8201-A-J101. The median duration of treatment was 13 months (range: 0.7 to 37). In this pooled safety population, the most common (≥
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 in DESTINY-Breast03. ENHERTU was administered by intravenous infusion once every three weeks. 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 (≥
Locally Advanced or Metastatic Gastric Cancer
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 once every three 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) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.
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 following 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 at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following 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 491 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg,
22% were ≥65 years and4% 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 (60% ) as compared to younger patients (49% ). Of the 125 patients with locally advanced or metastatic HER2‑positive 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. - 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 or severe renal impairment.
- Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.
To report SUSPECTED ADVERSE REACTIONS, contact
Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.
About
Disclosure:
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References
1 Sung H, et al. CA Cancer J Clin. 2021;10.3322/caac.21660.
2 Iqbal N, et al. Mol Biol Int. 2014;852748.
3 Wolff A, et al. Arch Pathol Lab Med. 2018;142(11):1364–1382.
4 Schalper K, et al. Arch Pathol Lab Med. 2014;138:213-219.
5 Ahn S, et al. J Pathol Transl Med. 2020;54(1):34–44.
6 Schettini F, et al. NPJ Breast Cancer. 2021;7:1.
7 Denkert C, et al. Lancet Oncol. 2021;22:1151-61.
8 Miglietta F, et al. NPJ Breast Cancer. 2021;7:137.
9 Eiger D, et al. Cancers. 2021;10.3390/cancers13051015.
10 Matutino A, et al. Current Oncology. 2018;25(S1):S131-S141.
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FAQ
What are the results of the DESTINY-Breast04 trial for ENHERTU?
How does ENHERTU compare to chemotherapy in breast cancer treatment?
What is the overall response rate of ENHERTU in the trial?
What is the significance of ENHERTU for HER2 low breast cancer patients?
What are the common side effects of ENHERTU reported in the trial?
