ENHERTU® Significantly Improved Both Progression-Free and Overall Survival in DESTINY-Breast04 Trial in Patients with HER2 Low Metastatic Breast Cancer
The pivotal DESTINY-Breast04 phase 3 trial demonstrated that ENHERTU® (trastuzumab deruxtecan) significantly improves progression-free survival (PFS) and overall survival (OS) in patients with HER2 low unresectable and/or metastatic breast cancer, compared to standard chemotherapy. This trial is historic as it marks the first HER2 directed therapy to show benefits in this patient group, potentially redefining breast cancer treatment classifications. Both Daiichi Sankyo and AstraZeneca are planning global regulatory submissions based on these promising results.
- Statistically significant improvement in progression-free survival (PFS) and overall survival (OS).
- First HER2 directed therapy showing benefits in HER2 low metastatic breast cancer.
- Meeting primary and key secondary endpoints in the clinical trial.
- None.
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First HER2 low metastatic breast cancer phase 3 results for
Daiichi Sankyo and AstraZeneca’s ENHERTU offer potential to redefine how the disease is classified and treated - Plans for global regulatory submissions are underway
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All patients in the trial received a HER2 test and the results were centrally confirmed. HER2 low status was defined as an immunohistochemistry (IHC) score of 1+ or IHC2+ with a negative in-situ hybridization (ISH) score.
HER2 expression is currently defined as either positive or negative.1 HER2 positive cancers are defined as IHC 3+ or IHC 2+/ISH+ and HER2 negative cancers are defined as IHC 0, IHC 1+ or IHC 2+/ISH-.1 Up to
HER2 testing is well-established to determine an appropriate treatment strategy in metastatic breast cancer. Targeting the lower range of HER2 expression may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.5 Currently, chemotherapy remains the only treatment option both for patients with HR positive tumors following progression on endocrine (hormone) therapy and for those who are HR negative.6
DESTINY-Breast04 met its primary endpoint where ENHERTU demonstrated superior PFS in previously-treated patients with HR positive, HER2 low metastatic breast cancer compared to the standard of care chemotherapy. The trial met the key secondary endpoint of PFS in patients with HER2 low metastatic breast cancer regardless of HR status (HR positive or HR negative). The trial also met other key secondary endpoints of OS in patients with HR positive disease and patients regardless of HR status at interim analysis.
The safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. Overall interstitial lung disease (ILD) rates were consistent with that observed in late-line HER2 positive breast cancer trials of ENHERTU with a lower rate of grade 5 ILD observed, as determined by an independent adjudication committee.
“ENHERTU continues to redefine the treatment of HER2 targetable cancers. DESTINY-Breast04 is the first ever phase 3 trial of a HER2 directed therapy in patients with HER2 low metastatic breast cancer to show a statistically significant and clinically meaningful benefit in progression-free and overall survival compared to standard treatment,” said
“Today’s historic news from DESTINY-Breast04 could reshape how breast cancer is classified and treated,” said
The data will be presented at an upcoming medical meeting and shared with global health authorities.
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 (n=480) or HR negative (n=60), 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 (regardless of HR status), OS in patients with HR positive disease and OS in all randomized patients (regardless of HR status). 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 approximately 540 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.7 More than two million cases of breast cancer were diagnosed in 2020 resulting in nearly 685,000 deaths globally.7
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.1 HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein in a cancer cell, and/or an ISH test, which counts the copies of the HER2 gene in cancer cells. 1,8 HER2 positive cancers are defined as IHC 3+, IHC 2+/ISH+ and HER2 negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.1 Up to
HER2 testing is well-established to determine an appropriate treatment strategy in metastatic breast cancer. Targeting the lower range of HER2 expression may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.5 Currently, chemotherapy remains the only treatment option both for patients with HR positive tumors following progression on endocrine (hormone) therapy and for those who are HR negative.6
About ENHERTU
ENHERTU® (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the
ENHERTU (5.4 mg/kg) is approved in more than 40 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 (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
About the
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:
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Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
This indication is approved under accelerated approval based on tumor 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 gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
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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 234 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 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4mg/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. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (
Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. When LVEF is >
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 safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).
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.
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Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg,
26% were ≥65 years and5% were ≥75 years. No overall differences in efficacy 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 (53% ) as compared to younger patients (42% ). 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. - 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
References:
1 Iqbal N, et al. Mol Biol Int. 2014;852748.
2 Tarantino P, et al. J Clin Oncol. 2020;38(17):1951-1962
3 Ahn S, et al. J Pathol Transl Med. 2020; 54(1): 34–44.
4 Miglietta F, et al. NPJ Breast Cancer. 2021; 7:137.
5 Eiger D, et al. Cancers. 2021; 10.3390/cancers13051015.
6 Matutino A, et al. Current Oncology. 2018; 25(S1):S131-S141.
7 Sung H, et al. CA Cancer J Clin. 2021; 10.3322/caac.21660.
8 Wolff A, et al. Arch Pathol Lab Med (2018) 142 (11): 1364–1382.
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