ENHERTU® (fam-trastuzumab deruxtecan-nxki) granted Priority Review in the US for patients with HER2-low or HER2-ultralow metastatic breast cancer who have received at least one line of endocrine therapy
AstraZeneca and Daiichi Sankyo's supplemental Biologics License Application (sBLA) for ENHERTU has been granted Priority Review in the US for treating HER2-low or HER2-ultralow metastatic breast cancer patients who have received at least one endocrine therapy. This is based on positive results from the DESTINY-Breast06 Phase III trial. The FDA action date is anticipated during Q1 2025.
ENHERTU also received Breakthrough Therapy Designation in this setting. The trial showed ENHERTU reduced the risk of disease progression or death by 37% compared to chemotherapy, with a median PFS of 13.2 months vs 8.1 months. Results were consistent in both HER2-low and HER2-ultralow expression patients.
If approved, ENHERTU would be the first HER2-directed therapy and antibody-drug conjugate for this patient population prior to chemotherapy for metastatic breast cancer.
La domanda di licenza biologica supplementare (sBLA) di AstraZeneca e Daiichi Sankyo per ENHERTU è stata concessa Revisione Prioritaria negli Stati Uniti per il trattamento dei pazienti con cancro al seno metastatico HER2-basso o HER2-ultrabasso che hanno ricevuto almeno una terapia endocrina. Questo si basa sui risultati positivi del DESTINY-Breast06 trial di Fase III. La data di azione della FDA è attesa entro il Q1 2025.
ENHERTU ha anche ricevuto la Designazione di Terapia Innovativa in questo contesto. Lo studio ha mostrato che ENHERTU ha ridotto il rischio di progressione della malattia o morte del 37% rispetto alla chemioterapia, con una PFS mediana di 13,2 mesi vs 8,1 mesi. I risultati sono stati coerenti sia nei pazienti con espressione HER2-bassa che HER2-ultrabassa.
Se approvato, ENHERTU sarebbe la prima terapia e coniugato anticorpale diretto a HER2 per questa popolazione di pazienti prima della chemioterapia per il cancro al seno metastatico.
La Solicitud de Licencia Biológica Suplementaria (sBLA) de AstraZeneca y Daiichi Sankyo para ENHERTU ha recibido la Revisión Prioritaria en EE. UU. para tratar a pacientes con cáncer de mama metastásico HER2-bajo o HER2-ultrabajo que han recibido al menos una terapia endocrina. Esto se basa en resultados positivos del ensayo de Fase III DESTINY-Breast06. Se anticipa que la fecha de acción de la FDA sea durante el Q1 2025.
ENHERTU también ha recibido la Designación de Terapia Revolucionaria en este contexto. El estudio mostró que ENHERTU redujo el riesgo de progresión de la enfermedad o muerte en un 37% en comparación con la quimioterapia, con una PFS mediana de 13.2 meses frente a 8.1 meses. Los resultados fueron consistentes tanto en pacientes con expresión HER2-baja como HER2-ultrabaja.
Si se aprueba, ENHERTU sería la primera terapia dirigida a HER2 y conjugado anticuerpo-fármaco para esta población de pacientes antes de la quimioterapia para el cáncer de mama metastásico.
AstraZeneca와 Daiichi Sankyo의 보충 생물학적 면허 신청(sBLA)이 ENHERTU에 대해 우선 검토를 부여받았으며, 이는 최소 한 차례의 내분비 요법을 받은 HER2 저표현 또는 HER2 극저표현 전이성 유방암 환자를 치료하기 위한 것입니다. 이는 DESTINY-Breast06 3상 시험의 긍정적인 결과를 기반으로 하고 있습니다. FDA의 결정 날짜는 2025년 1분기로 예상됩니다.
ENHERTU는 이 설정에서 혁신 치료 지정도 받았습니다. 시험에서 ENHERTU는 화학요법과 비교해 질병 진행 또는 사망의 위험을 37% 줄였으며, 중앙 무진 진행 기간(PFS)은 13.2개월 대 8.1개월로 나타났습니다. 결과는 HER2 저표현 및 HER2 극저표현 환자 모두에서 일관성을 보였습니다.
승인될 경우, ENHERTU는 전이성 유방암에 대한 화학요법 이전에 이 환자 집단을 위한 첫 번째 HER2 표적 요법이자 항체-약물 접합체가 될 것입니다.
La demande de licence biologique supplémentaire (sBLA) d'AstraZeneca et Daiichi Sankyo pour ENHERTU a été accordée Priorité de Revue aux États-Unis pour traiter les patients atteints de cancer du sein métastatique HER2-bas ou HER2-ultrabas qui ont reçu au moins une thérapie endocrinienne. Cela est basé sur des résultats positifs de l'essai de Phase III DESTINY-Breast06. La date d'action de la FDA est attendue durant le 1er trimestre 2025.
ENHERTU a également reçu la désignation de thérapie révolutionnaire dans ce contexte. L'essai a montré qu'ENHERTU réduisait le risque de progression de la maladie ou de décès de 37% par rapport à la chimiothérapie, avec une PFS médiane de 13,2 mois contre 8,1 mois. Les résultats étaient cohérents chez les patients à expression HER2-basse et HER2-ultrabasse.
Si approuvé, ENHERTU serait la première thérapie dirigée HER2 et conjugé anticorps-médicament pour cette population de patients avant la chimiothérapie pour le cancer du sein métastatique.
Der ergänzende biologischen Antrag (sBLA) von AstraZeneca und Daiichi Sankyo für ENHERTU wurde in den USA eine Prioritätsprüfung für die Behandlung von Patienten mit HER2-niedrigem oder HER2-ultraniedrigem metastasierenden Brustkrebs, die mindestens eine endokrine Therapie erhalten haben, gewährt. Dies basiert auf positiven Ergebnissen aus der DESTINY-Breast06 Phase-III-Studie. Das Datum für die FDA-Aktion wird im Q1 2025 erwartet.
ENHERTU erhielt auch die Breakthrough-Therapy-Designierung in diesem Zusammenhang. Die Studie zeigte, dass ENHERTU das Risiko für das Fortschreiten der Krankheit oder den Tod um 37% im Vergleich zur Chemotherapie reduzierte, mit einer medianen PFS von 13,2 Monaten gegenüber 8,1 Monaten. Die Ergebnisse waren sowohl bei Patienten mit HER2-niedriger als auch HER2-ultraniedriger Expression konsistent.
Im Falle einer Genehmigung wäre ENHERTU die erste HER2-direktive Therapie und das Antikörper-Wirkstoff-Konjugat für diese Patientengruppe vor der Chemotherapie bei metastasierendem Brustkrebs.
- ENHERTU granted Priority Review and Breakthrough Therapy Designation by FDA
- 37% reduction in risk of disease progression or death vs chemotherapy
- Median PFS of 13.2 months with ENHERTU vs 8.1 months with chemotherapy
- Consistent results in both HER2-low and HER2-ultralow expression patients
- Potential to be first HER2-directed therapy for this patient population before chemotherapy
- FDA action date not until Q1 2025
- Safety profile shows potential for interstitial lung disease and neutropenia
Insights
The FDA's Priority Review and Breakthrough Therapy Designation for ENHERTU in HER2-low and HER2-ultralow metastatic breast cancer is a significant development for AstraZeneca and Daiichi Sankyo. This could potentially expand ENHERTU's market reach to a broader patient population, including those with HER2-ultralow expression.
Key points:
- The DESTINY-Breast06 Phase III trial showed a 37% reduction in the risk of disease progression or death compared to chemotherapy
- Median progression-free survival was 13.2 months with ENHERTU vs 8.1 months with chemotherapy
- If approved, ENHERTU would be the first HER2-directed therapy for these patients prior to chemotherapy
- The potential market is substantial, with an estimated 85-90% of HR-positive, HER2-negative tumors possibly being HER2-low or HER2-ultralow
This expansion could significantly increase ENHERTU's revenue potential, solidifying its position as a key growth driver for AstraZeneca's oncology portfolio. Investors should monitor the FDA's decision, expected in Q1 2025, as approval could positively impact AstraZeneca's stock performance.
The DESTINY-Breast06 trial results are clinically significant, potentially changing the treatment paradigm for HR-positive metastatic breast cancer patients. The efficacy of ENHERTU in both HER2-low and HER2-ultralow populations is particularly noteworthy.
Key clinical implications:
- ENHERTU showed consistent benefit across HER2-low and HER2-ultralow subgroups, addressing an unmet need
- The 13.2-month median PFS is impressive compared to current standards of care in this setting
- Safety profile was consistent with previous trials, with no new concerns identified
- This could provide a new option for patients who have progressed on endocrine therapy but before chemotherapy
The potential to use ENHERTU earlier in the treatment sequence and in a broader patient population could significantly improve outcomes for many breast cancer patients. However, careful patient selection and monitoring for side effects, particularly ILD/pneumonitis, will be important if approved.
Based on DESTINY-Breast06 Phase III trial which demonstrated a statistically significant and clinically meaningful progression-free survival benefit for ENHERTU
If approved, AstraZeneca and Daiichi Sankyo’s ENHERTU will be the first HER2 directed therapy and ADC for patients prior to receiving chemotherapy for metastatic breast cancer
ENHERTU also granted Breakthrough Therapy Designation in the US for this patient population
The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is anticipated during the first quarter of 2025.
ENHERTU was also recently granted Breakthrough Therapy Designation (BTD) by the FDA in this setting. BTD accelerates the development and regulatory review of potential new medicines intended to treat a serious condition and address a significant unmet medical need.
HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “While endocrine therapies are widely used in the initial treatment of HR-positive metastatic breast cancer, most patients see limited benefit with additional lines of treatment, and subsequent chemotherapy is often associated with poor response rates and outcomes. The results from DESTINY-Breast06 show that ENHERTU has the potential to evolve the current HR-positive treatment landscape and become the first targeted treatment for patients with HER2-low or HER2-ultralow expression following endocrine therapy.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “This Priority Review highlights the potential to expand the existing indication of ENHERTU in HER2-low metastatic breast cancer to include use in an earlier disease setting as well as in a broader patient population that includes HER2-ultralow. We look forward to working closely with the FDA with the goal of bringing ENHERTU to more patients as quickly as possible.”
The sBLA is based on data from the DESTINY-Breast06 Phase III trial presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and recently published in The New England Journal of Medicine.
In the trial, ENHERTU reduced the risk of disease progression or death by
Results were consistent between patients with HER2-low expression and HER2-ultralow expression. In the primary endpoint analysis of patients with HER2-low expression, ENHERTU showed a median PFS of 13.2 months compared to 8.1 months for chemotherapy (HR 0.62;
The safety profile of ENHERTU in DESTINY-Breast06 was consistent with previous clinical trials of ENHERTU in breast cancer with no new safety concerns identified.
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.
ENHERTU is already approved in more than 65 countries, including the US, for patients with HER2-low metastatic 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.
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
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.5 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.5 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.6 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.
HER2 status in the trial was confirmed by central laboratory and was performed on an archival tumor sample obtained at the time of initial metastatic diagnosis or later. If archival tissue was not available, a fresh tissue sample was required.
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
ENHERTU (fam-trastuzumab deruxtecan-nxki)
ENHERTU (fam-trastuzumab deruxtecan-nxki) 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 (5.4mg/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 (5.4mg/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 (5.4mg/kg) is approved in more than 45 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 and/or DESTINY-Lung05 trials. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ENHERTU (6.4mg/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 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
ENHERTU (5.4mg/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 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 US may be contingent upon verification and description of clinical benefit in a confirmatory trial.
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 (fam-trastuzumab deruxtecan-nxki), 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 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 MSD (Merck & Co., Inc. in 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
- National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed September 2024.
- 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.
- 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.
- 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.
- 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.
US- 93544 | Last Updated 9/2024
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FAQ
What is the new potential indication for ENHERTU (AZN) based on the DESTINY-Breast06 trial?
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