New data from the DESTINY-Breast01 trial reinforce the efficacy of ENHERTU® in HER2-positive metastatic breast cancer, while the new data from the SERENA-1 Phase I trial show strong efficacy and safety profile for next-generation oral SERD AZD9833 in HR-positive advanced breast cancer.
WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca will unveil new developments across a range of stages and subtypes of breast cancer at the 2020 San Antonio Breast Cancer Symposium (SABCS), which will be held virtually from 8 to 11 December.
Key abstracts include:
- New data from the DESTINY-Breast01 Phase II trial, which reinforce the durable efficacy seen with ENHERTU® (fam-trastuzumab deruxtecan-nxki) in HER2-positive metastatic breast cancer following two or more prior anti-HER2 based regimens
- New results from the SERENA-1 Phase I trial, which demonstrate strong efficacy and safety for a next-generation oral selective oestrogen receptor degrader (SERD), AZD9833 as a monotherapy and in combination with CDK4/6 inhibitor, palbociclib, in HR-positive, HER2-negative advanced breast cancer
José Baselga, Executive Vice President, Oncology R&D, said: “We are committed to transforming outcomes for women diagnosed or living with breast cancer by advancing a new generation of promising potential new medicines. The updates from the comprehensive DESTINY breast program reflect the potential of ENHERTU to help a wide range of breast cancer patients, while the encouraging data from the SERENA-1 Phase I trial paves the way for a clinical development program to help patients with hormone receptor-positive disease.”
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “Significant progress has been made to improve outcomes for those living with breast cancer but there is still much work to be done. At SABCS 2020, our dedication to transforming the lives of those living with breast cancer will be front and center. With new updates from six different approved and potential new medicines, we are directly addressing patients’ greatest unmet needs and are potentially redefining treatment. Additionally, we are making an impact through collaborations with the scientific community to accelerate innovation.”
New, longer-term data from DESTINY-Breast01 to be presented at SABCS will highlight the updated efficacy and safety profiles of ENHERTU in patients with previously-treated HER2-positive metastatic breast cancer with an additional 9.4 months of follow up.
Furthermore, AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) will showcase several TiP abstracts that highlight how the companies are building on the impressive results of ENHERTU in patients with HER2-positive metastatic breast cancer. (Read more…) These include trials to explore the potential of ENHERTU in earlier lines of treatment and stages of disease and in new breast cancer settings, including patients with low levels of HER2 expression. They also include combinations with other anti-cancer medicines such as paclitaxel, FASLODEX (fulvestrant), IMFINZI (durvalumab) and the potential new medicine capivasertib, an AKT-inhibitor.
AstraZeneca will present new efficacy and safety results from the dose escalation and expansion cohort of SERENA-1, a Phase I clinical trial of next-generation oral SERD AZD9833 as a monotherapy and in combination with the CDK4/6 inhibitor palbociclib in women with HR-positive breast cancer.
Building on the updated SERENA-1 findings, the Company will present two Phase II trial-in-progress (TiP) abstracts for the potential new medicine AZD9833, evaluating its efficacy and safety in previously treated post-menopausal women with advanced breast cancer and its biological effects in women with treatment-naïve early-stage breast cancer.
AstraZeneca is also presenting real-world evidence to understand outcomes for patients with germline BRCA mutations, and treatment patterns among patients with HER2-positive metastatic breast cancer. The Company will also showcase data on the potential role of artificial intelligence and digital pathology in measuring levels of HER2 expression in patients with breast cancer.
Additionally, AstraZeneca recognizes the important role of externally sponsored scientific research (ESR) in expanding the medical and scientific understanding of the Company’s medicines, and in identifying associated areas of unmet need in breast cancer. More than half of the AstraZeneca abstracts at this year’s SABCS are ESR studies with AstraZeneca medicines across the various subtypes of breast cancer.
Abstracts to be presented at 2020 SABCS featuring AstraZeneca medicines and pipeline molecules include:*
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Abstract Title |
Lead Author |
Abstract Details |
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ENHERTU (fam-trastuzumab deruxtecan-nxki)1 |
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Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer |
Modi S |
PD3-06
Spotlight Poster-Discussion 3 – Advances in HER2 Positive Disease
Date: Wednesday, December 9, 2020 Time: 6:30-7:45pm CT |
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Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: a 2-part, phase 1b, multicenter, open-label study |
Hamilton E |
PD3-07
Spotlight Poster-Discussion 3 – Advances in HER2 Positive Disease
Date: Wednesday, December 9, 2020 Time: 6:30-7:45pm CT |
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Novel approach to HER2 quantification: digital pathology coupled with AI-based image and data analysis delivers objective and quantitative HER2 expression analysis for enrichment of responders to trastuzumab deruxtecan (T-DXd; DS-8201), specifically in HER2-low patients |
Gustavson M |
PD6-01
Spotlight Poster-Discussion 6 – Novel Approaches to Pathology and Imaging
Date: Thursday, December 10, 2020 Time: 3:30-4:45pm CT |
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A real-world evidence study of treatment patterns among patients with HER2-positive metastatic breast cancer |
Collins J |
PS7-82
Poster Session 7 – Epidemiology
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Solti-1804 HER2-PREDICT: A biomarker research study of DS8201-A-U301 -U302 and -U303 Trials [TiP]* |
Prat A |
OT-03-07
Ongoing Trials Posters – Antibody-drug Conjugates
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual, invasive early breast cancer after neoadjuvant therapy: a randomized, phase 3 trial (DESTINY-Breast05) [TiP] |
Geyer CE Jr |
OT-03-01
Ongoing Trials Posters – Antibody-drug Conjugates
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Trastuzumab deruxtecan (T-DXd; DS-8201) vs investigator’s choice of chemotherapy in patients with hormone receptor–positive (HR+), HER2 low metastatic breast cancer whose disease has progressed on endocrine therapy in the metastatic setting: a randomized, global phase 3 trial (DESTINYBreast06) [TiP] |
Bardia A |
OT-03-09
Ongoing Trials Posters – Antibody-drug Conjugates
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: a phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07) [TiP] |
Andre F |
OT-03-04
Ongoing Trials Posters – Antibody-drug Conjugates
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: a phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08) [TiP] |
Jhaveri K |
OT-03-05
Ongoing Trials Posters – Antibody-drug Conjugates
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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LYNPARZA (olaparib)2 |
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Real-world clinical outcomes of patients with BRCA-mutated (BRCAm) HER2-negative metastatic breast cancer: a CancerLinQ® study |
Miller R |
PS7-66
Poster Session 7 – Epidemiology
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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DOLAF- An international multicenter phase II trial of durvalumab (MEDI4736) plus OLAparib plus Fulvestrant in metastatic or locally advanced ER-positive, HER2-negative breast cancer patients selected using criteria that predict sensitivity to olaparib* |
Guiu S |
OT-13-05
Ongoing Trials Posters – Immunotherapy
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer: results of Phase I expansion cohorts |
Krebs MG |
PS11-18
Poster Session 11 – Systemic Therapies II – New
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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FASLODEX (fulvestrant) |
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Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III Estrogen Receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): an ALTERNATE trial analysis. (Alliance A011106)* |
Ellis MJ |
PD2-10
Spotlight Poster Discussion 2 – Refining Targeted Therapy in HR+ Disease
Date: Wednesday, December 9, 2020 Time: 5:15-6:30pm CT |
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Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive and HER2 negative breast cancer resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106)* |
Ma CX |
GS4-05
General Session 4
Date: Friday, December 11, 2020 Time: 9:45-10:00am ET |
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Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL)* |
Perez-Garcia JM |
PS10-17
Poster Session 10 – Systemic Therapies I – Targeted
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Serum thymidine kinase activity in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant within the PYTHIA trial* |
Malorni L |
PS5-05
Poster Session 5 – Response Prediction Biomarkers II
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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GEICAM/2014-03 (Registem): a prospective registry of unresectable locally advanced or metastatic breast cancer: Characteristics of a subset of patients with triple negative subtype* |
Jara C |
PS7-25
Poster Session 7 Epidemiology
Wednesday, December 9, 2020: 8:00 AM CT |
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Evaluating serum thymidine kinase in hormone receptor positive metastatic breast cancer patients receiving first line endocrine therapy in the SWOG S0226 trial* |
Paoletti I |
PS2-04
Poster Session 2 – Markers, Pathology
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Characteristics of HR+/HER2- patients with recurrent disease by HER2 expression from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM)* |
Alvarez I |
PS7-24
Poster Session 7 – Epidemiology
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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GEICAM/2014-03 (Registem): A prospective registry of advanced breast cancer: a subset of triple negative breast cancer patients with HER2 low expression* |
Jara C |
PS7-35
Poster Session 7 – Epidemiology
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Characteristics of HR+/HER2- patients with recurrent disease from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM)* |
Alvarez I |
PS7-08
Poster Session 7 – Epidemiology
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial* |
Pascual J |
PS5-02
Poster Session 5 – Response Prediction Biomarkers II
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Plk1 expression and efficacy of palbociclib in advanced hormonal receptor-positive breast cancer patients from PEARL study (GEICAM/2012-03)* |
Guerro-Zotano A |
PS2-01
Poster Session 2 – Markers, Pathology
Date: Wednesday, December 9, 2020 Time: 8:00am |
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Mutational profile from circulating tumor DNA in triple negative breast cancer: results from the prospective registry of unresectable locally advanced or metastatic breast cancer GEICAM/2014-03 (RegistEM)* |
Guerro-Zotano A |
PS5-22
Poster Session 5 – Response Prediction Biomarkers II
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: Validation using a novel gene signature of HER2 activation |
Alsaleem M |
PS6-11
Poster Session 6 – Prognostic Factors
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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AZD9833 |
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Updated data from SERENA-1: A phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer |
Baird R |
PS11-05
Poster Session 11 – Systemic Therapies II – New
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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SERENA-2: A randomised, open-label, parallel-group, multicentre phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer |
Oliveria M |
OT-09-02
Ongoing Trials Posters – Endocrine Therapy
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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A randomised, open-label, parallel-group, multicentre phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2) [TiP] |
Oliveria M |
OT-09-02
Ongoing Trials Posters – Endocrine Therapy
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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A randomised, pre-surgical study to investigate the biological effects of AZD9833 in women with ER-positive HER2-negative primary breast cancer (SERENA-3) [TiP] |
Robertson J F R |
OT-09-05
Ongoing Trials Posters – Endocrine Therapy
Date: Wednesday, December 9, 2020 Time: 8:00am CT |
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*Denotes ESR
FDA-Approved Indication for ENHERTU
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 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.
IMPORTANT SAFETY INFORMATION
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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. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).
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 prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).
Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.
Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. 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.
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 (0.9%) of asymptomatic LVEF decrease were reported. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.
Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.
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.
Adverse Reactions
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 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.
ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.
The most common adverse reactions (frequency ≥20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).
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 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were ≥65 years and 5% 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%).
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