Datopotamab deruxtecan plus Imfinzi demonstrated robust and durable tumour responses in 1st-line treatment of patients with metastatic triple-negative breast cancer in BEGONIA Phase Ib/II trial

AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan plus Imfinzi showed a confirmed objective response rate of 79%

Two ongoing Phase III trials are evaluating datopotamab deruxtecan in patients with triple-negative breast cancer

Updated results from the BEGONIA Phase Ib/II trial for the cohort of patients treated with datopotamab deruxtecan (Dato-DXd) plus Imfinzi (durvalumab) (Arm 7) showed that the combination demonstrated durable tumour responses and no new safety signals in patients with previously untreated advanced or metastatic triple-negative breast cancer (TNBC) with six months additional follow-up from the previous data cut-off.

These data will be presented today in a mini oral session at the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, Spain (379MO).

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

Approximately 300,000 people worldwide are diagnosed annually with TNBC, the most aggressive breast cancer subtype.1-2 Less than half of patients with metastatic TNBC respond to current 1st-line treatment options which can include chemotherapy alone or in combination with an immunotherapy.2-4 Among patients with tumours that do respond to initial treatment, disease progression is common and rapid, often occurring within two years.2,4-6

Results showed that datopotamab deruxtecan plus Imfinzi, an anti-PD-L1 therapy, demonstrated a confirmed objective response rate (ORR) of 79% (n=49 of 62) including six complete responses (CRs) and 43 partial responses (PRs). Responses were observed regardless of PD-L1 expression level. Median progression-free survival (PFS) was 13.8 months (95% confidence interval [CI] 11-not calculable [NC]) and median duration of response (DoR) was 15.5 months (95% CI: 9.9-NC) with 11.7 months of follow-up.

Peter Schmid, MD, Barts Cancer Institute, London, United Kingdom, and investigator in the trial, said: “These results for datopotamab deruxtecan plus durvalumab in the first-line triple-negative breast cancer setting are highly encouraging, particularly the 79% objective response rate. This magnitude of response is especially notable given the majority of patients in this cohort have PD-L1-low tumours, representing a population for whom treatment has long been limited to standard chemotherapy.”

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “Progress in the first-line advanced triple-negative breast cancer setting has been modest for years and new therapeutic strategies are needed to improve outcomes for patients with this aggressive breast cancer subtype. These updated results from the BEGONIA trial reinforce our confidence in the potential for datopotamab deruxtecan to become a new, important treatment modality in this setting as we eagerly await results from our ongoing Phase III triple-negative breast cancer programme.”

Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo, said: “Disease progression after initial treatment is a reality for patients with triple-negative breast cancer, underscoring the need for more durable treatment options. These findings showcase the potential of datopotamab deruxtecan in previously untreated advanced triple-negative breast cancer and, following the positive results of our TROPION-Breast01 Phase III trial, build on the growing body of evidence for the potential use of this TROP2-directed antibody drug conjugate, alone and in combinations, in several subtypes of breast cancer.”

The safety profile of datopotamab deruxtecan in combination with Imfinzi was consistent with the known safety profiles of both agents. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 57% of patients. The most common Grade 3 or higher TEAEs were increased amylase (18%), stomatitis (11%), constipation (2%), fatigue (2%), vomiting (2%) and decreased appetite (2%). There were three interstitial lung disease (ILD) events adjudicated as drug-related by an independent committee including two Grade 2 events and one Grade 1 event.

In Arm 7 of the BEGONIA trial (n=62), the majority of patients (n=54) had tumours with low PD-L1 expression (tumour area positivity [TAP] <10%). Seven patients had tumours with high PD-L1 expression (TAP ≥10%). As of the 2 February 2023 data cut-off, 29 patients (47%) remained on study treatment.

Summary of BEGONIA Arm 7 Efficacy Results

Efficacy Measure (as assessed by investigator)

All Patients (n=62)

ORR, confirmed (95% CI)

79% (n=49) (66.8-88.3)

CR rate  

10% (n=6)

PR rate

69% (n=43)

Median DoR (95% CI)

15.5 months (9.9-not calculable)

Median PFS (95% CI)

13.8 months (11.0-not calculable)

CR; complete response; CI, confidence interval; DCR, disease control rate; ORR, objective response rate; PR, partial response; PD, progressive disease; SD, stable disease
i ORR is (complete response + partial response)

AstraZeneca and Daiichi Sankyo have two Phase III trials evaluating datopotamab deruxtecan in TNBC. TROPION-Breast02 is comparing datopotamab deruxtecan to chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-L1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without Imfinzi versus investigator’s choice of therapy in patients with Stage I-III TNBC with residual disease after neoadjuvant therapy.

Several presentations featured during the ESMO 2023 Congress are showcasing the strength and depth of data for datopotamab deruxtecan across multiple tumour types and settings, including results from the TROPION-Lung01 and TROPION-Breast01 Phase III trials.


Triple-negative breast cancer
Breast cancer is the most common cancer in the world and leading cause of cancer-related death.1 More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.1

While some breast cancers may test positive for oestrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three.2 Approximately 15% of breast cancer tumours (300,000 cases annually) are considered triple-negative which is the most aggressive breast cancer subtype.1-2 1st-line treatment for advanced or metastatic TNBC usually consists of chemotherapy alone or in combination with an immunotherapy – options generally associated with response rates between 30 to 50%.2-4 Among patients with tumours that do respond to initial treatment, disease progression is common and rapid, often occurring within two years.2,4-6 The average overall survival of patients living with advanced or metastatic TNBC is 12 to 18 months, with only about 12% of patients living five years following diagnosis.7-8

TROP2 is a protein broadly expressed in several solid tumours, including TNBC.9 TROP2 is associated with increased tumour progression and poor survival in patients with breast cancer.9-10

BEGONIA is an open-label, two-part, multicentre Phase Ib/II trial evaluating Imfinzi in combination with oncology therapies with or without paclitaxel for the 1st-line treatment of metastatic TNBC. Arm 7 of the trial is evaluating the safety, tolerability and preliminary efficacy of datopotamab deruxtecan (6.0 mg/kg) in combination with Imfinzi (1120 mg) in patients with previously untreated, unresectable locally advanced or metastatic TNBC. The primary endpoints are safety and tolerability. Secondary endpoints are investigator-assessed ORR, PFS and DOR.

Enrolment is currently underway for Arm 8 of the BEGONIA trial, which is evaluating datopotamab deruxtecan plus Imfinzi in patients with TNBC whose tumours have high levels of PD-L1 expression.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of six lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple TROP2-targetable tumours, including non-small cell lung cancer (NSCLC), TNBC and HR-positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials. AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.

Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Additionally, Imfinzi is approved in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indication in lung cancer, Imfinzi is also approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer (BTC) and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC) in the US, EU, Japan and several other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively. Imfinzi is approved in previously treated patients with advanced bladder cancer in a small number of countries.  

Since the first approval in May 2017, more than 200,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combination with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal cancers and other solid tumours.

Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019 and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

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 tumour environment.

With Enhertu (trastuzumab deruxtecan), a HER2-directed 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 Faslodex (fulvestrant) and Zoladex (goserelin) and aims to reshape the HR-positive space with next-generation SERD and potential new medicine camizestrant as well as a potential first-in-class AKT kinase inhibitor, capivasertib. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting.

PARP inhibitor Lynparza (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 Canada) continues to research Lynparza in these settings and to explore its potential in earlier disease.

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 Imfinzi (durvalumab), capivasertib in combination with chemotherapy, and Imfinzi in combination with other oncology medicines, including Lynparza 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 catalyse 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 (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit hd122.net and follow the Company on social media @AstraZeneca.

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1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.

2. O’Reilly D, et al. Overview of recent advances in metastatic triple negative breast cancer. World Journal of Clinical Oncology. 2021;12(3): 164-182.

3. Bergin A, et al. Triple-negative breast cancer: recent treatment advances. F1000Res. 2019; 8:10.12688/f1000research.18888.1.

4. Zhang Y, et al. Genomic features of rapid versus late relapse in triple negative breast cancer. BMC Cancer. 2021; 21(568).

5. Cortes J, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022; 387: 217-226. 10.1056/NEJMoa2202809.

6. Emans L, et al. Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study. JNCI J Natl Cancer Inst. 2021; 113(8): djab004.

7. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: http://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed October 2023.  

8. Sharma P, et al. Biology and Management of Patients with Triple-Negative Breast Cancer. Oncologist. 2016; 21(9): 1050-62. 10.1634/theoncologist.2016-0067.

9. Lin H, et al. Significantly upregulated TACSTD2 and Cyclin D1 correlate with poor prognosis of invasive ductal breast cancer. Exp Mol Pathol. 2013;94(1):73-8.

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