Datopotamab deruxtecan showed encouraging and durable efficacy in patients with heavily pretreated HR-positive, HER2-low or negative metastatic breast cance

First results for AstraZeneca and Daiichi Sankyo’s TROP2-directed ADC in this setting reported from TROPION-PanTumor01 Phase I trial. Pivotal TROPION-Breast01 Phase III trial is ongoing, evaluating datopotamab deruxtecan in these patients in earlier lines of treatment.

Initial results from the TROPION-PanTumor01 Phase I trial of datopotamab deruxtecan (Dato-DXd) showed encouraging and durable efficacy in patients with heavily pretreated hormone receptor (HR)-positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [ISH] negative) or HER2-negative (IHC 0) unresectable or metastatic breast cancer. Safety results were consistent with previous trials of datopotamab deruxtecan. Results were presented today at the 2022 San Antonio Breast Cancer Symposium (abstract #PD13-08).

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

In this cohort of TROPION-PanTumor01 (n=41), datopotamab deruxtecan demonstrated an objective response rate (ORR) of 27% as assessed by blinded independent central review (BICR). All responses were partial (n=11) and 56% of patients achieved stable disease (n=23). The disease control rate (DCR) was 85% and median progression-free survival (PFS) was 8.3 months (95% confidence interval [CI], 5.5-11.1). With median follow-up of 13.7 months, the median duration of response (DoR) and the median overall survival (OS) had not been reached with 59% of patients alive for more than one year.

Approximately 70% of breast cancer tumours are considered HR-positive and HER2-low or negative.¹ For patients with HR-positive, HER2-low or negative metastatic breast cancer that progress on or are not suitable candidates for endocrine therapy, the current standard of care is single-agent chemotherapy.²

Funda Meric-Bernstam, Chair, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, and investigator in the TROPION-PanTumor01 trial, said: “Patients with HR-positive, HER2-low or negative metastatic breast cancer who are not eligible for endocrine therapy or have exhausted treatment options have a poor prognosis. These preliminary results with datopotamab deruxtecan in patients with heavily pretreated HR-positive, HER2-low or negative metastatic breast cancer are encouraging and warrant further evaluation in this setting.”

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “Many of these patients with metastatic breast cancer in TROPION-PanTumor01 had exhausted most of their available treatment options, having received a striking median of five prior regimens including a CDK4/6 inhibitor for nearly all patients. These promising results with datopotamab deruxtecan in such a heavily pretreated patient population support our strong belief that this TROP2-directed antibody drug conjugate has the potential to improve outcomes for patients with HR-positive, HER2-low or negative breast cancer in this, and possibly earlier settings.”

Mark Rutstein, Global Head, Oncology Clinical Development, Daiichi Sankyo, said: “These results add to the growing body of data demonstrating the potential of datopotamab deruxtecan to treat certain types of metastatic breast cancer. We look forward to the continued evaluation of our TROP2-directed antibody drug conjugate, including comparisons to standard therapy in earlier lines of treatment for HR-positive, HER2-low or negative metastatic breast cancer through our ongoing TROPION-Breast01 Phase III trial.”

Patients in the TROPION-PanTumor01 trial were heavily pretreated, receiving a median of five lines of prior regimens in the metastatic setting (range 3-10). Prior treatments included CDK4/6 inhibitors (95%), capecitabine (83%), taxanes (59%), anthracyclines (54%), neoadjuvant chemotherapy (37%), mTOR inhibitors (29%) and PI3KCA inhibitors (20%). As of data cut-off on 22 July 2022, five patients remained on study treatment.

The safety profile of datopotamab deruxtecan was consistent with previous data with no new safety signals identified. The most common Grade 3 or higher treatment-emergent adverse events (TEAEs) were decreased lymphocyte count (15%), stomatitis (10%), anaemia (7%), dyspnoea (2%) and fatigue (2%). Serious TEAEs were observed in six patients (15%), including one death due to dyspnoea that was not considered treatment-related. Treatment discontinuations due to an adverse event occurred in five patients (12%). No cases of Grade 3 or higher diarrhoea or febrile neutropenia were observed. One case of Grade 3 interstitial lung disease was adjudicated as treatment-related.

Summary of Results

CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not evaluable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease

ⁱ As assessed by BICR

ⁱⁱ ORR is (CR + PR)

ⁱⁱⁱ DCR is (CR + PR + SD + non-CR/non-PD)

AstraZeneca and Daiichi Sankyo have a broad clinical development programme for datopotamab deruxtecan in breast cancer, including the ongoing pivotal TROPION-Breast01 Phase III trial evaluating datopotamab deruxtecan in patients with HR-positive, HER2-low or negative, inoperable or metastatic breast cancer previously treated with chemotherapy.

Notes
 

HR-positive breast cancer

Breast cancer is the most common cancer and one of the leading causes of cancer-related deaths worldwide.³ More than two million breast cancer cases were diagnosed in 2020, with nearly 685,000 deaths globally.³

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both) is the most common subtype of breast cancer with approximately 70% of breast cancer tumours considered HR-positive and HER2-low or negative.¹

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER), and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with cyclin-dependent kinase (CDK) 4/6 inhibitors.^4-6 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.⁶ Once this occurs, the treatment options are limited – with chemotherapy being the current standard of care – and survival rates are low with 30% of patients anticipated to live beyond five years after diagnosis.^1,2,6

Optimising endocrine therapy and overcoming resistance for patients with ER-driven disease at all stages of treatment as well as identifying new therapies for those who no longer have ER-driven disease are active areas of focus for breast cancer research. 

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is broadly expressed in several types of solid tumours, including HR-positive, HER2-low or negative breast cancer.^7-8 TROP2 expression is an unfavourable prognostic factor for overall survival in all types of breast cancer.⁷

TROPION-PanTumor01

TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial evaluating the safety and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours that have relapsed or are refractory to standard treatment or for which no standard treatment is available. The dose escalation portion of the trial enrolled patients with non-small cell lung cancer (NSCLC) to assess the safety and efficacy of datopotamab deruxtecan to determine the recommended dose for expansion (6mg/kg). The dose expansion part of TROPION-PanTumor01 is enrolling several different cohorts including patients with NSCLC, triple-negative breast cancer (TNBC), HR-positive, HER2-low or negative breast cancer, small cell lung cancer, urothelial, gastric, pancreatic, castration-resistant prostrate and esophageal cancer.

Safety endpoints include dose-limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DoR, time to response, PFS and OS. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.

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 three leading 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, via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 10 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple TROP2-targetable tumours, including TNBC, HR-positive, HER2-low or negative breast cancer and NSCLC. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

AstraZeneca and Daiichi Sankyo collaboration

AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of 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 oral selective estrogen receptor degrader (ngSERD) 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 with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in these settings and to explore its potential in earlier disease.

To bring much-needed treatment options to patients with TNBC, 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
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 astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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References

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