Last but not least: antibody-drug conjugates in hormone receptor-positive metastatic breast cancer.
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ABSTRACT:
SUBMITTER: Stecklein SR
PROVIDER: S-EPMC10210013 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
Last but not least: antibody-drug conjugates in hormone receptor-positive metastatic breast cancer.
Annals of oncology : official journal of the European Society for Medical Oncology 20201008 12
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Project description:The identification of the HER2 alteration as an actionable oncogenic driver in breast cancer has propelled the development of HER-targeting monoclonal antibodies (mAb) such as trastuzumab and pertuzumab, which led to dramatic improvements in survival outcomes. Lately, the great strides made toward developing antibody-conjugation methods have led to the development of a new class of compelling compounds, the antibody-drug conjugates (ADCs) targeting HER2 which have profoundly transformed the treatment landscape of breast cancer. HER2-targeting ADCs, trastuzumab-emtansine and trastuzumab-deruxtecan, have improved the overall survival in the second and third-line settings with manageable adverse events. Other HER2-targeting ADCs using novel technological advances in the antibody, linker and/or payload conception have shown promising activity in preclinical and clinical studies and some of them are now being evaluated in larger clinical trials. Multiple challenges still impede the success of ADCs in breast cancer namely the lack of a comprehensive understanding of resistance mechanisms as well as the mechanisms of action of ADCs in special subgroups of patients such as those with low or ultra-low HER2 expression and patients with brain or leptomeningeal metastases (BM). In this framework, we review the approved indications and ongoing trials for HER2-targeting ADCs, across patient subgroups, including those with BM and discuss the associated potential mechanisms of action and resistance. Last, we provide an overview of the future perspectives involving HER2-targeting ADCs in breast cancer.
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Project description:Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20-30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.
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Project description:Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. TROP-2 expression is higher in HER2-negative breast tumors (HR+/HR-) and is associated with worse survival. Sacituzumab govitecan (SG) is a first-in-class TROP-2-directed ADC with an anti-TROP-2 antibody conjugated to SN-38, a topoisomerase inhibitor via a hydrolysable linker. This hydrolysable linker permits intracellular and extracellular release of the membrane permeable payload enabling the "bystander effect" contributing to the efficacy of this agent. There was significant improvement in progression free survival (PFS) and overall survival (OS) with SG versus chemotherapy in pretreated metastatic triple negative breast cancer (TNBC), resulting in regulatory approval. Common adverse events (AE) reported were neutropenia and diarrhea. SG also demonstrated clinical activity versus chemotherapy in a phase III trial of HR+/HER2-metastatic breast cancer (MBC) and is under evaluation in first-line metastatic and early stage TNBC as well. Datopotamab deruxtecan (Dato-DXd) is a TROP-2 ADC that differs from SG in that it has a cleavable tetrapeptide linker and a more potent topoisomerase inhibitor payload. This construct is highly stable in circulation with a longer half-life than SG, and undergoes cleavage in presence of intracellular lysosomal proteases. Dato-DXd demonstrated preliminary efficacy in unselected metastatic TNBC, with common AEs of low-grade nausea and stomatitis. Dato-DXd is being investigated in phase III studies in metastatic TNBC and HR+/HER2- MBC. These novel TROP-2 ADCs have the potential to deliver enhanced efficacy with reduced toxicity in MBC and possibly in early stage breast cancer (EBC).
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Project description:Endocrine therapy has historically formed the basis of treatment of metastatic hormone receptor-positive breast cancer. The development of endocrine resistance has led to the development of newer endocrine drug combinations. Use of the CDK4/6 inhibitors has significantly improved progression-free survival in this group of patients. There are multiple studies of the use of P13K inhibitors and mTOR inhibitors for use as subsequent lines of therapy, particularly for endocrine resistance. The optimal sequencing of therapy should be based on medical comorbidities, prior adjuvant therapies, quality of life, side-effect profile, and disease-free interval.
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Project description:Estrogen receptor modulators and estrogen deprivation have become standards of care for hormone receptor-positive metastatic breast cancer. However, after traditional first-line endocrine monotherapy treatment, the disease typically progresses despite the initial high rate of clinical benefit. Multiple studies have aimed at optimizing treatment strategies to improve upon clinical benefit beyond the traditional single-agent endocrine treatment. With the availability of new data and novel therapies, the clinical practice challenge becomes how best to define the optimal treatment sequence to maximize clinical benefit. In this review, we present treatment options clinically relevant to the management of hormone-positive, her2-negative metastatic breast cancer, and we propose a treatment algorithm based on the current literature.
| S-EPMC6001771 | biostudies-literature
Project description:Hormone receptor positive tumors represent the most common form of breast cancer and account for most of the deaths from the disease. Endocrine therapy represents the main initial therapeutic strategy for these patients and has been associated with significant clinical benefits in a majority of patients. While in early stages endocrine therapy is administered as part of a curative approach once clinical metastases develop, the disease is considered incurable and the main management objectives are tumor control and quality of life. The two major clinical paradigms of always indicating endocrine therapy in the absence of visceral crises and sequencing endocrine treatments have been guiding our therapeutic approach to these patients. However, for many decades, we have delivered endocrine therapy with a 'one size fits all' approach by applying agents that interfere with hormone receptor signaling equally in every clinical patient scenario. We have been unable to incorporate the well-known biologic principle of different degrees of hormone receptor dependency in our therapeutic recommendations. Recent developments in the understanding of molecular interactions of hormone signaling with other important growth factor, metabolic and cell division pathways have opened the possibility of improving results by modulating hormone signaling and interfering with resistance mechanisms yet to be fully understood. Unfortunately, limitations in the design of trials conducted in this area have made it difficult to develop predictive biomarkers and most of the new combinations with targeted agents, even though showing improvements in clinical endpoints, have been directed to an unselected population of patients. In this review we explore some of the current and most relevant literature in the management of hormone receptor positive advance breast cancer.
| S-EPMC4622303 | biostudies-literature
Project description:Although targeted drugs improved the therapeutic effect of HER2-positive breast cancer, the long-term prognosis was still poor. In this regard, the research and development of antibody-drug conjugates (ADCs) came into being and made a lot of progress. ADCs had the characteristics of both chemotherapeutic agents and targeted agents by combining chemotherapeutic agents and targeted agents through a linker. It not only had a strong anti-tumor effect on HER2-positive breast cancer, but also had certain anti-tumor effects on HER2-low and even HER2-negative patients. In addition, the clinical researches of ADCs combined with immune checkpoint inhibitors (ICIs) therapy had also made a great breakthrough. This review aimed to summarize the clinical progress of ADCs, in particular the two drugs approved by the US Food and Drug Administration (FDA) for HER2-positive metastatic breast cancer as well as to summarize the current status of ADCs in combination with ICIs.
| S-EPMC9747846 | biostudies-literature
Project description:Breast cancer (BC) remains a leading cause of cancer-related mortality in women, with hormone receptor-positive (HR+) tumors accounting for a significant proportion of cases. Despite advancements in endocrine therapy (ET), resistance remains a challenge in metastatic settings. The use of cyclin-dependent kinases 4/6 (CDK4/6) inhibitors in combination with endocrine therapy has notably improved survival. In China, when patients develop resistance to CDK4/6 inhibitors (CDK4/6i) or face financial constraints that prevent their use, chemotherapy becomes the standard treatment approach. This highlights an urgent need for effective treatments following CDK4/6i therapy. ESG401 is a novel trophoblast cell-surface antigen 2 (Trop2) directed antibody-drug conjugate (ADC) with promising preclinical and early clinical efficacy and safety data. We report a case of a 61-year-old female with HR+HER2- metastatic breast cancer (MBC) who developed resistance to fulvestrant and subsequent chemotherapy but achieved a durable partial response (PR) lasting more than 22.5 months following ESG401 treatment. This case underscores the potential role of Trop2-directed ADCs, such as ESG401, in overcoming endocrine resistance and providing meaningful clinical benefit in heavily pretreated patients with HR+/HER2- MBC. Furthermore, the patient's exceptionally long clinical benefit distinguishes her from other patients receiving ESG401 treatment. Further exploration of the use of ESG401 in HR+HER2- MBC patients, as well as a deeper understanding of the characteristics of patients that may impact sustained efficacy, in expanded clinical trials is warranted.
| S-EPMC11631905 | biostudies-literature
Project description:BackgroundAntibody-drug conjugates (ADCs) have been the preferred regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after trastuzumab. Unfortunately, there is little data showing which ADCs should be chosen for those patients whose treatment with tyrosine kinase inhibitors (TKIs) failed. This study aims to analyze the efficacy and safety between novel anti-HER2 ADCs and trastuzumab emtansine (T-DM1) for those with TKIs failure.Materials and methodsHER2-positive MBC using ADCs from January 2013 to June 2022 were included, and all of them were treated with TKIs. The primary study endpoint was progression-free survival (PFS), and the secondary study endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety.ResultsA total of 144 patients with 73 patients in the novel anti-HER2 ADCs group and 71 patients in the T-DM1 group. In these novel ADCs, 30 patients received trastuzumab deruxtecan (T-Dxd), 43 patients receive other novel ADCs. The median PFS in the novel ADCs group and T-DM1 group were 7.0 months versus 4.0 months, respectively, and ORR was 54.8% versus 22.5%, CBR was 65.8% versus 47.9%, respectively. In subgroups analysis, the PFS were both significantly improved in patients receiving T-Dxd and other novel ADCs compared with T-DM1. The most common grades 3-4 adverse events in the novel anti-HER-2 ADCs group were neutropenia (20.5%) and thrombocytopenia (28.1%) in the T-DM1 group.ConclusionsIn patients with HER2-positive MBC previously treated with TKIs, both T-Dxd and other novel anti-HER2 ADCs yielded statistically significant better PFS than T-DM1 did, with tolerable toxicities.
| S-EPMC10546815 | biostudies-literature
Project description: Not available
| S-EPMC10632570 | biostudies-literature