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.
Project description:Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody-drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.
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).
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.
Project description:Effective treatments for metastatic disease have eluded precision oncology efforts and represent a major unmet need. The L1 cell adhesion molecule (L1CAM) is a transmembrane protein expressed by populations of Metastasis Stem cells (MetSC), that are enriched for the ability to reinitiate and propel metastatic growth and display phenotypic plasticity and resistance to conventional chemotherapies. Notably, L1CAM+ MetSC have been detected in numerous human solid tumor types and in multiple disseminated organ sites. As a selective marker of MetSC, L1CAM is a promising candidate for molecularly targeted drugs aimed at eliminating metastases, yet strategies to date have not achieved clinical success. Here, we develop antibody-drug conjugates to deliver highly toxic PNU-159682 payloads to L1CAM-expressing cells. We report the generation of monoclonal antibodies (mAb) with high binding affinity, specificity and selectivity for the human L1CAM extracellular domain. After further optimization of the L1CAM mAbs, PNU-159682 was conjugated to generate ADC variants with both cleavable and non-cleavable linkers, with an average drug-antibody-ratio (DAR) of four. The three ADCs (Y-004, Y-005 and Y-006) potently killed cells with varying levels of surface L1CAM expression. L1CAM ADCs given as monotherapy resulted in robust tumor growth control and extended survival in mice harboring subcutaneous L1CAM+ xenografts or L1CAM+ lung metastases, with safety analyses indicating a feasible therapeutic window. Our findings provide strong proof-of-concept to extend preclinical development of these novel L1CAM ADCs as therapeutic agents for advanced cancer.
Project description:Antibody-drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancer, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development. The therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy, and targeted agents are occurring.
Project description:Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work; we summarize the ADCs' recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.
Project description:Antibody-drug conjugates (ADCs) have emerged as a promising class of anticancer agents. Currently, the Food and Drug Administration has granted approval to 12 compounds, with 2 later undergoing withdrawal. Moreover, several other compounds are currently under clinical development at different stages. Despite substantial antitumoral activity observed among different tumor types, adverse events and the development of resistance represent significant challenges in their use. Over the last years, an increasing number of clinical trials have been testing these drugs in different combinations with other anticancer agents, such as traditional chemotherapy, immune checkpoint inhibitors, monoclonal antibodies, and small targeted agents, reporting promising results based on possible synergistic effects and a potential for improved treatment outcomes among different tumor types. Here we will review combinations of ADCs with other antitumor agents aiming at describing the current state of the art and future directions.
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.