Future potential targets of antibody-drug conjugates in breast cancer

 

by Chiara Corti, Luca Boscolo Bielo, Ambra Carnevale Schianca, Beatrice Taurelli Salimbeni, Carmen Criscitiello, Giuseppe Curigliano 

 

The Breast: VOLUME 69, P312-322, JUNE 2023 (Published: March 24, 2023)

 

Abstract

Metastatic breast cancer (BC) remains an incurable disease. Besides endocrine and targeted agents, chemotherapy is still a relevant therapeutic option for this disease. Recently, antibody-drug conjugates (ADCs) have shown to overcome the lack of tumor specificity and systemic toxicity typically associated with traditional chemotherapies, thus improving the therapeutic index. To effectively exploit this technological breakthrough, identification of optimal target antigens (Ags) is of utmost importance. To make the ideal target, differential expression of target Ags between healthy and cancer tissues, as well as specific mechanisms of ADC internalization after Ag-antibody interaction are required.

Therefore, several in silico strategies to identify and characterize new promising candidate Ags have been developed. If initial in vitro and in vivo positive data are documented, thus providing a biological rationale for further Ag investigation, early phase clinical trials are designed. In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. However, promising new Ags are currently under investigation, with encouraging results especially coming from targeting HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7–H4.

In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided.

 

Antibody drug conjugates targeting HER2: Clinical development in metastatic breast cancer

 

by Elie Rassy, Layal Rached, Barbara Pistilli 

 

The Breast: VOLUME 66, P217-226, DECEMBER 01, 2022

 

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.

 

Current challenges and unmet needs in treating patients with human epidermal growth factor receptor 2-positive advanced breast cancer

 

by Matti Aapro, Fatima Cardoso, Giuseppe Curigliano, Alexandru Eniu, Joseph Gligorov, Nadia Harbeck, Andreas Mueller, Olivia Pagani, Shani Paluch-Shimon, Elzbieta Senkus, Beat Thürlimann, Khalil Zaman 

 

The Breast: Published: July 30, 2022

 

Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed.

 

Accelerating progress in early triple-negative breast cancer: A viewpoint on antibody-drug conjugates, back from St Gallen breast cancer conference 2021

 

by Dario Trapani, Giuseppe Curigliano 

 

The Breast: Published: December 13, 2021

 

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast tumors, associated with dismal prognosis. Innovative treatments have expanded the therapeutic options for selected patients with advanced disease (mTNBC). Inter alia, the new class of molecules of antibody-drug conjugates (ADCs) has rapidly positioned in the setting of mTNBC, providing significant benefits in pretreated patients. With the advent of ADCs, progresses have been marked in targeting TNBC. Tackling this ‘un-targetable’ tumor type has been the real enterprise of the last years, overcoming the original sin of classification of TNBC in a default ‘non-positive’ category, ultimately grouping together a spectrum of heterogeneous diseases. As such, ADCs have opened an ‘identity crisis’ for TNBC treatments. These molecules are composed of a backbone of monoclonal antibody (MAb), exploiting the best role they are engineered for: recognize antigens. But ADCs are linked to cytotoxic payloads, resulting in tailored delivery of highly active agents, with the intent to spare non-targeted tissues. At the end, they interpret essentially a new pharmacological delivery model to treat tumors

The implementation of ADCs has first modernized the view on MAb clinical utilization: not really only to switch-off hyperactive tumorigenic signaling; ADCs can exert anti-neoplastic activities in disregard of the biologic functions of their pharmacological receptors: antigens are linked, payloads are released, cancer cells are killed via internalized chemotherapies. Such a change in perspective implies that: (i) ADCs can exploit activity across multiple tumor types – delivering agnostically, based on antigen expressions; (ii) ADCs offer an attractive perspective for treatment personalization, based on the multiple targetable antigens that can be identified in a single patient - a possible declination of the theranostic paradigm. Agnosticity and theranosticity, however, will be reached only with an optimal trade-off between antibody specificity – to avoid off-target effects and non-specific activity related to the release of the payload in the bloodstream – and patient tolerance of the cumulative toxicities. Pursuing precision in this context will require understanding better how these new ADCs tailor the targets; perhaps, most importantly, there must be better knowledge on what is the minimal amount of membrane antigen to be expressed, to determine ADCs efficacy, and if traditional techniques like immuno-histochemistry are sensitive enough for this purpose.