The evolving therapeutic landscape of trastuzumab-drug conjugates: Future perspectives beyond HER2-positive breast cancer. (February 2023)

• Record Type: Journal Article
• Authors: von Arx, Claudia; De Placido, Pietro; Caltavituro, Aldo; Di Rienzo, Rossana; Buonaiuto, Roberto; De Laurentiis, Michelino; Arpino, Grazia; Puglisi, Fabio; Giuliano, Mario; Del Mastro, Lucia
• Is Part Of: Cancer treatment reviews. Volume 113(2023)
• Publication Date: 2023-02
• Subjects: ADCs -- HER2-low breast cancer -- Colon-rectal cancer -- Non-small-cell lung cancer -- Gastric cancer -- Trastuzumab; Cancer -- Periodicals; Cancer -- Treatment -- Periodicals; Neoplasms -- therapy -- Periodicals; Cancer -- Périodiques; Cancer -- Traitement -- Périodiques; Cancer -- Treatment; Electronic journals; Periodicals; 616.99406
• DOI: 10.1016/j.ctrv.2022.102500
• Languages: English
• ISSNs: 0305-7372

Abstract

Highlights: Antibody-drug conjugates (ADCs) use mABs affinity to their receptors to vehiculate highly potent cytotoxic molecules into cancer cells. ERBB2 (HER2) has been the most largely studied drug target in cancer cells. HER2-targeting MAbs have achieved successful results only in breast cancer and gastric cancers. Trastuzumab-DCs ( T -DCs) have obtained successful results in HER2-expressing solid tumor treatment as well as in HER2-low breast cancers. T -DCs can represent the future of treatment of HER2-expressing solid tumor and a selected group of tumors with low expression or mutation of HER2. Abstract: A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional chemotherapeutics with highly selective targeted monoclonal antibodies. Anti-HER2 therapies selectively target cancer cells expressing human epidermal growth factor receptor 2 (HER2), among them trastuzumab has been the first HER2-targeting monoclonal antibody to achieve successful results that made it the backbone of anti-HER2 therapies. Trastuzumab drug conjugates ( T -DCs), use trastuzumab as a selective antibody to lead cytotoxic drugs inside cancer cells. Trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan ( T -Dxd) are the two approved T -DCs. T -Dxd along with other five T -DCs represents "second generation ADCs" that has been firstly tested in HER2 positive breast cancer (BC) and then in HER2-low BC and other cancers showing promising results thanks to extraordinary and innovative pharmacokinetic and pharmacodynamic characteristics. The evidence generated so far are establishing them as a completely new class of agents effective in solid cancer treatments but also warrants physicians against unconventional toxicity profiles. The role of T -DCs in HER2-positive BC has been largely reviewed, while in this review, we provided for the first time in literature an overview of trastuzumab drug conjugates ( T -DCs) approved and/or in clinical development with a specific focus on their efficacy and safety profile in HER2-low BC and other solid tumours different from BC. We started by analysing T -DCs biological characteristics that underly the differences in T -DCs pharmacodynamics and safety profile, then presented the main evidence on the activity and efficacy of these emerging T -DCs in HER2-low BC and other HER2 overexpressing and/or mutated solid tumours and lastly, we provided an overview of the complex and still evolving scenario in which these compounds should be allocated. A specific focus on possible combination strategies with other drugs such as immunotherapy, chemotherapy and target therapy, to increase T -DCs activity and eventually overcome future upcoming resistance mechanisms, are here also critically reviewed.