Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review
Antibody-drug conjugates are an elegant approach to cancer treatment that couples the specificity of monoclonal antibodies to the cytotoxicity of classic chemotherapy agents, permitting, at least in theory, increased activity and reduced toxicity. In breast cancer, the early success of trastuzumab-emtansine (T-DM1) in the HER2-positive metastatic setting led to great hopes, later dashed by results in the early setting (KRISTINE trial) and in combination with pertuzumab (MARIANNE trial). Parallel to this, development of ADCs in breast cancer has suffered other setbacks, including the recent failure of other agents (MM-302) as well as the suspension of a few programs (XMT-1522, ADCT-502) with the overall effect of dampening the impetus of this concept and halting/delaying the progress of drugs associated with it, particularly when immunotherapy is at the center of so many efforts. Numerous antibody-drug conjugates remain, however, in development, and could prove successful. Critically, ADCs could permit the introduction of novel concepts such as the expansion of potent anti-HER2 therapy to HER2-low breast cancer, treatment beyond resistance to T-DM1, and synergy in combination with immune checkpoint blockade. In the early setting, the ATEMPT trial may show that T-DM1 reduces toxicity while maintaining good outcomes for lower risk HER2+ patients. ADCs based on bispecific antibodies are also in development. Finally, breakthroughs are occurring in the orphan triple-negative breast cancer subtype with agents targeting surface proteins. The recent results of Sacituzumab govitecan suggest substantial activity in heavily pre-treated patients and underscore the enduring relevance of antibody drug conjugates as a path towards better outcomes.
KeywordsBreast cancer Antibody-drug conjugates T-DM1 Sacituzumab govitecan DS–8201a SYD0985
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Conflict of Interest
Noam Pondé has received travel support from Roche/Genentech, Janssen-Cilag, and Mundipharma, as well as speaker’s fees from Mundipharma. The institute he works for has received research funding from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, and Servier. Philippe Aftimos has received travel support from Roche, MSD, and Amgen; consulting fees from Synthon, Boehringer/Ingleheim, and Macrogenics; and speaker Fees from Amgen and Novartis. The institute he works for has received research funding from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, and Servier. Martine Piccart is a board member of Radius. She has received honoraria as a consultant from AstraZeneca, Lilly, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Camel-IDS, Crescendo Biologics, Periphagen, Huya, Debiopharm, PharmaMar, G1 Therapeutics, Menarini, Seattle Genetics, Immunomedics, and Oncolytics. Her institute has received research funding from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, and Servier.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
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