Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review.

OPINION STATEMENT: 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.