Dr McCann on Future Needs in Breast Cancer Drug Development

“Even though we know the antigen, the linker, and the payload, sometimes the AEs are difficult to predict. That’s why, even though we have multiple drugs that target topoisomerase I, for example, the AE profiles of trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan are all different. What I’m most looking forward to are trials [evaluating drugs] with a different payload.”

Kelly Elizabeth McCann, MD, PhD, an associate professor at the University of California San Diego, discussed different classes of agents that are under investigation for the treatment of patients with breast cancer.

McCann began by highlighting the evolving paradigm of antibody-drug conjugates (ADCs) and the necessity for diversifying the payload mechanisms of these agents within clinical research. She also spotlighted the emerging interest in bispecific antibodies that use dual targets, noting clinical trials currently evaluating agents in this class, such as those targeting the VEGF pathway alongside either PD-1 or PD-L1. These innovative therapeutic approaches represent a significant and noteworthy area of focus within the current breast cancer treatment development sphere, according to McCann. She also emphasized her interest in drug candidates that diverge from the traditional use of topoisomerase I inhibitors, noting that any ADC featuring a unique payload mechanism captures substantial clinical attention.

Furthermore, McCann explained the inherent difficulties in rolling out these therapies in clinical trials, primarily due to the unpredictable nature of their adverse effect (AE) profiles. McCann noted that even when the specific antigen, linker, and payload of a drug are known, the resulting AEs remain difficult to predict. This phenomenon is clearly demonstrated by comparing current topoisomerase I inhibitor–containing ADCs such as fam-trastuzumab deruxtecan-nxki (Enhertu), sacituzumab govitecan-hziy (Trodelvy), and datopotamab deruxtecan-dlnk (Datroway); despite targeting the same enzyme, these agents are associated with different AE profiles. Ultimately, McCann stressed the importance of prioritizing future clinical trials that investigate agents with diverse payloads to better understand these complexities and expand effective treatment options for patients.