Dr Tolaney on Sequencing Available ADCs in Breast Cancer

Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers, associate director, Susan F. Smith Center for Women's Cancers, senior physician, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses the current utilization of antibody-drug conjugates (ADCs) in patients with hormone receptor (HR)–positive, HER2-negative breast cancer, highlighting the question of sequencing among available agents.

For patients with HR-positive disease, the treatment armamentarium includes 2 approved ADCs: fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and sacituzumab govitecan-hziy (Trodelvy), with the potential approval of datopotamab deruxtecan (Dato-DXd; DS-1062a) on the horizon, Tolaney begins. However, the question of the optimal utilization of these agents has introduced a layer of complexity and uncertainty, she states. T-DXd is commonly employed in patients with HER2-low/HR-positive disease who have received 1 or 2 lines of prior chemotherapy, Tolaney explains. Conversely, sacituzumab govitecan is the preferred second-line option for patients with HER2-zero status.

Perplexity arises when contemplating the course of treatment for patients upon disease progression on ADCs, Tolaney continues. For instance, the efficacy and feasibility of using sacituzumab govitecan after T-DXd is unknown, Tolaney says. The similar payloads and different targets of these ADCs amplify this dilemma. Both agents feature topoisomerase 1 inhibitor payloads. However, T-DXd targets HER2 and sacituzumab govitecan targets TROP2, she emphasizes. Tolaney notes that this commonality in payloads raises concerns about potential cross-resistance, prompting the need for a more nuanced understanding of sequential ADC usage.

Recent data presented at the 2023 ASCO Annual Meeting indicated that patients who receive an ADC following a prior ADC have a short progression-free survival. However, some patients experienced surprisingly durable benefits with this approach, Tolaney expands, which underscores the complexity and uncertainty in navigating the sequential use of these ADCs, she says. Ongoing real-world studies are evaluating outcomes with sequential ADC use, and upcoming prospective trials designed to investigate ADC sequencing are poised to shed more light on this intricate matter, she imparts. Until the findings from these studies unfold, the optimal sequential application of T-DXd and sacituzumab govitecan remains an enigma, necessitating a cautious and thoughtful approach to patient treatment in the absence of definitive guidelines, Tolaney concludes.