EV combines enfortumab (a nectin-4-directed antibody) with vedotin (an anti-mitotic agent) and SG combines sacituzumab (a trop-2-directed antibody) with govitecan (a topoisomerase inhibitor) in an effort to specifically target cytotoxic chemotherapeutic agents to bladder cancer cells. Given the interest in combining approved systemic therapies with radiation therapy (RT) in muscle-invasive bladder cancer (MIBC) in a bladder-sparing approach, this study sought to characterize the combined effects of RT and ADCs in bladder cancer preclinical models.
First, the effects of RT on ADC target expression were explored. Within bladder cancer cell lines, there was a correlation between baseline RNA and protein levels for both nectin-4 and trop-2. Clinically-relevant RT doses modestly impacted nectin-4 and trop-2 levels across models, but importantly, radiation-induced loss of nectin-4 or trop-2 was not observed in any of the tested models.
The combined activity of EV and SG with RT in bladder cancer cell lines was then investigated. Across cell lines, EV and SG showed additive cytotoxicity with RT (Figure 1). In some cases, such as SG plus RT in KU19-19 cells, the synergy between ADC treatment and RT was observed. Furthermore, the combined effects of EV and SG with RT were investigated in vivo in surgically implanted orthotopic mouse models of bladder cancer. Treatment with EV and SG plus RT resulted in lower proliferation and greater DNA damage and apoptosis. In a separate in vivo experiment, the combination of EV and SG plus RT resulted in significant decreases in tumor size and weight compared to any agent alone (Figure 2). Taken together, these data demonstrate that EV and SG plus RT were well-tolerated and had additive antitumor activity in preclinical bladder cancer models.
The current paradigm for trimodality therapy (TMT) includes bladder-directed RT delivered concurrently with a radiosensitizing agent; however, the optimal radiosensitizing agent is unknown. This study provides evidence that EV and SG can be safely and effectively combined with RT, establishing a preclinical rationale that supports the design of clinical trials combining EV or SG with radiation for MIBC.
Written by: Vincent D’Andrea,1,2 Yuzhen Zhou,2 Kent Mouw1,2
- Brigham & Women’s Hospital, Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA