Zhou et al. first evaluated baseline expression levels of Nectin4 (EV target) and Trop2 (SG target) in bladder cancer cell lines. There was variability in the expression of targets at both the RNA and protein levels but no correlation between baseline protein expression and survival after radiation treatment. Radiation led to mild but opposing changes in different cell lines, whereby target expression increased after radiation in some cell lines but did not change in others. There was an additive toxic effect on cancer cells, as measured through apoptosis and DNA damage, upon treatment with radiation and EV or SG.
The investigators subsequently tested these findings in vivo using a xenograft mouse model. In tumor-bearing mice, combination treatment with EV or SG combined with radiation was associated with lower tumor proliferation and higher DNA damage and apoptosis of tumor cells. To compare the efficacy of single agents versus the combination treatment plus radiation, additional cohorts were treated with vehicle, EV or SG alone, radiation alone, or EV or SG with radiation. Treatment with EV or SG with radiation decreased tumor size and weight relative to any of the other cohorts, suggesting possible synergism. The treatments were well tolerated in all treatment arms.
This study sheds light on the potential efficacy of EV and SG with radiation therapy in earlier stages of bladder cancer. The lack of pattern or predictability in baseline and post-treatment target expression underscores the need for in-depth studies on the biomarkers predicting response to EV and SG treatment. Evaluating the role of adding immunotherapy to combinations of antibody-drug conjugates and radiation therapy is needed.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
References:
- Zhou Y, D'Andrea VD, Shanmugam SP, et al. Activity of Enfortumab Vedotin and Sacituzumab Govitecan with Radiation in Preclinical Models of Bladder Cancer. Eur Urol. Published online March 23, 2024. doi:10.1016/j.eururo.2024.03.013
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