Josh Drago, Assistant Attending Physician, Breast Medicine Service at Memorial Sloan Kettering Cancer Center, shared on LinkedIn:
“ADC target selection has relied on a persistent dogma for years: Pick targets which are expressed at high levels on tumor cells, but at low or absent levels on normal cells.
However, target-dependent ADC delivery is a product of two factors: expression and internalization.
What if we are missing targets which may be present at very low levels but are rapidly internalized?
In this manuscript, published in AACR Journals Clinical Cancer Research, we investigate the illustrative example of activating ERBB2 mutations in Breast Cancer. We show that patients with ERBB2-mutant metastatic breast cancer exhibit improved responses to T-DXd, even at very low levels of HER2 expression by IHC, including cases of HER2-null breast cancer that would be ineligible to receive T-DXd on label.
Preclinically, activating kinase domain mutations in ERBB2 promote enhanced internalization and cytotoxicity of T-DXd at the same level of HER2 expression. This builds on prior work in non-small cell lung cancer by Bob Li and Maurizio S., which has led to major clinical advances.
Of course, target-dependent ADC internalization is only part of the drug efficacy story, and we have long been advocating for multiplex biomarkers incorporating ADC payload sensitivity and other factors. However, evolving our understanding of ADC-target interactions can open up a new way of thinking about drug delivery, with important implications for drug design and patient selection.
Congratulations to Nicholas Mai, Sharanya Nag, and Bo Liu for the excellent work, and with gratitude to Sarat Chandarlapaty and the rest of the ADC translational group at MSKCC for the ongoing scientific partnership.”
Title: ERBB2 Activating Mutations Promote Enhanced Internalization and Activity of Trastuzumab Deruxtecan in HER2-non-amplified Metastatic Breast Cancer
Authors: Nicholas Mai, Sharanya Nag, Bo Liu, Wanyi Chen, Atif Ali Hashmi, Sophia Zelizer, Anton Safonov, Sherry Shen, Fresia Pareja, Charlie White, Yuan Chen, Pedram Razavi, Komal Jhaveri, Shanu Modi, Sarat Chandarlapaty, Joshua Z. Drago
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