Targeting Trop-2 as a Cancer Driver

The Trop-2–targeting antibody-drug conjugate (ADC) sacituzumab govitecan (SG) has been approved by the US Food and Drug Administration and European Medicines Agency for therapy of patients with breast and urothelial carcinomas, paving the way for Trop-2 targeting for cancer therapy. To our knowledge, Shimizu et al have presented the first in-human, phase I TROPION-PanTumor01 dose-escalation study of the Trop-2–targeting ADC datopotamab deruxtecan (Dato-DXd) in non–small-cell lung cancer. In this trial, 210 patients received up to 8 mg/kg intravenously on day 1 of each 21-day cycle (once every 3 weeks) Dato-DXd. The objective response rate was 26%, with a median progression-free survival and overall survival of 6.9 months and 11.4 months, respectively. Any-grade treatment-emergent adverse events and treatment-related AEs occurred in 54% and 26% of patients, respectively. The mode of action of Dato-DXd, as well as that of SG, is inhibition of topoisomerase I in replicating cells on internalization and payload release. An improved understanding of Trop-2 biological functions and signaling pathways may lead to better management of drug-related toxicities and to an increased impact of Trop-2–targeted therapies.