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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Thursday, September 26, 2024
In the multicenter phase II DAISY trial, the anti-HER2 antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) demonstrated clinically meaningful efficacy in patients with HER2-positive and HER2-low metastatic breast cancer, as well as antitumor activity in those with a HER2 immunohistochemistry score of 0. At the European Society for Medical Oncology (ESMO) Congress 2024 (Abstract 343MO), Maria Fernanda Mosele, MD, of Gustave Roussy, Villejuif, France, and colleagues presented their findings regarding the mechanisms of action and resistance in this population.
“T-DXd does not seem to activate CD8-positive T lymphocytes within the immune tumor microenvironment,” the investigators commented. “Furthermore, spatial ERBB2 expression does not emerge as a significant determinant of T-DXd efficacy in patients with HER2-nonexpressing metastatic breast cancer. Recurrent driver alterations were not identified as contributing factors to resistance.”
In this supplementary biomarker analysis, the activation of CD8-positive T lymphocytes was assessed via multiplex immunohistochemistry for granzyme B in biopsies obtained from a population of patients with various levels of HER2 expression at baseline and during treatment (n = 24). The investigators used a novel in situ hybridization assay to examine the baseline biopsies with a HER2 immunohistochemistry score of 0 (n = 20). Whole-exome sequencing was performed in biopsies taken at baseline (n = 92) and after disease progression (n = 30).
The density of granzyme B/CD8–positive T lymphocytes was not found to significantly increase during treatment with T-DXd in samples taken on the first day of cycles two and three (P = .76). There did not seem to be a significant association between the spatial distribution of ERBB2 RNA expression and response to T-DXd (P = .39). Moreover, in the analyzable samples at baseline and after disease progression, the investigators found neither recurrent driver alterations associated with resistance nor additional SLX4 mutations.
Disclosure: For full disclosures of the study authors, visit cslide.ctimeetingtech.com.
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