medwireNews: The response to trastuzumab deruxtecan (T-DXd) in patients with metastatic breast cancer differs significantly by tumoral levels of HER2 expression, indicate results from the DAISY trial.
Furthermore, around two-thirds of patients who progressed on T-DXd had a decrease in HER2 expression at the time of progression, reported Maria Fernanda Mosele (Gustave Roussy - Cancer Campus, Villejuif, France) at the ESMO Breast Cancer Congress 2022, held in Berlin, Germany.
These findings suggest that “HER2 expression is a key determinant of T-DXd antitumor activity,” she commented.
The presenter explained that the phase 2 trial was developed “to better understand the mechanism of action of T-DXd,” a HER2-directed antibody–drug conjugate that has shown antitumor activity against both HER2-overexpressing and HER2-low metastatic breast cancer.
The 179 patients recruited to the trial, all of whom had received at least one prior line of treatment in the metastatic setting (38% had received six or more lines), were allocated to one of three cohorts based on HER2 expression:
- HER2 overexpressing (n=68), defined as a HER2 immunohistochemistry (IHC) score of 3+ or IHC 2+ and a positive in situ hybridization result;
- HER2 low (n=73), defined as HER2 IHC 2+ and a negative in situ hybridization result or IHC 1+; or
- HER2 negative (n=38), defined as HER2 IHC 0.
Treatment with T-DXd at a dose of 5.4 mg/kg every 3 weeks achieved an objective response rate of 71.0% in the HER2-overexpressing cohort, 37.5% in the HER2-low cohort, and 30.0% in the HER2-negative cohort, with statistically significant differences between the groups.
Progression-free survival – assessed at a median follow-up of 15.6 months – also differed significantly by HER2 expression levels, at a median of 11.1, 6.7, and 4.2 months in the HER2-overexpressing, low, and negative cohorts, respectively.
The researchers then conducted several exploratory translational analyses, the first of which demonstrated that T-DXd distribution was lower in HER2-negative tumor samples than those with higher levels of HER2.
And another analysis focusing on 20 patients who progressed on T-DXd showed that 65% had lower levels of HER2 at the time of progression than at baseline.
In conclusion, Mosele outlined several ongoing experiments, including the assessment of “T-DXd distribution in tumor biopsies at progression” and the development of “[m]ore sensitive methods to detect HER2 expression in HER2 IHC 0 tumor biopsies at baseline.”
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