Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial
Fernanda Mosele1,2, Elise Deluche3, Amelie Lusque4
1INSERM U981, Gustave Roussy, Villejuif, France.
Abstract:
The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3-81) in cohort 1, 37.5% (95% CI 26.4-49.7) in cohort 2 and 29.7% (95% CI 15.9-47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8-64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7-65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960 .).
Insights
Trastuzumab deruxtecan (T-DXd) shows significant efficacy in HER2-overexpressing and HER2-low metastatic breast cancer. While HER2 expression influences T-DXd effectiveness, other factors may also contribute to treatment response.
Area of Science:
- Oncology
- Pharmacology
- Medical Research
Background:
- Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate used for breast cancer.
- The precise mechanisms of action and resistance to T-DXd are not fully understood.
- Evaluating T-DXd efficacy across varying HER2 expression levels is crucial.
Purpose of the Study:
- To assess the efficacy and safety of T-DXd in metastatic breast cancer patients with HER2-overexpressing, HER2-low, and HER2-non-expressing tumors.
- To investigate the relationship between HER2 expression levels and T-DXd treatment response.
- To explore potential additional mechanisms influencing T-DXd efficacy.
Main Methods:
- The Phase 2 DAISY trial enrolled patients with different HER2 expression levels (cohorts 1, 2, and 3).
- Objective response rate (ORR) was the primary endpoint, with safety as a secondary endpoint.
- T-DXd staining in tumors and ERBB2 expression levels were analyzed in relation to response.
Main Results:
- The confirmed ORR was 70.6% in HER2-overexpressing, 37.5% in HER2-low, and 29.7% in HER2-non-expressing metastatic breast cancer.
- The primary endpoint was met for HER2-overexpressing and HER2-low cohorts.
- T-DXd staining correlated with HER2 expression, and no new safety concerns were identified.
Conclusions:
- T-DXd demonstrates significant efficacy in HER2-overexpressing and HER2-low metastatic breast cancer.
- HER2 expression is a key determinant of T-DXd efficacy, but other factors may also play a role.
- The study met its primary endpoints, supporting T-DXd's role in treating these patient populations.
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