Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer

Abstract

Background: The previous second-line treatment for HER2-positive metastatic breast cancer were ado-trastuzumab emtansine (T-DM1); however, its activity is decreased in tumors with heterogenous, reduced, or loss of HER2 expression. Trastuzumab deruxtecan (T-DXd) has recently been developed as a novel antibody-drug conjugate to overcome resistance to T-DM1. However, clinical evidence on its ability to overcome this resistance is limited.

Materials and methods: We retrospectively analyzed data for patients with HER2-positive metastatic breast cancer who received T-DXd at our institution from April 2020 to March 2021. We evaluated the associations between clinicopathological and molecular biomarkers and the efficacy of T-DXd.

Results: Twenty-two patients were enrolled in this study. The median progression-free survival (PFS) was 9.7 months (95% confidence interval [CI], 7.0-not reached [NR]), and the objective response rate (ORR) was 61.9%. The ORR and PFS were comparable between patients with HER2 immunohistochemistry scores of 3+ and 2+/1+ at initial diagnosis (ORR: 50.0% vs. 72.7%, p = 0.39; median PFS, 9.7 months [95%CI, 2.6-NR] vs. 8.3 months [95%CI, 7.1-NR]; hazard ratio, 1.86 [95%CI, 0.53-6.57], p = 0.34). Two patients with heterogenous HER2 expression had a partial response or long stable disease (≥6 months). Three of four patients with re-biopsy samples after anti-HER2 targeted therapy and with latest HER2 immunohistochemistry scores of 1+ experienced partial responses (75.0%) to T-DXd, but none had responded to prior T-DM1.

Conclusions: T-DXd demonstrated favorable activity in clinical practice. Moreover, T-DXd showed meaningful benefit in patients with heterogeneity, reduction, or loss of HER2 expression.

Keywords: Ado-trastuzumab emtansine; Biomarker; HER2-Positive metastatic breast cancer; Trastuzumab deruxtecan.

Fig. 1

Efficacy of trastuzumab deruxtecan. A. Kaplan–Meier curve of progression-free survival. Dashed line indicates 95% confidence interval. B. Waterfall plot of maximum percentage change in tumor size from baseline measured using RECIST version 1.1. One patient was excluded due to no target lesion.

Fig. 2

Comprehensive clinicopathological and molecular factors in patients with HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan. PFS for each patient shown at the top. Clinicopathological and molecular factors for each patient are shown. Each column represents one patient.