Trastuzumab Deruxtecan Benefit by Baseline Genomic Status Among Patients With HR-Positive, HER2-Low Metastatic Breast Cancer

According to an exploratory biomarker analysis from the phase 3 DESTINY-Breast06 trial, trastuzumab deruxtecan (T-DXd) showed a greater benefit than chemotherapy regardless of PI3K pathway, ESR1, or BRCA1/2 mutations among patients with HER2-low or HER2-ultralow, hormone receptor (HR)-positive metastatic breast cancer.

In the open-label, DESTINY-Breast06 trial, there was a clinically meaningful improvement to progression-free survival (PFS) for patients treated with T-DXd (13.2 months) compared with physician’s choice of chemotherapy (8.1 months). Patients enrolled had HR-positive and HER2-low, defined as immunohistochemistry (IHC) 1+ or IHC 2+ with in situ hybridization-negative, or HER2-ultralow, defined as IHC 0 with membrane staining, metastatic breast cancer and had received at least 1 line of endocrine-based therapy.

There were 625 patients with evaluable ctDNA samples and putative tumor content. Efficacy outcomes including confirmed objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review were measured across key genomic subgroups such as PI3K pathway, ESR1 mutations, and BRCA1/2 mutations.

There were genomic alterations observed in 45.0% of patients in the PI3K pathway subgroup, 51.5% of patients in in the ESR1 mutation subgroup, and 7.7% of patients in the BRCA1/2 mutation subgroup.

The median PFS was 13.2 months for T-DXd vs 7.1 months with chemotherapy in the PI3K pathway subgroup, 11.3 months vs 7.0 months in the ESR1 mutation group, and 21.4 months vs 5.6 months in the BRCA1/2 subgroup. The confirmed ORR was 57.6% for T-DXd vs 41.5% for chemotherapy in the PI3K pathway subgroup, 60.2% vs 32.1% in the ESR1 mutation subgroup, and 80.0% vs 39.3% in the BRCA1/2 subgroup.

Study authors concluded that T-DXd “demonstrated a greater clinical benefit vs [physician’s choice of chemotherapy] regardless of PI3K pathway, ESR1, or BRCA1/2 mutation.”

Source:

Dent R, Curigliano G, Hu X, et al. Exploratory biomarker analysis of trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in HER2-low/ultralow, hormone receptor-positive (HR+) metastatic breast cancer (mBC) in DESTINY-Breast06 (DB-06). Presented at 2025 Annual ASCO Meeting. May 30-June 3, 2025; Chicago, IL. Abstract 1013