142 Exploratory Biomarker Analysis of Trastuzumab Deruxtecan Versus Physician’s Choice of Chemotherapy in HER2-Low/Ultralow, Hormone Receptor–Positive Metastatic Breast Cancer in DESTINY-Breast06

Background

DESTINY-Breast06 (NCT04494425), a randomized, open-label, phase 3 trial, demonstrated a clinically meaningful progression-free survival (PFS) benefit with trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC [capecitabine, nab-paclitaxel, or paclitaxel]; PFS; 13.2 vs 8.1 months [hazard ratio, 0.64]) in patients with hormone receptor–positive (HR+), HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization–negative) or HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer after 1 or more endocrine-based therapy (primary data cutoff: March 18, 2024). Based on DESTINY-Breast06, T-DXd received US FDA and European Medicines Agency approval for HER2-low or HER2-ultralow unresectable or metastatic breast cancer that has progressed on 1 or more endocrine therapy in the metastatic setting. PI3K/AKT pathway, ESR1, and BRCA1/2 mutations are potentially actionable biomarkers that can inform treatment decision making in this setting. We report an exploratory circulating tumor DNA (ctDNA) analysis of DESTINY-Breast06 evaluating clinical outcomes based on baseline genomic status.

Methods

Baseline ctDNA profiling in blood samples was assessed via Guardant OMNI 500-gene liquid biopsy assay. In total, 625 patients had evaluable ctDNA samples and putative tumor content, of whom 318 had received T-DXd and 307 had received TPC and comprised the biomarker-evaluable population presented herein. Baseline characteristics and efficacy outcomes were evaluated in key genomic subgroups (PI3K/AKT pathway, ESR1m, BRCA1/2m), including confirmed objective response rate (cORR) and PFS, both by blinded independent central review.

Results

Genomic alterations were observed in 45.0% (PI3K/AKT pathway, n = 281), 51.5% (ESR1m, n = 322), and 7.7% (BRCA1/2m, n = 48) of patients. The median PFS (PFS) for each mutational subgroup was 13.2 and 7.1 months (PI3K pathway), 11.3 and 7.0 months (ESR1 mutation), and 21.4 and 5.6 months (BRCA1/2 mutation) for T-DXd and TPC, respectively. T-DXd improved PFS and cORR outcomes compared with TPC across all mutational subgroups reported (Table).

Conclusions

In this exploratory ctDNA analysis, T-DXd demonstrated a greater clinical benefit in terms of improved PFS and cORR vs TPC regardless of PI3K/AKT pathway, ESR1, or BRCA1/2 mutation status. The findings support T-DXd as an effective treatment across patients with HR+, HER2-low or HER2-ultralow metastatic breast cancer after 1 or more endocrine-based therapy regardless of PIK3/AKT pathway, ESR1 or BRCA1/2 mutation status.