DESTINY-Breast06: T-DXd Outperforms Chemo in HER2-Low/Ultralow HR+ mBC Across Mutations

In an abstract at the 2025 American Society of Clinical Oncology (ASCO) Annual meeting, data from the DESTINY-Breast 06 (DB-06) [NCT04494425] study shows that the use of trastuzumab deruxtecan (T-Dxd) enhances progression-free survival (PFS) and confirmed objective response rate (cORR) when compared with the physician’s choice of chemotherapy (TPC) in patients diagnosed with HER2-low/ultralow, hormone receptor–positive (HR+) metastatic breast cancer (mBC).

In this abstract, the researchers provided data from an exploratory analysis of circulating tumor DNA (ctDNA) focusing on baseline genomic status.

Dr. Rebecca Dent, National Cancer Centre Singapore and colleagues wrote, “DB-06 (NCT04494425), a Phase 3, randomized, open-label study, demonstrated a clinically meaningful progression-free survival (PFS; 13.2 vs 8.1 months [hazard ratio: 0.64]) benefit with T-DXd vs TPC (capecitabine, nab-paclitaxel, or paclitaxel) in patients with HR+, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+ / in situ hybridization–negative) or -ultralow (IHC 0 with membrane staining) mBC after at least one endocrine-based therapy (primary data cutoff: March 18, 2024).”

The Guardant OMNI 500-gene liquid biopsy assay was employed to evaluate baseline circulating tumor DNA (ctDNA) analysis in blood samples. For this study, 625 patients had evaluable ctDNA samples and putative tumor content and comprised the biomarker evaluable population (BEP) presented herein.

Researchers assessed baseline characteristics and treatment effectiveness across major genomic subgroups, including phosphatidylinositol 3-kinase (PI3K) pathway mutations, estrogen receptor (ESR1) mutations, and BReast CAncer gene 1 and BReast CAncer gene 2 (BRCA1/2) mutations. This evaluation focused on the confirmed objective response rate (cORR) and progression-free survival (PFS), using blinded independent central review.

The results showed that genomic alterations occurred in 45.0% (PI3K pathway, n=281), 51.5% (ESR1, n=322), and 7.7% (BRCA1/2, n=48) of participants.  The median PFS (mPFS) for each mutational subgroup was reported as: 13.2 months for those receiving (T-DXd) versus 7.1 months (TPC) months for the PI3K pathway, 11.3 months (T-DXd) versus 7.0 months (TPC) for the ESR1m pathway, and 21.4 months (T-DXd) versus 5.6 months (TPC) for BRCA1/2.

Moreover, T-DXd enhanced PFS and cORR outcomes across all mutational subgroups compared with TPC. Results revealed that cORR for T-DXd versus TPC were 57.6% versus 41.5%, respectively, for the PI3K pathway and 60.2% and 32.1%, respectively, for T-DXd and TOC for the ESR1m. Finally, for  BRCA1/2m, the cORR was noted as 80% for T-DXd and 39.3% for TOC.

“In this exploratory ctDNA analysis, T-DXd demonstrated a greater clinical benefit vs TPC regardless of PI3K pathway, ESR1, or BRCA1/2 mutation,” concluded the researchers.