T-DXd Yields PFS Across Mutation Subtypes for HR+, HER2-low Breast Cancer

In the biomarker-evaluable population, the median progression-free survival was 13.9 months in patients treated with T-DXd vs 8.2 months in patients treated with physician’s choice of chemotherapy.

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) was efficacious regardless of baseline PI3K/AKT pathway, ESR1, or BRCA1/2 mutation status in patients with hormone receptor (HR)–positive, HER2-low or HER2-ultralow metastatic breast cancer after at least 1 prior line of endocrine-based therapy, according to an exploratory biomarker analysis of the phase 3 DESTINY-Breast06 trial (NCT04494425) presented at the 2025 American Society of Clinical Oncology Annual Meeting.¹

In the biomarker-evaluable population (n = 625), the median progression-free survival (PFS) was 13.9 months (95% CI, 12.3-15.4) in patients treated with T-DXd vs 8.2 months (95% CI, 6.9-9.5) in patients treated with physician’s choice of chemotherapy (HR, 0.63; 95% CI, 0.52-0.76). The confirmed objective response rate (ORR) was 59.4% (95% CI, 53.8%-64.9%) vs 33.9% (95% CI, 28.6%-39.5%), respectively.

In the intention-to-treat population (n = 866), the median PFS was 13.2 months (95% CI, 12.0-15.2) with T-DXd vs 8.1 months (95% CI, 7.0-9.0) with chemotherapy (HR, 0.64; 95% CI, 0.54-0.76). The confirmed ORR was 57.3% (95% CI, 52.5%-62.0%) vs 31.2% (95% CI, 26.8%-35.8%), respectively.

PI3K/AKT pathway mutations were observed in 45.0% (n = 281) of patients who were biomarker evaluable. For patients with PI3K/AKT pathway wildtype, the median PFS was 13.1 months (95% CI, 11.1-15.4) with T-DXd (n = 179) vs 8.1 months (95% CI, 6.8-9.6) with chemotherapy (n = 165; HR, 0.61; 95% CI, 0.47-0.79); the confirmed ORRs by blinded independent central review (BICR) were 60.9% vs 27.3%, respectively. For those with PI3K/AKT pathway mutation, the median PFS was 13.2 months (95% CI, 9.9-15.5) with T-DXd (n = 139) vs 7.1 months (95% CI, 6.0-9.5) with chemotherapy (n = 142; HR, 0.65; 95% CI, 0.48-0.87); the confirmed ORRs were 57.6% vs 41.5%, respectively.

ESR1 mutations were observed in 51.5% (n = 322) of the biomarker-evaluable population. For those with ESR1 wildtype, the median PFS with T-DXd (n = 152) was 15.2 months (95% CI, 12.3-17.3) vs 8.1 months (95% CI, 6.9-9.6) with chemotherapy (n = 151; HR, 0.59; 95% CI, 0.44-0.79); the confirmed ORRs were 58.6% vs 35.8%, respectively. In those with ESR1 mutation, the median PFS was 11.3 months (n = 166; 95% CI, 9.8-13.5) vs 7.0 months (n = 156; 95% CI, 5.6-9.3), respectively (HR, 0.64; 95% CI, 0.49-0.83); the confirmed ORRs were 60.2% vs 32.1%, respectively.

BRCA1/2 mutations were observed in 7.7% (n = 48) of the biomarker-evaluable population. In those with wildtype status, the median PFS was 12.9 months (95% CI, 10.9-14.5) with T-DXd (n = 298) and 8.2 months (95% CI, 6.9-9.6) with chemotherapy (n = 279; HR, 0.69; 95% CI, 0.56-0.85); the confirmed ORRs were 58.1% vs 33.3%, respectively. In those with BRCA1/2 mutation, the median PFS was 21.4 months (95% CI, 15.2-not evaluable [NE]) with T-DXd (n = 20) vs 5.6 months (95% CI, 4.1-6.9) with chemotherapy (n = 28; HR, 0.14; 95% CI, 0.05-0.33); the confirmed ORRs were 80.0% vs 39.3%.

The overall biomarker-evaluable population’s confirmed ORR was 59.4% (95% CI, 53.8%-64.9%) with T-DXd vs 33.9% (95% CI, 28.6%-39.5%) with chemotherapy.

In those with PI3K/AKT pathway wildtype, the median second progression-free survival (PFS2) was 19.2 months (95% CI, 17.3-23.7) with T-DXd and 14.9 months (95% CI, 12.7-17.1) with chemotherapy (HR, 0.61; 95% CI, 0.46-0.81); in those with mutation status, the median PFS2 was 19.5 months (95% CI, 15.7-26.4) vs 13.6 months (95% CI, 11.4-15.2), respectively (HR, 0.59; 95% CI, 0.44-0.79).

In those with ESR1 wildtype, the median PFS2 was 20.0 months (95% CI, 17.0-23.8) with T-DXd vs 14.6 months (95% CI, 11.8-16.4) with chemotherapy (HR, 0.63; 95% CI, 0.47-0.84); in those with ESR1 mutation, the median PFS2 was 19.4 months (95% CI, 17.1-25.3) vs 13.7 months (95% CI, 12.5-16.7), respectively (HR, 0.58; 95% CI, 0.43-0.77).

In those with BRCA1/2 wildtype, the median PFS2 was 19.2 months (95% CI, 17.3-20.8) with T-DXd vs 14.9 months (95% CI, 12.7-16.7) with chemotherapy (HR, 0.66; 95% CI, 0.53-0.81); in those with mutation status, the median PFS2 was 33.7 months (95% CI, 27.7-NE) vs 11.8 months (95% CI, 8.4-14.6), respectively (HR, 0.17; 95% CI, 0.06-0.42).

“Findings in the biomarker-evaluable population were consistent with those in the [intention-to-treat] population² and provide evidence that T-DXd is an effective treatment across patients with HR-positive, HER2-low or HER2-ultralow [metastatic breast cancer] after 1 or more endocrine-based therapies regardless of PI3K/AKT pathway, ESR1 or BRCA1/2 mutation status,” wrote lead study author Rebecca Dent, MD, MSc, of the Division of Medical Oncology at the National Cancer Centre Singapore in Singapore, with coauthors in the presentation.¹

A total of 866 patients were enrolled in the trial, 625 of whom were included in the biomarker-evaluable population; patients were randomly assigned, in a 1:1 ratio, to receive either 5.4 mg/kg of T-DXd once every 3 weeks or physician’s choice of chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel).

Eligible patients had HR-positive metastatic breast cancer with HER2-low or HER2-ultralow status and were chemotherapy-naïve in the metastatic breast cancer setting. Prior lines of therapy permitted included 2 or more lines of endocrine therapy with or without targeted therapy for metastatic breast cancer, or 1 line of therapy for metastatic breast cancer and progression 6 months or less after starting first-line endocrine therapy plus a CDK4/6 inhibitor, or recurrence 24 months or fewer after starting adjuvant endocrine therapy.

The trial’s primary end point was PFS by BICR in HER2-low patients. Secondary and exploratory end points included PFS in the intention-to-treat population, overall survival, PFS2, safety, and biomarkers.

For the biomarker analysis, blood samples were collected from patients at baseline; circulating tumor DNA profiling was conducted via GuardantOMNI™ 500-gene liquid biopsy assay.

Because this was an exploratory analysis, no formal significance testing was conducted, and no corrections were made for multiple testing.

Reference

1. 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). J Clin Oncol. 2025:42(suppl 16):1013. doi:10.1200/JCO.2025.43.16_suppl.1013
2. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086