In the phase 3 DESTINY-Breast06 trial, the overall biomarker-evaluable population’s confirmed ORR was 59.4% with T-DXd vs 33.9% with chemotherapy.
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.