At the 2024 annual meeting of the American Society of Clinical Oncology (ASCO), Dr Giuseppe Curigliano from the University of Milan and the European Institute of Oncology presented the primary results from the DESTINY-Breast06 trial demonstrating that trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) over physician's choice chemotherapy in patients with hormone receptor (HR)-positive, HER2-low or HER2-ultralow metastatic breast cancer treated with prior endocrine therapy.
Outcomes for patients with HR-positive HER2-negative metastatic breast cancer after CDK4/6 inhibitor-based therapy are poor. To address this area of unmet need, the phase 3 DESTINY-Breast06 trial evaluated treatment with T-DXd in patients with HER2-low (immunohistochemistry [IHC]2+/in situ hybridization [ISH]- and IHC1+) or HER2-ultralow (IHC0 with faint or incomplete membrane staining in at least 10% of tumor cells) expression. The phase 3 study randomly assigned 866 patients after prior endocrine-based therapy to receive either T-DXd (n=436) or physician's choice of chemotherapy (n=430; capecitabine, nab-paclitaxel, or paclitaxel). The primary endpoint of the study was PFS by blinded independent central review in the HER2-low population.
Median patient age was 58 years in the T-DXd arm and 57 years in the physician’s choice arm. Approximately 89% of patients had received prior CDK4/6 inhibitors, and the majority had 2 prior lines of therapy. Capecitabine was the most commonly used chemotherapy (60%) on the control arm. HER2-ultralow was found in 17.4% of patients in the T-DXd arm and 17.7% of patients in the chemotherapy arm.
With a median duration of follow-up of 18.2 months, T-DXd treatment led to significantly prolonged PFS in the HER2-low (median:13.2 vs 8.1 months, hazard ratio [HR] = 0.62; P<.0001), ITT (median:13.2 vs 8.1 months, HR = 0.63; P<.0001), and HER2-ultralow (median: 13.2 vs 8.3 months; HR=0.78) populations. The improvement in PFS held for all subgroups analyzed.
The overall survival rate at 12-months was 87.0% vs 81.1% (HR=0.81) in the ITT population, 87.6% vs 81.7% in the HER2-low population, and 84.0% vs 78.7% in the HER2-ultralow population for T-DXd and physician’s choice chemotherapy, respectively. Crossover to T-DXd occurred in 18% of patients in the ITT and 20% of patients with HER2-low disease.
The overall response rate (ORR) in the intent-to-treat population was 57.3% for T-DXd versus 31% for chemotherapy. In the HER2 ultralow population, the ORR was 61.8% for T-DXd, with a clinical benefit rate of 76%.
Patients on T-DXd had a longer median treatment duration (11 months vs 5.6 months for chemotherapy). The most common adverse event leading to treatment discontinuation was interstitial lung disease (ILD) for trastuzumab deruxtecan and peripheral sensory neuropathy for chemotherapy.
Further research is needed to determine the optimal sequencing of T-DXd with other therapies and to refine the HER2 testing criteria to better identify patients who will benefit from this treatment. Additionally, long-term follow-up is required to assess overall survival and quality of life outcomes. The results of the DESTINY-Breast06 study were published simultaneously in the New England Journal of Medicine and highlight the evolving landscape of treatment options for metastatic breast cancer, offering hope for improved outcomes in this challenging disease.
Curigliano G, et al. "DESTINY Breast06 Study Results: Trastuzumab Deruxtecan in HER2 Low and Ultralow Metastatic Breast Cancer." Presented at ASCO 2024. LBA1000.
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