Longer progression-free survival with targeted therapy for patients with metastatic breast cancer

Abstract

Select patients with metastatic breast cancer who received trastuzumab deruxtecan (T-DXd) after endocrine therapy had significantly longer progression-free survival (PFS) than patients treated with chemotherapy according to the results of the DESTINY-Breast06 trial presented at the San Antonio Breast Cancer Symposium and published in The New England Journal of Medicine.^{1, 2}

Specifically, patients with hormone receptor–positive (HR+) metastatic breast cancer with low human epidermal growth factor receptor 2 (HER2) who were treated with T-DXd had a median PFS of 13.2 months versus 8.1 months for those treated with chemotherapy. This represents a 38% reduction in the risk of disease progression or death for those treated with T-DXd (hazard ratio, 0.62; 95% CI, 0.52–0.75; p < .001).

Similarly improved PFS was seen for patients with ultralow HER2 expression (a score of 0 on an immunohistochemical [IHC] analysis with membrane staining), although the main outcome of the study was PFS among patients with HER2-low disease (a score of 1+ or 2+ on an IHC analysis and negative results on in situ hybridization).

DESTINY-Breast06 is a phase 3, multicenter, open-label trial in which 866 patients with HR+ metastatic cancer with low or ultralow HER2 expression who had received one or more lines of endocrine-based therapy (and no previous chemotherapy) were randomized to T-DXd (n = 436) or chemotherapy (n = 430) according to the physician’s choice. T-DXd, an antibody–drug conjugate, was administered every 3 weeks. Among the patients, 713 had HER2-low disease, and 153 had HER2-ultralow disease.

The results provide more clarity on the sequencing of T-DXd in patients with metastatic breast cancer with low HER2 expression. Although T-DXd has shown efficacy in this setting when delivered after chemotherapy, its efficacy when delivered earlier after endocrine-based therapy is unknown.

Giuseppe Curigliano, MD, PhD, senior deputy director at the European Institute of Oncology in Milan, says that the study is important because it shows that T-DXd could become the new standard of care for patients with HR+, HER2-low, or HER2-ultralow metastatic breast cancer. “These data underscore the potential for treatment with T-DXd across the spectrum of HR+ breast cancer, further redefining the treatment of metastatic breast cancer,” he says.

Oladapo Yeku, MD, PhD, associate editor of NEJM Evidence, said in an audio interview that the “study supports the hypothesis that antibody–drug conjugates, such as trastuzumab deruxtecan, are effective in earlier lines of treatment even when patients have not been exposed to conventional cytotoxic chemotherapy.”³

When he was asked what factors should be considered when one is considering using T-DXd or chemotherapy in this setting, he cited the different types of toxicities associated with each type of treatment.

The study found that more patients in the T-DXd group than the chemotherapy group experienced grade 3 or higher adverse events (52.8% vs. 44.4%). Notably, more patients treated with T-DXd experienced interstitial lung disease or pneumonitis (22.3% vs. 0.2% in the chemotherapy group) and left ventricular dysfunction (8.1% vs. 3.8%).

Dr Yeku highlighted the potentially serious adverse event of interstitial lung disease in patients treated with T-DXd and said that the finding underscores the need for ongoing vigilance in patients receiving this treatment.