DESTINY-Breast03: Improving Outcomes in Metastatic HER2-Positive Breast Cancer

The treatment of metastatic, HER2-positive breast cancer has improved dramatically in recent years as more effective therapies have been introduced. The standard first-line therapy remains a taxane combined with dual HER2 targeting with trastuzumab and pertuzumab, the so-called Cleopatra regimen. On disease progression, most patients would receive the antibody-drug conjugate trastuzumab-emtansine (T-DM1). Thereafter, a variety of HER2 therapies could be considered, including recently approved trastuzumab deruxtecan (T-DXd) and the triplet of trastuzumab, tucatinib, and capecitabine.

The DESTINY-Breast03 study is an industry-sponsored, phase 3, multicenter randomized trial comparing T-DXd to T-DM1 in patients with HER2-positive metastatic breast cancer who had previously been treated with a taxane and trastuzumab. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), response rate (RR), and safety. Of 524 patients, median age was 54 years, 51% had ER-positive tumors, 61% had received pertuzumab, and 22% had stable brain metastases.

At 12 months, the PFS rate was 75.8% in patients receiving T-DX-d versus 34.1% in those receiving T-DM1 (P<0.001). RR was 79.7% in those receiving T-DX-d versus 34.2% in those receiving T-DM-1. Overall survival data were immature at the time of the analysis. Drug-related interstitial lung disease, a concern from early trials of T-DXd, was reported in 10.5% of patients on T-DX-d versus 1.9% on T-DM1, though no cases were grade 4 or 5.