Trastuzumab Deruxtecan Plus Pertuzumab in HER2-Positive Metastatic Breast Cancer

Key Takeaways

• Trastuzumab deruxtecan plus pertuzumab was linked to a lower risk of progression or death than THP, with a hazard ratio of 0.56.
• Confirmed response was 85.1% versus 78.6%, complete response was 15.1% versus 8.5%, and median duration of response was 39.2 versus 26.4 months.
• Grade 3 or higher adverse events occurred in 63.5% and 62.3%, while drug-related interstitial lung disease or pneumonitis was more frequent with trastuzumab deruxtecan plus pertuzumab and included two grade 5 events.

In the phase 3 DESTINY-Breast09 trial, first-line trastuzumab deruxtecan plus pertuzumab was associated with longer median progression-free survival than THP in HER2-positive advanced or metastatic breast cancer. Patients in this study had received no previous chemotherapy or HER2-directed therapy for metastatic disease. At the February 26, 2025, cutoff, median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab and 26.9 months with THP.

Patients were randomly assigned in a 1:1:1 ratio to trastuzumab deruxtecan plus pertuzumab, trastuzumab deruxtecan plus placebo, or THP. This prespecified interim analysis includes only the trastuzumab deruxtecan plus pertuzumab and THP groups. The trastuzumab deruxtecan plus placebo arm remained blinded until the final progression-free survival analysis. Progression-free survival assessed by blinded independent central review was the primary end point in this first-line comparison.

For progression or death, the hazard ratio was 0.56 with a 95% confidence interval of 0.44 to 0.71. The reported P value was less than 0.00001, and the superiority boundary P value was 0.00043. Confirmed and complete response rates were higher with trastuzumab deruxtecan plus pertuzumab than with THP. Median duration of response was also longer with the trastuzumab deruxtecan regimen.

Grade 3 or higher adverse events occurred in 63.5% of patients receiving trastuzumab deruxtecan plus pertuzumab and 62.3% receiving THP. The most common grade 3 or higher events were neutropenia, hypokalemia, and anemia with trastuzumab deruxtecan plus pertuzumab, and neutropenia, leukopenia, and diarrhea with THP. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% and 1.0%, respectively. These events were grade 1 or 2 in 44 patients and grade 5 in 2 patients with trastuzumab deruxtecan plus pertuzumab, whereas all THP events were grade 1 or 2.

Safety was a secondary end point, and the overall safety profile was consistent with the known profiles of the individual treatments. The authors concluded that trastuzumab deruxtecan plus pertuzumab resulted in a significantly lower risk of progression or death than THP when used first line in HER2-positive advanced or metastatic breast cancer. They also reported that no new safety signals were identified in this interim analysis.