Dr Rugo on Research Needed to Clarify the Role of T-DXd Plus Pertuzumab in HER2+ Breast Cancer

"Using [T-DXd plus pertuzumab] markedly improved PFS [vs THP]. What we want to know is: How [should we] use this in clinical practice, and for which patients?"

Hope S. Rugo, MD, a professor in the Department of Medical Oncology & Therapeutics Research, division chief of Breast Medical Oncology, and director of the Women’s Cancers Program at City of Hope, discussed the clinical significance and application of findings from the phase 3 DESTINY-Breast09 trial (NCT04784715) evaluating fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) in HER2-positive advanced/metastatic breast cancer.

Findings from DESTINY-Breast09 presented at the 2025 ASCO Annual Meeting demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with T-DXd plus pertuzumab, with a 44% reduction in the risk of disease progression or death compared with standard-of-care (SOC) trastuzumab (Herceptin) plus pertuzumab and a taxane (THP; HR, 0.56; 95% CI, 0.44-0.71; P < .00001). The benefit was consistent across all prespecified subgroups, Rugo stated.

The regimen’s safety profile was notable for a low incidence of interstitial lung disease (ILD)–related deaths, with only 2 patients (0.5%) affected, Rugo stated. Although acknowledging that any ILD-related death is concerning, she emphasized that this small number is encouraging from a clinical perspective. Rugo also noted that the significant PFS improvement seen with T-DXd plus pertuzumab represents a substantial advance compared with THP, Rugo stated.

Determining how these findings could be applied in clinical practice, including identifying which patients are most likely to benefit, is therefore highly important, Rugo stated. Most patients treated in the metastatic setting will likely have de novo metastatic disease, she added, referencing a news release from the phase 3 DESTINY-Breast11 trial (NCT05113251), which is evaluating T-DXd followed by THP compared with an anthracycline-based regimen plus THP in patients with HER2-positive early breast cancer.

The reported improvement in pathologic complete response (pCR) in DESTINY-Breast11 suggests that a sequential regimen may be beneficial regarding both adverse effect management and the potential to avoid anthracyclines, Rugo continued. If these pCR rates translate into improved disease-free survival, this approach could become the SOC for patients with larger tumors in the neoadjuvant setting, potentially curing more patients with early-stage HER2-positive disease, she explained.

Rugo emphasized the need to define optimal treatment duration with T-DXd plus pertuzumab in DESTINY-Breast09, raising the question of whether patients should continue therapy until progression, or whether shorter treatment periods with subsequent maintenance might suffice. Endocrine therapy and CDK4/6 inhibitors also have a potential use for patients with estrogen receptor–positive disease, highlighting the importance of balancing efficacy with quality of life, she said.

Ongoing studies are expected to provide further insights into optimal sequencing and maintenance strategies, Rugo said. Although T-DXd plus pertuzumab may represent a new first-line SOC, additional research is needed to refine treatment duration, maintenance strategies, and the integration of targeted therapies to maximize patient outcomes and tolerability, Rugo concluded.