T-DXd Plus Pertuzumab Improves QOL, Safety in HER2+ Breast Cancer

Patient-reported outcomes (PROs) from the phase 3 DESTINY-Breast09 trial (NCT04784715) demonstrated superior quality-of-life (QOL) symptoms and fewer gastrointestinal and skin/mucosal symptoms for patients with HER2-positive advanced or metastatic breast cancer who received fam-trastuzumab deruxtecan (T-DXd; Enhertu) plus pertuzumab (Perjeta) vs those who received standard-of-care treatment.^1,2

Data were presented at the 2025 San Antonio Breast Cancer Symposium by Mothaffar F. Rimawi, MD, of the Dan L. Duncan Comprehensive Cancer Center and Baylor College of Medicine, Houston, Texas.

The DESTINY-Breast09 trial compared T-DXd plus pertuzumab to the standard-of-care regimen of trastuzumab (Herceptin), pertuzumab, and taxane as a first-line therapy for patients with HER2-positive advanced or metastatic breast cancer. Previous results show that T-DXd plus pertuzumab demonstrated an improvement in progression-free survival.

In September 2025, the FDA granted priority review to the supplemental biologics license application of T-DXd for the first-line treatment of patients with unresectable or metastatic HER2-positive breast cancer.

In total, 383 patients received 5.4 mg/kg of T-DXd every 3 weeks, plus an 840 mg loading dose of pertuzumab, followed by 420 mg every 3 weeks. In the trastuzumab, pertuzumab, and taxane arm, 387 patients received a standard-of-care combination of the 3 drugs.

Patient-Reported Outcomes

Compared with trastuzumab, pertuzumab, and taxane, T-DXd plus pertuzumab presents a distinct QOL profile. Patients receiving T-DXd plus pertuzumab reported more gastrointestinal symptoms, including nausea, vomiting, constipation, and appetite loss. This patient group also experienced fewer issues with skin and mucosal symptoms, nosebleeds, and extremity swelling.

Patients in both arms reported similar levels of pain control, fatigue, and overall treatment tolerability. Furthermore, the majority of patients on both treatments successfully maintained or improved their physical function throughout the study.

The PRO end points were time to deterioration in pain, proportion of patients experiencing deterioration in treatment-related symptoms, proportion of patients with maintained or improved physical function, and the overall adverse effect burden as reported by patients.

The impact on pain and physical function was largely similar between the investigational T-DXd plus pertuzumab arm and the trastuzumab, pertuzumab, and taxane arm.

The median time to deterioration in pain was not reached in either treatment arm. The statistical analysis showed a similar risk of pain deterioration for both groups (HR, 0.95; 95% CI, 0.74–1.21).

A high percentage of patients in both arms maintained or improved their physical function. At cycle 2, 82.9% of patients in the T-DXd plus pertuzumab arm (n = 328) maintained or improved physical function vs 82.4% of patients in the trastuzumab, pertuzumab, and taxane arm (n = 341). At cycle 27 (18.7 months), 75.4% of patients in the T-DXd plus pertuzumab arm (n = 187) maintained or improved their physical function vs 77.7% of patients in the trastuzumab, pertuzumab, and taxane arm (n = 166).

The primary differences in patient experience emerged in the specific types of adverse effects reported. Patients in the T-DXd plus pertuzumab arm experienced a worsening of gastrointestinal issues, specifically nausea/vomiting (49.1% vs 30.2%). Conversely, patients in this arm reported less deterioration in skin and mucosal symptoms, including nosebleeds and extremity swelling (22.9% vs 33.5% at cycle 2; 37.4% vs 41.8% at cycle 27). Fatigue deterioration was comparable between the 2 arms at cycles 2 (41.2% vs 41.9%) and 27 (38.0% vs 35.5%), recognized as 2 key time points in the study.

The PROs from the DESTINY-Breast09 trial provide crucial context to the primary efficacy and safety results. The data conclude that T-DXd plus pertuzumab offers durable pain control and maintains physical function, outcomes comparable to the standard-of-care trastuzumab, pertuzumab, and taxane regimen.

“Patients reported T-DXd and [trastuzumab, pertuzumab, and taxane] as similarly tolerable over time,” Rimawi concluded during the presentation. “The risk of clinically meaningful deterioration was similar, although data are still immature at this interim analysis.”

Reference

Rimawi M, Loibl S, Jiang Z, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with HER2-positive (HER2+) advanced/metastatic breast cancer (a/mBC): patient-reported outcomes (PROs) from the DESTINY-Breast09 study. Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF6-07.