T-DXd Plus Pertuzumab Displays Significant PFS Benefit Over SOC Therapy in Frontline HER2+ Advanced Breast Cancer

Sara M. Tolaney, MD, MPH

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) could soon represent a new standard of care (SOC) for patients with HER2-positive advanced or metastatic breast cancer following encouraging data from the phase 3 DESTINY-Breast09 trial (NCT04784715), according to Sara M. Tolaney, MD, MPH.

During the 2025 ASCO Annual Meeting, Tolaney presented findings from DESTINY-Breast09, which examined T-DXd in combination with pertuzumab vs a taxane plus trastuzumab (Herceptin) and pertuzumab for the frontline treatment of patients with HER2-positive advanced or metastatic breast cancer. Patients who received T-DXd plus pertuzumab (n = 383) achieved a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not calculable [NC]) compared with 26.9 months (95% CI, 21.8-NC) in the THP arm (n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001). Additionally, the confirmed overall response rates in the respective arms were 85.1% (95% CI, 81.2%-88.5%) and 78.6% (95% CI, 74.1%-82.5%) and complete response (CR) rates were 15.1% and 8.5%, respectively.

“At the time of this interim analysis, there were very strict criteria that were set for superiority, and T-DXd plus pertuzumab compared [with] THP met those criteria, but the T-DXd plus placebo arm did not,” Tolaney said in an interview with OncLive®. “We found that T-DXd and pertuzumab led to a statistically significant and clinically meaningful difference in PFS. The benefit was seen across all the subgroups that were [examined], including the stratification factors: prior treatment, hormone receptor status, and PIK3CA mutation status.”

Tolaney is the chief of the Division of Breast Oncology, the associate director of the Susan F. Smith Center for Women’s Cancers, and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

In the interview, Tolaney discussed the design of DESTINY-Breast09, the safety data from the study, and the future of T-DXd in the frontline setting of HER2-positive advanced or metastatic breast cancer.

OncLive: What was the rationale for DESTINY-Breast09?

Tolaney: [Approximately] 15% to 20% of [patients with] breast cancer have HER2-positive disease. Outcomes for [patients with] metastatic HER2-positive breast cancer have dramatically evolved over [recent] years since we’ve seen the introduction of T-DXd, which is approved as a second-line SOC [treatment] based on unprecedented results from the [phase 3] DESTINY-Breast03 trial [NCT03529110] where we saw a median PFS of 29.0 months [95% CI, 23.7-40.0]. Given the robust data with this drug, there’s been a lot of interest in trying to move it into the first-line setting, particularly since we know that the SOC for first-line HER2-positive metastatic breast cancer is THP, which has a [median] PFS of [approximately] 19 months. DESTINY-Breast09 was [designed] to investigate T-DXd in the upfront setting.

What were some notable design characteristics of the trial?

DESTINY-Breast09 [enrolled] patients in the first-line setting with metastatic HER2-positive disease and randomly assigned them to one of three arms: T-DXd plus placebo, T-DXd plus pertuzumab, or THP. The primary end point was the PFS of T-DXd and pertuzumab vs THP and T-DXd plus placebo vs THP. The two T-DXd-containing arms were not powered to be compared with each other.

How could the updated efficacy data presented at ASCO affect clinical practice?

Seeing that T-DXd and pertuzumab is, in essence, doubling PFS and nearly doubling the CR rate compared with THP means that this hopefully will become a new SOC option for our patients. It’s tremendous to see the progress that we’re making for patients with metastatic HER2-positive breast cancer and it’s nice to have another highly effective treatment for them.

Were there any new safety signals?

The adverse effects [AEs] that we saw were consistent with the potential AEs of both T-DXd and pertuzumab. The most common [any-grade] AEs included nausea, diarrhea, and neutropenia. The rates of grade 3/4 AEs and of serious AEs were similar between the T-DXd plus pertuzumab arm and the THP arm. However, there were more dose interruptions and reductions in the T-DXd plus pertuzumab arm compared with the THP arm. We also saw a 12.1% rate of [any-grade] interstitial lung disease [ILD] with T-DXd and pertuzumab. The majority of those ILD events were low grade, but there were two grade 5 events. Overall, the safety was consistent with what we know about the toxicities for T-DXd and pertuzumab.

What are the next steps for DESTINY-Breast09?

[Patients in] the study are still in follow-up, and we’ll need to wait for the final PFS analysis to understand how T-DXd [monotherapy] performs. At the time of the final analysis, we’ll get those data [regarding] T-DXd vs THP. Hopefully there will be more to come from this trial.

Reference

Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008