The FDA has granted breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab for the first-line treatment of adult patients with HER2-positive unresectable or metastatic breast cancer.
The designation was supported by data from the phase 3 DESTINY-Breast09 trial (NCT04784715).
“This breakthrough therapy designation provides further recognition of the potential benefit of [T-DXd] in combination with pertuzumab in the first-line setting of HER2-positive metastatic breast cancer,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release “If approved, [T-DXd] will continue to redefine the treatment of metastatic breast cancer as these latest results from DESTINY-Breast09 demonstrate a median progression-free survival [PFS] of more than 3 years when using [T-DXd] plus pertuzumab in this disease setting, which is an improvement over the current standard of care that has been in place for more than a decade.”
Findings from DESTINY-Breast09 presented at the 2025 ASCO Annual Meeting demonstrated that patients treated with T-DXd plus pertuzumab (n = 383) achieved a median PFS of 40.7 months (95% CI, 36.5-not calculable [NC]) per blinded independent central review (BICR) compared with 26.9 months (95% CI, 21.8-NC) for those given the combination of trastuzumab (Herceptin), pertuzumab, and a taxane (THP; n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001).2 At 24 months, the respective PFS rates were 70.1% (95% CI, 64.8%-74.8%) and 52.1% (95% CI, 46.4%-57.5%).
In May 2022, the FDA granted full approval to T-DXd for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within 6 months of therapy completion.3 This regulatory decision was supported by data from the phase 3 DESTINY-Breast03 trial (NCT03529110).
DESTINY-Breast09 Overview
The randomized, multicenter, open-label study enrolled patients with HER2-positive advanced or metastatic breast cancer who were naive to systemic therapy in the metastatic setting.2 Patients who received perioperative therapy needed to have a disease-free interval of more than 6 months following last chemotherapy or HER2-targeted therapy in the neoadjuvant or adjuvant setting. Notably, 1 prior line of endocrine therapy in the metastatic setting was allow, and patients with asymptomatic/inactive brain metastases were permitted to enroll.
Patients were randomly assigned to receive T-DXd plus placebo (n = 387), T-DXd plus pertuzumab (n = 383), or THP (n = 387). Notably, data from the T-DXd plus placebo arm remained blinded at the time of this analysis. Stratification factors included disease status (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutation status (detected vs undetected).
Along with the primary end point of BICR-assessed PFS, overall survival (OS) was a key secondary end point. Other secondary end points comprised investigator-assessed PFS, overall response rate (ORR), duration of response (DOR), time to second progression, and safety.
Breaking Down Further Efficacy and Safety Data
The confirmed ORR was 85.1% (95% CI, 81.2%-88.5%) in the T-DXd plus pertuzumab arm vs 78.6% (95% CI, 74.1%-82.5%) in the THP arm. The median DORs were 39.2 months (95% CI, 35.1-NC) and 26.4 months (95% CI, 22.3-NC), respectively.
OS data were immature but suggested a trend favoring the T-DXd plus pertuzumab arm (HR, 0.84; 95% CI, 0.59-1.19).
Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.7% of patients in the T-DXd plus pertuzumab arm (n = 381) vs 99.0% of patients in the THP arm (n = 382). The rates of TEAEs possibly related to treatment were 97.9% and 96.6%, respectively. The respective rates of grade 3 or higher possibly treatment-related TEAEs were 54.9% and 52.4%. Serious TEAEs occurred at rates of 27.0% and 25.1%, respectively.
In the T-DXd plus pertuzumab arm, TEAEs led to any treatment discontinuation, any dose interruptions, and any dose reductions in 20.7%, 68.8%, and 45.9% of patients, respectively. These respective rates were 28.3%, 49.0%, and 19.9% in the THP arm. TEAEs led to death in 3.4% of patients in the experimental arm, including 1.3% due to possibly treatment-related TEAEs. These rates were 0.8% and 0.3%, respectively, in the THP arm.
Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis was reported at any-grade in 12.1% of patients in the T-DXd plus pertuzumab arm vs 1.0% of patients in the THP arm. In the experimental arm, most ILD was grade 1 (4.5%) or grade 2 (7.1%), although 2 patients (0.5%) experienced grade 5 ILD/pneumonitis. These toxicities were grade 1 (0.5%) or grade 2 (0.5%) in the THP arm.
References
- Enhertu plus pertuzumab granted breakthrough therapy designation in the U.S. as first-line therapy for patients with HER2 positive metastatic breast cancer. News release. Daiichi Sankyo. July 17, 2025. Accessed July 17, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202507/20250717_E.pdf
- Tolaney S, 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
- FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed July 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer