A supplemental new drug application (sNDA) has been submitted to Japan’s Ministry of Health, Labour and Welfare seeking the approval of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in combination with pertuzumab (Perjeta) for the treatment of patients with HER2-positive unresectable or recurrent breast cancer.1
The submission is supported by findings from the phase 3 DESTINY-Breast09 trial (NCT04784715), which were presented during a special late-breaking oral session and press briefing at the 2025 ASCOAnnual Meeting.1,2In the trial, trastuzumab deruxtecan plus pertuzumab (n = 383) generated 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) achieved with standard first-line trastuzumab, pertuzumab, and taxane (THP) therapy (n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001).2 The respective PFS rates for the T-DXd and THP arms were 93.0% (95% CI, 89.9%-95.2%) vs 87.8% (95% CI, 84.0%-90.7%) at 6 months, 85.9% (95% CI, 81.9%-89.1%) vs 72.4% (95% CI, 67.4%-76.8%) at 12 months, and 70.1% (95% CI, 64.8%-74.8%) vs 52.1% (95% CI, 46.4%-57.5%) at 24 months.
Key TakeawaysA supplemental new drug application has been submitted in Japan seeking approval for T-DXd combined with pertuzumab for treating patients with HER2-positive unresectable or recurrent breast cancer.The DESTINY-Breast09 trial demonstrated that T-DXd plus pertuzumab significantly extended median PFS to 40.7 months, representing an impressive improvement over the 26.9 months achieved by the current SOC for first-line HER2-positive disease.This regulatory filing follows the approval of T-DXd for HER2-low or -ultralow metastatic breast cancer in Japan.
“In DESTINY-Breast09, [T-DXd] plus pertuzumab demonstrated a median PFS of more than 3 years, which represents an impressive improvement over the current standard of care [SOC],” Yuki Abe, PhD, head of the R&D Division in Japan and head of Research at Daiichi Sankyo, explained in a news release.1
Notably, this sNDA submission follows T-DXd’s approval in Japan on August 25, 2025, for patients with hormone receptor–positive, HER2-low or -ultralow metastatic breast cancer after at least 1 endocrine therapy, based on findings from the phase 3 DESTINY-Breast06 trial (NCT04494425).3
“Following the recent approval of [T-DXd] in Japan for the treatment of HER2-low or HER2-ultralow metastatic breast cancer, this new submission of [T-DXd] plus pertuzumab for the first-line treatment of patients with HER2-positive disease underscores the commitment of Daiichi Sankyo to bring [T-DXd] to as many patients as possible in this region across certain subtypes of metastatic breast cancer,” Abe added.1
What Is the Design of DESTINY-Breast09?
DESTINY-Breast09 is a global, multicenter, randomized, open-label study evaluating the efficacy and safety of trastuzumab deruxtecan administered at 5.4 mg/kg, either as monotherapy or in combination with pertuzumab, compared with the SOC regimen of THP as first-line therapy in patients with HER2-positive metastatic breast cancer.4
A total of 1157 patients were enrolled across sites in Africa, Asia, Europe, and North America.1,2,4 Patients were randomly assigned 1:1:1 to receive T-DXd monotherapy plus a pertuzumab-matching placebo (n = 387), T-DXd plus pertuzumab, or THP. Randomization was stratified by disease setting (de novo metastatic disease vs progression from early-stage disease), hormone receptor status, and PIK3CA mutation status.
The primary end point of the study is progression-free survival (PFS) as assessed by blinded independent central review in both the T-DXd monotherapy and combination arms. Secondary end points include investigator-assessed PFS, overall survival, objective response rate, duration of response, pharmacokinetics, and safety.
The arm evaluating T-DXd monotherapy vs THP remains blinded to patients and investigators and will continue to the final PFS analysis.1
What Was the Safety Profile of T-DXd Plus Pertuzumab in DESTINY-Breast09?
The most common any-grade treatment-emergent adverse effects (TEAEs) observed with T-DXd/pertuzumab and THP, respectively, were nausea (71.1% vs 28.8%), diarrhea (55.9% vs 54.2%), neutropenia (48.8% vs 44.5%), and fatigue (48.3% vs 34.6%). Grade 3 or higher TEAEs most frequently reported included neutropenia (23.9% vs 33.2%), hypokalemia (10.2% vs 1.6%), and anemia (8.4% vs 3.7%).
ReferencesEnhertu plus pertuzumab supplemental new drug application submitted in Japan as first-line therapy for patients with HER2-positive metastatic breast cancer. Daiichi Sankyo. News Release. October 7, 2025. Accessed October 7, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202510/20251007_E.pdfTolaney 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.LBA1008Enhertu approved in Japan as first HER2 directed medicine for patients with HER2 low or HER2 ultralow metastatic breast cancer following at least one endocrine therapy. News release. Daiichi Sankyo. August 25, 2025. Accessed August 26, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202508/20250825_E2.pdfTrastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated May 6, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT04784715
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