FDA Approves Trastuzumab Deruxtecan (T-DXd) Plus Pertuzumab for First-Line HER2-Positive Metastatic Breast Cancer

The FDA has granted full approval to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) for the first-line treatment of adult patients with unresectable or metastatic HER2+ breast cancer. This decision was supported by results from the Phase 3 DESTINY-Breast09 trial, which demonstrated significant improvements in progression-free survival (PFS) and objective response rates (ORR) compared with the standard trastuzumab, pertuzumab, and taxane (THP) regimen.

T-DXd Plus Pertuzumab Profile & Mechanism

• Profile: Antibody-drug conjugate (T-DXd) targeting HER2 paired with the HER2 dimerization inhibitor pertuzumab.
• Mechanism: T-DXd delivers a topoisomerase I inhibitor payload selectively to HER2-expressing tumor cells, while pertuzumab blocks HER2 heterodimerization, enhancing antitumor efficacy.
• Target Population: Adult patients with unresectable or metastatic HER2-positive breast cancer (IHC 3+ or ISH-positive).
• Delivery System: Intravenous (IV) administration every 3 weeks until disease progression or unacceptable toxicity.
• Treatment Schedule: Every 3 weeks until disease progression or unacceptable toxicity.

DESTINY-Breast09 Study Design (NCT04784715)

• Study Design: Phase 3, randomized, multicenter, open-label trial
• Study Objective: Evaluate the efficacy of T-DXd plus pertuzumab compared with standard trastuzumab, pertuzumab, and taxane (THP) in the first-line treatment of unresectable or metastatic HER2-positive breast cancer.
• Participants: 770 adult patients with unresectable or metastatic HER2-positive breast cancer
  • 383 – T-DXd plus pertuzumab
  • 387 – trastuzumab, pertuzumab, and taxane (THP)
• Primary Endpoint: Progression-free survival (PFS) assessed by a blinded independent review committee (BICR) using RECIST 1.1 criteria.
• Secondary Endpoints: Overall survival (OS), investigator-assessed PFS, objective response rate (ORR), duration of response (DOR), PFS2, and safety.

Study Outcomes

• Primary Endpoint — Progression-Free Survival (PFS)
  • Median PFS was 40.7 months (95% CI, 36.5‑NC) with T‑DXd + pertuzumab versus 26.9 months (95% CI, 21.8‑NC) for those given trastuzumab (Herceptin), pertuzumab, and a taxane (THP; HR 0.56; P < .00001).
  • The PFS benefit was observed consistently across subgroups, including hormone receptor status, disease setting (de novo versus recurrent), and PIK3CA mutation status.
• Key Secondary Enpoints:
  • Objective Response Rate (ORR): 85.1% (95% CI, 81.2‑88.5) with T‑DXd + pertuzumab versus 78.6% (95% CI, 74.1‑82.5) with THP.
    • Complete responses occurred in 15.1% of patients on T‑DXd + pertuzumab versus 8.5% with THP.
  • Duration of Response (DOR): Median DOR was 39.2 months with T‑DXd + pertuzumab versus 26.4 months with THP.
  • Overall Survival (OS): At the interim analysis, OS data were immature but showed a favorable trend for T‑DXd + pertuzumab (HR 0.84; 95% CI, 0.59‑1.19).

Regulatory Milestones

• Approval Date: December 15, 2025.
• Regulatory Pathway: Priority Review of the supplemental Biologics License Application (sBLA), granted based on positive DESTINY‑Breast09 Phase 3 results showing a substantial progression‑free survival benefit.
• Approval Review: The sBLA was also reviewed under the FDA’s Real‑Time Oncology Review (RTOR) program, which allows FDA reviewers to evaluate parts of the submission as they become available to expedite the overall review process

Safety

• Overall Adverse Effects (AEs):
  • The combination therapy was associated with a high incidence of treatment-emergent AEs, consistent with known profiles of HER2-targeted ADCs and pertuzumab. Most patients experienced any-grade AEs, with the most frequent being nausea, fatigue, alopecia, diarrhea, and neutropenia.
• Severity of Toxicity:
  • Grade ≥3 AEs were observed in a meaningful subset of patients, primarily neutropenia, anemia, and elevated liver enzymes. Serious AEs occurred but were manageable with dose modifications or supportive care.
• Interstitial Lung Disease (ILD)/Pneumonitis: A known risk with T-DXd, ILD was reported in ~10% of patients, with fatal events rare (~1–2%). Close monitoring and early intervention with corticosteroids are recommended.
• Treatment Modifications:
  • Dose reductions, interruptions, or discontinuations were required in some patients to manage toxicities. The combination was generally tolerable, with safety consistent with prior T-DXd and pertuzumab experience.

While AEs are common, the safety profile is manageable with proactive monitoring and adherence to guidelines, allowing patients to derive significant efficacy benefits from this chemotherapy-sparing, targeted therapy combination.

Development Status

• Current Status: The combination of T‑DXd plus pertuzumab has been approved by the FDA for the first‑line treatment of adults with unresectable or metastatic HER2‑positive breast cancer, supported by positive DESTINY‑Breast09 data showing a significant progression‑free survival improvement over standard therapy.
• Prescribing information: Available at Drugs@FDA
• Side Effect Reporting: Healthcare professionals are encouraged to report negative side effects to the FDA

Sources:

Tolaney, Sara M., 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.” Journal of Clinical Oncology, vol. 43, no. 17_suppl, 10 June 2025, https://doi.org/10.1200/jco.2025.43.17_suppl.lba1008. Accessed 5 June 2025.

Ryan, Chris, and Kristi Rosa. “FDA Approves T-DXd plus Pertuzumab for HER2+ Breast Cancer.” OncLive, MJH Life Sciences, 15 Dec. 2025, www.onclive.com/view/fda-approves-t-dxd-plus-pertuzumab-for-her2-breast-cancer. Accessed 15 Dec. 2025.