T-DXd Plus Pertuzumab Improves Outcomes in HER2+ Breast Cancer With Brain Metastases

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) plus pertuzumab (Perjeta) improved systemic and intracranial outcomes vs a taxane, trastuzumab (Herceptin), and pertuzumab (THP) in patients with HER2-positive advanced or metastatic breast cancer and brain metastases at baseline, according to findings from an exploratory analysis of the phase 3 DESTINY-Breast09 trial (NCT04784715) presented at the 2026 ESMO Congress.¹

Among patients with brain metastases at baseline per blinded independent central review (BICR) who received T-DXd plus pertuzumab (n = 31) or THP (n = 30), the median systemic progression-free survival (PFS) was 36.5 months (95% CI, 19.1-not estimable [NE]) vs 11.1 months (95% CI, 7.5-15.4; HR, 0.30; 95% CI, 0.14-0.60), respectively, and the 12-month systemic PFS rates were 86.5% vs 39.4%, respectively. The respective median central nervous system (CNS) PFS values were NE (95% CI, 19.1 months-NE) vs 9.7 months (95% CI, 4.2-19.2; HR, 0.26; 95% CI, 0.11-0.57), and the 12-month CNS PFS rates were 88.9% vs 42.5%.

The confirmed objective response rate (ORR) was 83.9% (95% CI, 66.3%-94.5%) with T-DXd plus pertuzumab vs 70.0% (95% CI, 50.6%-85.3%) with THP, and the confirmed CNS ORRs were 51.6% (95% CI, 33.1%-69.8%) vs 26.7% (95% CI, 12.3%-45.9%), respectively. CNS complete responses occurred in 35.5% vs 23.3% of patients.

“These findings further strengthen the body of evidence which supports the CNS activity of [T-DXd] in the first line [HER2-positive] setting,” Cristina Saura, MD, PhD, of Vall d’Hebron University Hospital and the Vall d’Hebron Institute of Oncology in Barcelona, Spain, stated in a presentation of the data.

What was the design of the DESTINY-Breast09 trial?

DESTINY-Breast09 is a randomized, multicenter trial of patients with HER2-positive advanced or metastatic breast cancer who had not received systemic therapy for advanced disease, other than 1 line of endocrine therapy. Those previously treated with neoadjuvant or adjuvant chemotherapy or HER2-targeted therapy could enroll if they had received their last dose more than 6 months earlier, and patients with inactive or asymptomatic brain metastases were allowed. Patients were randomly assigned 1:1:1 to receive T-DXd at 5.4 mg/kg plus pertuzumab (n = 383), THP (n = 387), or T-DXd plus placebo (n = 387); stratification factors were de novo vs recurrent disease, hormone receptor status, and PIK3CA mutation status. The taxane was paclitaxel or docetaxel. The primary end point was PFS per BICR using RECIST 1.1 criteria, with overall survival (OS) as the key secondary end point.

Every patient underwent brain MRI or CT at baseline and at the end of treatment, but regular imaging during treatment was required only for patients whose baseline brain metastases were identified by the investigator. In this exploratory analysis, BICR retrospectively reviewed all brain scans after treatment ended and assessed systemic and CNS responses in the T-DXd/pertuzumab and THP arms of the intention-to-treat population (n = 770). Eligible patients had brain metastases at baseline per BICR that were either clinically inactive or treated and asymptomatic without a need for corticosteroids or anticonvulsants, had gone at least 2 weeks between the end of whole brain radiotherapy and enrollment, and had at least 1 follow-up brain scan. The data cutoff for this current analysis was February 26, 2025, and the median follow-up was 23.6 months (range, 2.8-41.4).

A total of 61 patients with BICR-confirmed brain metastases at baseline were included. The median age was 56 years (range, 27-79) with T-DXd plus pertuzumab and 54 years (range, 26-71) with THP, and 64.5% and 60.0% of patients, respectively, had an ECOG performance status of 0. Compared with THP, the T-DXd/pertuzumab arm included more patients from Asia (54.8% vs 36.7%), more of those with HER2 immunohistochemistry (IHC) 3+ tumors (90.3% vs 80.0%), and more of those with de novo disease (35.5% vs 23.3%). Prior brain radiotherapy had been given to 22.6% and 20.0% of patients at a median of 26.0 (range, 20-43) and 29.0 days (range, 15-90), respectively, before treatment began.

What did earlier DESTINY-Breast09 results show for T-DXd plus pertuzumab in HER2-positive breast cancer?

On December 15, 2025, the FDA approved T-DXd plus pertuzumab as first-line therapy for adult patients with unresectable or metastatic HER2-positive breast cancer (IHC 3+ or in situ hybridization–positive), based on data from DESTINY-Breast09.² In the trial, the median PFS per BICR was 40.7 months (95% CI, 36.5-NE) with T-DXd plus pertuzumab vs 26.9 months (95% CI, 21.8-NE) with THP (HR, 0.56; 95% CI, 0.44-0.71; P < .0001), and the confirmed ORRs per BICR was 87% (95% CI, 83%-90%) vs 81% (95% CI, 77%-85%), respectively. The OS data were immature at the time of the PFS analysis.

How durable were responses with T-DXd plus pertuzumab in patients in DESTINY-Breast09 with brain metastases?

Systemic responses with T-DXd plus pertuzumab were complete in 9.7% and partial in 74.2% of patients, whereas all responses with THP were partial (70.0%).¹ The median systemic DORs were 35.1 months (95% CI, 17.1-NE) vs 10.5 months (95% CI, 6.7-30.1), respectively, and the median CNS DORs were NE (95% CI, 14.3 months-NE) vs 18.5 months (95% CI, 8.3-NE). Objective CNS responses occurred in 16 patients receiving T-DXd plus pertuzumab and 8 patients receiving THP.

Among the 32 patients with brain metastases identified by both BICR and investigator assessment (n = 16 per arm), the respective systemic ORRs were 87.5% (95% CI, 61.7%-98.4%) vs 62.5% (95% CI, 35.4%-84.8%), and the CNS ORRs were 75.0% (95% CI, 47.6%-92.7%) vs 31.3% (95% CI, 11.0%-58.7%).

The investigators concluded that the findings support the use of T-DXd plus pertuzumab as first-line therapy in HER2-positive advanced or metastatic breast cancer.

Disclosures: Saura reported receiving institutional support from Amgen, AstraZeneca, Bayer Pharma, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Byondis B.V., Cooperative breast cancer group SOLTI, Cytomx Therapeutics, Daiichi Sankyo, Debiopharm International S.A., Eli Lilly, F. Hoffmann–La Roche Ltd, GlaxoSmithKline, Immunomedics, Innoup Farma, Janssen-Cilag S.A., Macrogenics, Menarini, Merck, Merus, Mirati, Novartis, Pfizer, Pharma Mar, Puma, Roche, Sanofi, Seattle Genetics, Servier, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK, and Taiho Pharma USA Inc.; and serving in advisory, speaker, or committee roles for AstraZeneca, Aventik Medical S.L.U., Boehringer Ingelheim, Bristol Myers Squibb, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann–La Roche Ltd, Genentech, Gilead, GlaxoSmithKline, Innoup, Eli Lilly, Macrogenics, Menarini, Merck, Merus, Millennium, Novartis, PeerVoice PSL Group, Pfizer, Pharmalex Spain SLU, Philips, Pierre Fabre, PintPharma, Puma, Reveal Genomics S.L., Roche, Sanofi, SeaGen, Synthon Biopharmaceuticals, and Zymeworks.

References

1. Saura C, Loibl S, Jiang Z, et al. A DESTINY-Breast09 analysis of trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for patients with HER2+ advanced/metastatic breast cancer (a/mBC) and baseline (BL) brain metastases (BMs). Paper presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA49.
2. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. FDA. December 15, 2025. Accessed October 28, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive