In the phase III DESTINY-Breast09 trial, first-line treatment with the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) plus the monoclonal antibody pertuzumab significantly delayed disease progression by more than 1 year—nearly doubling the time of disease control—over standard treatment with trastuzumab plus pertuzumab and a taxane in patients with metastatic HER2-positive breast cancer, reported Sara M. Tolaney, MD, MPH, FASCO, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, Boston, and coauthors at a special session at the 2025 ASCO Annual Meeting.¹ The study is the first to show a statistically significant and clinically meaningful improvement in progression-free survival in this patient group since the CLEOPATRA trial established the current standard of care more than a decade ago.²

Sara M. Tolaney, MD, MPH, FASCO

Median progression-free survival was 40.7 months with T-DXd plus pertuzumab vs 26.9 months with trastuzumab plus pertuzumab and a taxane (THP); hazard ratio [HR] = 0.56; P < .00001), a benefit that was consistent across subgroups. Median duration of response was substantially longer, and the rate of complete response was almost doubled. Overall survival data were immature, but a favorable trend has already emerged for the novel regimen, according to Dr. Tolaney.

“These data suggest that T-DXd plus pertuzumab may represent a new first-line standard of care for patients with metastatic HER2-positive breast cancer,” she commented. “While these data are from an interim analysis, the combination of T-DXd and pertuzumab is so dramatically better than THP that it is reasonable to consider changing practice based on the data.”

Dr. Tolaney put the findings into clinical context: “Outcomes for patients with metastatic HER2-positive disease have dramatically evolved since the introduction of T-DXd, which is currently approved as a second-line standard of care based on the results from DESTINY-Breast03,³ where we saw an unprecedented 29-month progression-free survival. There’s been much interest in trying to move T-DXd into the first-line setting, particularly knowing that the current first-line standard of care, THP, is associated with a progression-free survival of a little under 19 months. We also know that about one-third of patients who start first-line therapy for metastatic HER2-positive disease do not go on to receive a second line of treatment…. There’s also been interest in seeing if we could further enhance the efficacy of T-DXd by adding pertuzumab.”

The HER2-directed antibody-drug conjugate T-DXd consists of a potent payload of an exatecan derivative, with a short systemic half-life. Once released, this membrane-permeable payload results in DNA damage and cell death; this causes destruction of targeted tumor cells and neighboring cells in the tumor microenvironment. The monoclonal antibody pertuzumab targets the extracellular dimerization domain of the HER2 protein and blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through the mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K) pathways.

About DESTINY-Breast09

DESTINY-Breast09 looked at outcomes for T-DXd in the first-line metastatic setting. The study included 1,157 patients with HER2-positive locally advanced or metastatic breast cancer not previously treated with chemotherapy or HER2-targeted agents for metastatic disease. Patients were randomly assigned to receive T-DXd plus placebo, T-DXd plus pertuzumab, or standard therapy with a taxane (paclitaxel or docetaxel given for at least six cycles) plus trastuzumab and pertuzumab (THP). The current interim analysis includes only patients from the T-DXd/pertuzumab and THP arms. Efficacy in the T-DXd monotherapy arm did not meet the threshold set for the interim analysis; therefore, follow-up on this arm will continue, and data will be reported at the final progression-free survival analysis.

Patients in the T-DXd arm received the drug until disease progression; if T-DXd was discontinued because of toxicity, trastuzumab could be added. Concurrent use of endocrine therapy was allowed after six cycles of T-DXd or discontinuation of the taxane in the THP arm. The primary endpoint was progression-free survival by blinded independent central review.

Key Findings

At a median follow-up of 29 months, the key findings for the T-DXd/pertuzumab and THP arms, respectively, follow:

• Median progression-free survival was 40.7 months vs 26.9 months (HR = 0.56; P < .00001), a consistent benefit seen across subgroups.
• At 2 years, 70.1% vs 52.1% of patients remained progression-free.
• Objective response rate was 85.1% vs 78.6%; complete response rate was 15.1% vs 8.5%.
• Median duration of response was 39.2 months vs 26.4 months.
• Median time from randomization to disease progression on second-line therapy was not reached with T-DXd plus pertuzumab and was 36.5 months with THP (HR = 0.60; P = .00038)

Dr. Tolaney further reported that postdiscontinuation therapy in the second line for the THP arm included T-DXd for 10% of patients and ado-trastuzumab emtansine (T-DM1) for 12%. Median treatment duration with T-DXd was 21.7 months vs 16.9 months with THP. In the THP arm, median number of taxane cycles was six with paclitaxel and eight with docetaxel.

Safety Profile

The number of grade 3 or 4 adverse events and the number of serious adverse events were similar between the arms (27.0% with T-DXd/pertuzumab and 25.1% with THP). However, on the T-DXd/pertuzumab arm, there were more dose interruptions (68.8% vs 49.0%) and dose reductions (45.9% vs 19.9%), as well as numerically more deaths (five vs one with THP). Patients given T-DXd plus pertuzumab had much longer treatment exposure (median, 22 months vs 17 months), Dr. Tolaney noted.

The most common treatment-emergent adverse events of any grade included diarrhea (55.9%), neutropenia (48.8%), and anemia (35.5%). Interstitial lung disease developed in 12% of patients receiving T-DXd plus pertuzumab, compared with 1% receiving THP; the majority were low-grade with the exception of two grade 5 events. The rate of left ventricular dysfunction was numerically higher with T-DXd plus pertuzumab, at 11% vs 7%. 

DISCLOSURE: Dr. Tolaney reported personal financial relationships with Aadi Bioscience, Ambrx, Artios Biopharmaceuticals, Arvinas, AstraZeneca, Bayer, BeiGene, Bicycle Therapeutics, BioNTech, Blueprint Medicines, Bristol Myers Squibb, Circle Pharma, Cullinan Oncology, Daiichi Sankyo, eFFECTOR Therapeutics, Eisai, Genentech, Hengrui Pharmaceutical (USA), Immunomedics/Gilead, Incyte, Jazz Pharmaceuticals, Johnson & Johnson, Launch Therapeutics, Lilly, Menarini Group, Merck, Mersana, Natera, Novartis, Pfizer, Reveal Genomics, Sanofi, Seagen, Sumitovant Biopharma, Summit Therapeutics, SystImmune, Tango Therapeutics, Zentalis Pharmaceuticals, Zuellig Pharma, and Zymeworks.

REFERENCES

1. Tolaney SM, Jiang Z, Zhang Q, et al: Trastuzumab deruxtecan + pertuzumab vs taxane + trastuzumab + pertuzumab for first-line treatment of patients with HER2-positive advanced/metastatic breast cancer: Interim results from DESTINY-Breast09. 2025 ASCO Annual Meeting. Abstract LBA1008. Presented June 2, 2025.

2. Swain SM, Miles D, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol 21:519-530, 2020.

3. Cortes J, Kim SB, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med 386:1143-1154, 2022.

EXPERT POINT OF VIEW

Invited discussant of DESTINY-Breast09, Claudine Isaacs, MD, FRCPC, FASCO, Professor of Medicine at Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, commented that fam-trastuzumab deruxtecan-nxki (T-DXd) plus pertuzumab “represents a possible new standard of care in the first-line setting, but questions remain about optimal sequencing and duration of therapy.

Claudine Isaacs, MD, FRCPC, FASCO

Dr. Isaacs referenced several transformative events in the landscape of metastatic HER2-positive breast cancer, most notably the addition of trastuzumab to first-line chemotherapy,¹ which reduced the risk of disease progression by 49%, and the addition of pertuzumab to trastuzumab in CLEOPATRA,² which improved overall survival by 16 months and supported this regimen as the standard of care for the past 13 years. The introduction of the antibody-drug conjugate T-DXd “marked another milestone,” she added; in DESTINY-Breast03, T-DXd provided an additional 22 months of progression-free survival over ado trastuzumab emtansine (T-DM1) in the second-line-plus setting and also reduced mortality by 36%.³

DESTINY-Breast09 has now evaluated T-DXd in the first-line setting, with interim results available for the T-DXd/pertuzumab and THP control arms. The almost 14-month prolongation in progression-free survival is “highly statistically significant and clinically meaningful,” with a benefit that is generally consistent across subgroups, Dr. Isaacs noted. “Given the short follow-up, and the fact that about 40% of the patients on the investigational arms still remain on T-DXd/pertuzumab, it is certainly possible that the median progression-free survival of this arm improves with further follow-up.”

Treatment Goals and Remaining Questions

In discussing her thoughts on how to integrate these data, Dr. Isaacs reminded listeners of the treatment goals for metastatic HER2-positive breast cancer: “to provide patients with the longest possible road ahead but, at the same time, to ensure that the road is as easy as possible with the fewest twists and turns and the fewest ups and downs, to enable our patients to thrive and live their lives as normally and fully as possible, for as long as possible.”

“We would all agree that T-DXd, both in the first- and second-line settings, is a highly active drug and one that we want in our therapeutic armamentarium. But, as given in this trial, it is an escalation of care,” she said. “For me, the outstanding questions are related to sequencing. Namely, do we have to give it in the first line to everyone, or could we have a more selective approach? Could we identify the 25% or so of patients with early disease progression on THP, where we would want to escalate to first-line T-DXd/pertuzumab, and, conversely, which markers would allow us to identify those with prolonged benefit to THP, where we could wait to give T-DXd in the second line? And, if we are giving it in the first line, how long do we need to give it?”

The data so far do not answer these questions, but helpful biomarkers are emerging, according to Dr. Isaacs. From studies, potential selection criteria for first-line use include brain metastases, significant visceral disease, recent disease progression after treatment in the early-stage, molecular markers of early disease progression (eg, PIK3CA mutation), HER2 drivers, and dynamic markers (eg, lack of early drop in circulating tumor DNA)—all of which need to be further validated.

“One also wonders if we could achieve a similar benefit with induction T-DXd plus pertuzumab until best response, followed by maintenance trastuzumab/pertuzumab. I suspect that many of us will be tempted to do this, but this is a data-free zone,” she cautioned. 

DISCLOSURE: Dr. Isaacs has served as a consultant to Arvinas, AstraZeneca, Genentech, Novartis, Pfizer, Gilead Sciences, Merck, and Seattle Genetics; has received royalties from Wolters Kluwer (UptoDate) and McGraw-Hill (Goodman and Gillman);and has received institutional research support from Tesaro/GSK, Seattle Genetics, Pfizer, AstraZeneca, BMS, Genentech, and Novartis.

REFERENCES

1. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001.

2. Swain SM, Miles D, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol 21:519-530, 2020.

3. Hurvitz SA, Hegg R, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 401:105-117, 2023.