Breast Cancer, First-Line Antibody Conjugate Slows Disease

The risk of progression of Her2-positive metastatic breast cancer decreased by 44% thanks to the first-line antibody drug conjugate trastuzumab deruxtecan in combination with pertuzumab. This is what emerges from one of the most significant studies presented today in the late-breaking oral session of the 2025 edition of the 2025 edition of the Annual Meeting of the American Society of Clinical Oncology (Asco). The positive results of the Phase 3 Destiny-Breast09 study show that trastuzumab deruxtecan in combination with pertuzumab demonstrated a statistically significant and clinically relevant improvement in progression-free survival (PFS) compared to taxane, trastuzumab and pertuzumab (Thp) as a first-line treatment of patients with Her2-positive metastatic breast cancer.

Trastuzumab deruxtecan is a DXd antibody drug conjugate (ADC) specific for the HER2 receptor. In the prespecified interim analysis, trastuzumab deruxtecan in combination with pertuzumab reduced the risk of disease progression or death by 44% compared with taxane, trastuzumab, and pertuzumab. Median progression-free survival was 40.7 months with trastuzumab deruxtecan in combination with pertuzumab compared with 26.9 months with taxane, trastuzumab, and pertuzumab as assessed by blinded independent central review (BICR). The PFS benefit with trastuzumab deruxtecan in combination with pertuzumab compared with taxane, trastuzumab, and pertuzumab was consistent across subgroups, including prespecified stratification factors of de novo or recurrent disease, hormone receptor (Hr) status, and Pik3Ca mutation status.

Investigator-assessed progression-free survival demonstrated a median PFS of 40.7 months with trastuzumab deruxtecan plus pertuzumab versus 20.7 months with taxane, trastuzumab, and pertuzumab. The confirmed objective response rate (ORR) with trastuzumab deruxtecan plus pertuzumab was 85.1% versus 78.6% with taxane, trastuzumab, and pertuzumab. The complete response rate (CR) was 15.1% with trastuzumab deruxtecan plus pertuzumab versus 8.5% with taxane, trastuzumab, and pertuzumab. The median duration of response (DOR) with trastuzumab deruxtecan plus pertuzumab exceeded three years (39.2 months) compared with just over two years (26.4 months) with taxane, trastuzumab, and pertuzumab.

Overall survival (OS) was not mature at the time of the interim analysis (16% maturity at data cutoff); however, interim OS data show an initial trend in favor of the combination of trastuzumab deruxtecan plus pertuzumab compared to taxane, trastuzumab, and pertuzumab. An additional experimental arm of the study evaluating trastuzumab deruxtecan monotherapy versus taxane, trastuzumab, and pertuzumab remains blinded to patients and investigators and will continue through the final analysis of progression-free survival.

"The Destiny-Breast09 study included over 1,100 patients with metastatic Her2-positive breast cancer," explains Giuseppe Curigliano, President-elect of ESMO (European Society of Medical Oncology), Professor of Medical Oncology at the University of Milan and Director of the Division of Development of New Drugs for Innovative Therapies at IEO in Milan. Destiny-Breast09 is the study with the largest number of patients conducted to date in the first-line treatment of Her2-positive metastatic disease. And it is the first study in more than a decade to demonstrate improved outcomes in the first-line setting for a large population of patients with Her2-positive metastatic breast cancer. Trastuzumab deruxtecan has demonstrated significant improvements in numerous parameters, from progression-free survival, to objective response rate, to complete response, to duration of response. These results may change clinical practice. Trastuzumab deruxtecan is an ADC-type drug, which combines a monoclonal antibody, trastuzumab, with a cytotoxic, deruxtecan, to treat specific types of cancer. It is highly selective for tumor cells, minimizing damage to surrounding healthy cells and increasing the effectiveness of treatment in patients with Her2-positive tumors."

"Italy has also actively contributed to the enrollment of patients in the Destiny-Breast09 study with 9 centers involved - underlines Valentina Guarneri, director of Oncology 2 of the Veneto Oncology Institute - IRCCS of Padua and full professor of Medical Oncology at the University of Padua -. Padua was the first Italian center for patients treated in the study. In Her2-positive tumors, the dual anti-Her2 blockade, trastuzumab and pertuzumab, associated with chemotherapy with taxane represents, to date, the standard first-line strategy. Patients often present disease progression approximately two years after the start of the standard first-line therapy. The current standard second-line treatment is represented by the antibody drug conjugate trastuzumab deruxtecan, in patients who have received one or more previous regimens based on anti-Her2 therapy. Destiny-Breast09 has highlighted the efficacy of trastuzumab deruxtecan also in the first line. With a progression-free survival With a median of more than three years, the Destiny-Breast09 results show that trastuzumab deruxtecan, in combination with pertuzumab, has the potential to become the new standard of care in the first-line setting."

"In 2024, in Italy, almost 53,700 new diagnoses of breast cancer were estimated, the most frequent in the entire population - says Saverio Cinieri, president of the Aiom Foundation -. In 6-7% of cases, breast cancer is metastatic already at diagnosis, but the majority of women living in Italy today with metastatic neoplasia have developed a relapse of the disease after treatment for the initial form".

Thanks to diagnostic and therapeutic progress, "the availability of new drugs, better supportive therapies and better integration of systemic therapies with local ones, the overall survival of these patients has significantly increased - concludes Cinieri - Metastatic Her2-positive breast cancer is becoming an increasingly curable disease, reaching the goal of chronicity in a significant number of cases, thanks to innovation and anti-Her2 drugs. It is important that all women with metastatic breast cancer are treated within the Breast Units, to guarantee them a multidisciplinary approach and a better life expectancy. It has been demonstrated, in fact, that therapeutic results also depend on the level of experience of the centers where the treatments are carried out".