HER2+ Breast Cancer Treatment: Sequencing ADCs & New First-Line Options

Shifting Treatment Paradigms in HER2-Positive Breast Cancer with the Rise of ADCs

The treatment landscape for HER2-positive metastatic breast cancer is undergoing a significant evolution, driven by the increasing prominence of antibody-drug conjugates (ADCs). A presentation at the March 20, 2026 Miami Breast Cancer Conference highlighted the growing complexity of sequencing therapies as new options emerge, challenging established norms. The potential for earlier use of ADCs, particularly trastuzumab deruxtecan (T-DXd), is prompting a re-evaluation of optimal treatment strategies.

For years, the standard first-line treatment for both hormone receptor-positive (HR+) and HR-negative (HR-) HER2+ metastatic breast cancer has been a combination of taxane chemotherapy alongside trastuzumab and pertuzumab, followed by maintenance therapy with trastuzumab-pertuzumab. This approach is firmly supported by the landmark CLEOPATRA trial, which demonstrated substantial improvements in progression-free survival (PFS) and overall survival (OS) compared to placebo plus trastuzumab and docetaxel. The PERUSE study reinforced this, showing consistent efficacy regardless of the specific taxane used – docetaxel, paclitaxel, or nab-paclitaxel – achieving a median PFS of 20.7 months and a median OS of 65.3 months.

However, the introduction and rapid success of T-DXd is forcing a reassessment. The DESTINY-Breast03 trial demonstrated a marked advantage for T-DXd over ado-trastuzumab emtansine (T-DM1) in the second-line setting, with significantly improved PFS (28.8 vs 6.8 months) and OS (52.6 vs 42.7 months). While interstitial lung disease remains a concern with T-DXd, occurring in 16.7% of patients compared to 3.4% with T-DM1, its efficacy has led to its adoption as the preferred second-line option.

First-Line Potential for T-DXd

More recently, data from the DESTINY-Breast07 and DESTINY-Breast09 trials are suggesting a potential role for T-DXd even earlier in the treatment course. DESTINY-Breast07 showed impressive objective response rates – 77.3% with T-DXd monotherapy and 84.0% with T-DXd plus pertuzumab – along with promising PFS rates at 12 and 18 months. Critically, DESTINY-Breast09 directly compared T-DXd plus pertuzumab to the standard taxane plus trastuzumab-pertuzumab (THP) regimen. The results were compelling: T-DXd plus pertuzumab significantly improved PFS (40.7 vs 26.9 months) across all prespecified subgroups, achieved higher complete response rates, and demonstrated a median response duration approaching three years. Early trends also indicate a potential OS benefit with the T-DXd combination, while maintaining a safety profile consistent with the individual drugs.

These findings are poised to influence regulatory decisions. The consideration of T-DXd plus pertuzumab by regulatory bodies in 2025 signals a potential shift towards ADC-driven regimens being used earlier in the treatment pathway. This shift, however, introduces new challenges. As Dr. Giuseppe Curigliano of the University of Milano and Istituto Europeo di Oncologia noted, carefully designed sequencing trials are needed to address overlapping targets, shared toxicities, potential cross-resistance, and real-world attrition rates.

Evolving Maintenance Strategies and Future Directions

The role of maintenance therapy is also evolving. The PATINA trial demonstrated that adding palbociclib to anti-HER2 therapy plus endocrine therapy extended PFS in HR+/HER2+ metastatic breast cancer patients after induction chemotherapy. Similarly, the HER2CLIMB-05 trial showed that adding tucatinib to trastuzumab-pertuzumab improved PFS. Ongoing studies, including heredERA, INAVO122, and DEMETHER, are aiming to personalize maintenance therapy based on the biological characteristics of the cancer.

The increasing use of ADCs earlier in treatment necessitates a more nuanced approach to sequencing. The goal is to ensure that initial efficacy gains translate into lasting benefits throughout the course of care. The field is moving beyond simply adding new agents to established regimens and towards a more individualized and strategically sequenced approach, recognizing that the optimal path will likely vary depending on the patient’s specific disease characteristics and response to therapy. The coming years will be crucial in defining these optimal sequences and maximizing the potential of these powerful new therapies.