Chinese Antibody-Drug Conjugate Shows Strong Efficacy in HER2-Low Metastatic Breast Cancer Trial

An investigational antibody-drug conjugate (ADC) demonstrated significant improvement in progression-free survival (PFS) compared to standard chemotherapy in patients with HER2-low metastatic breast cancer, according to results from a pivotal Chinese phase III trial.

The investigational agent, trastuzumab rezetecan, achieved a median PFS of 16.4 months versus 6.8 months with physician’s choice of chemotherapy in the overall study population (hazard ratio [HR] 0.27, 95% CI 0.21-0.34, P<0.001). This benefit was consistent across key subgroups, including chemotherapy-naive patients (median PFS 16.6 vs 6.8 months; HR 0.25, 95% CI 0.19-0.33, P<0.001) and regardless of hormone receptor (HR) status, according to findings presented at the European Society for Medical Oncology (ESMO) congress in Madrid and published concurrently in JAMA.

Overall survival (OS) data remain immature at the current analysis, but early results favor the trastuzumab rezetecan arm, with 12-month OS rates of 90.6% versus 81.4%, respectively (HR 0.67, 95% CI 0.48-0.94, nominal P=0.01).

Trastuzumab rezetecan combines a HER2-targeted monoclonal antibody with a potent topoisomerase I inhibitor. While already approved in China for non-small cell lung cancer and colorectal cancer, and carrying FDA orphan drug designation for gastric cancer, its positioning against established HER2-directed therapies remains uncertain. Notably, trastuzumab deruxtegan (T-DXd; Enhertu) currently holds multiple FDA approvals in breast cancer, including for HER2-positive, HER2-low, and HER2-ultralow disease.

In an accompanying editorial, Maria Fernanda Mosele, MD, and Fabrice André, MD, PhD, from Gustave Roussy in Villejuif, France, emphasized that the current study does not establish superiority over trastuzumab deruxtecan and noted that where T-DXd is available, it will likely remain the preferred option. They highlighted the clinical urgency of defining trastuzumab rezetecan’s role, suggesting sequential use strategies that might position it as a later-line therapy following earlier use of other ADCs.

ESMO discussant Barbara Pistilli, MD, also from Gustave Roussy, pointed out preclinical advantages of trastuzumab rezetecan, including enhanced membrane permeability and potency compared to T-DXd, along with faster systemic clearance that may translate into reduced off-target toxicities. However, she cautioned that without direct comparative trials, the true clinical benefits remain unproven.

“Pivotal trials should generate evidence for regulatory approval by comparing new ADCs with the current standard of care,” which in this setting continues to evolve around trastuzumab deruxtecan, Dr. Pistilli stated.

The HORIZON-Breast06 trial enrolled 551 patients (median age 55 years) across 73 Chinese hospitals and randomly assigned participants to trastuzumab rezetecan or physician’s choice of taxanes, eribulin, capecitabine, or gemcitabine chemotherapy. Most patients (81.5%) were chemotherapy-naive, with the remainder having received one prior line of treatment. Approximately 73% of patients had hormone receptor-positive disease.

Subgroup analyses revealed consistent PFS benefits across all major categories:

• Hormone receptor-positive: 16.4 vs 6.7 months (HR 0.24, 95% CI 0.18-0.33)
• Hormone receptor-negative: 16.5 vs 6.8 months (HR 0.34, 95% CI 0.22-0.54)
• Chemotherapy-treated patients: 13.9 vs 5.6 months (HR 0.32, 95% CI 0.19-0.54)

Investigators noted particular significance in the hormone receptor-negative subgroup—an aggressive form historically underserved by targeted interventions—where substantial clinical gains were achieved.

Safety profiles showed higher rates of grade ≥3 treatment-related adverse events (TRAEs) in the trastuzumab rezetecan arm (84.1%) compared to chemotherapy (67.9%), with serious TRAEs occurring in 37.7% versus 13.7%, respectively. Dose reduction due to TRAEs affected 50.4% of patients receiving trastuzumab rezetecan versus 29.2% in the chemotherapy group, while treatment discontinuation rates due to TRAEs were 8.7% and 6.3%, respectively. Interstitial lung disease developed in seven patients (2.5%) within the trastuzumab rezetecan cohort, including two grade 3 cases and one grade 4 event.

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