Trastuzumab Botidotin Outperforms T-DM1 in HER2+ Advanced Breast Cancer

Trastuzumab botidotin significantly improved progression-free survival (PFS) compared with trastuzumab emtansine (T-DM1; Kadcyla) in patients with human epidermal growth factor receptor 2 (HER2)-positive, unresectable or metastatic breast cancer previously treated with trastuzumab (Herceptin) and a taxane, according to final results from a phase 3 trial (NCT06968585) published in the Journal of Clinical Oncology.^1,2

The randomized, open-label, multicenter trial enrolled 365 patients across 57 centers in China between July 18, 2023, and April 26, 2024.³ Patients were randomly assigned 1:1 to receive trastuzumab botidotin (n = 182) or T-DM1 (n = 183). The primary end point was PFS assessed by blinded independent central review (BICR) in the intention-to-treat population.

Key Efficacy Findings

At a median follow-up of 14.9 months, median PFS was 11.1 months with trastuzumab botidotin vs 4.4 months with T-DM1, corresponding to a hazard ratio of 0.39 (95% CI, 0.30-0.51; nominal P <.0001). The PFS benefit with trastuzumab botidotin was consistent across prespecified subgroups, including patients categorized by prior lines of anti-HER2 therapy, prior treatment with pertuzumab or anti-HER2 tyrosine kinase inhibitors, and the presence of visceral metastases.

Treatment with trastuzumab botidotin also produced a higher objective response rate (ORR) than T-DM1. The ORR was 76.9% (95% CI, 70.1%-82.8%) with trastuzumab botidotin compared with 53.0% (95% CI, 45.5%-60.4%) with T-DM1. The overall survival (OS) findings remain immature, with median OS not reached in either treatment group at the time of the analysis. The OS hazard ratio was 0.62 (95% CI, 0.38-1.03).

Safety Profile of Trastuzumab Botidotin

The safety profile of trastuzumab botidotin differed from that of T-DM1, with ocular treatment-related adverse events representing a notable toxicity associated with trastuzumab botidotin. Investigators reported that, with use of a protocol-defined management algorithm, most ocular events generally recovered or resolved.

Trastuzumab botidotin was also associated with low incidences of pulmonary, hematologic, hepatic, and gastrointestinal toxicities relative to what has been observed with other agents in this class. Grade 3 or higher treatment-emergent adverse events occurred in 127 patients (69.8%) receiving trastuzumab botidotin and 116 patients (63.7%) receiving T-DM1.

Clinical Context

Trastuzumab botidotin is an antibody-drug conjugate (ADC) designed to target HER2 and deliver a cytotoxic payload to tumor cells. The ADC combines a HER2-directed monoclonal antibody with Duo-5, a tubulin inhibitor, through an enzyme-cleavable linker. Following binding to HER2 and internalization into tumor cells, the payload is released and induces G2/M cell-cycle arrest and apoptosis.

Based on results of the study, the agent was approved by China's National Medical Products Administration for adults with unresectable or metastatic HER2-positive breast cancer who have received at least 1 prior anti-HER2 therapy. Further follow-up will help define the durability of treatment benefit and OS outcomes.

REFERENCES

1. Zhang J, Ouyang Q, Zhang Q, et al. Trastuzumab Botidotin Versus Trastuzumab Emtansine in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A Phase III, Open-Label, Randomized Controlled Trial. J Clin Oncol. Published online September 11, 2026. doi:10.1200/jco-26-00602

2. Results from Phase III Study of Trastuzumab Botidotin versus T-DM1 in HER2-Positive Breast Cancer Published in JCO. News release. Sichuan Kelun-Biotech Biopharmaceutical. September 14, 2026. Accessed September 16, 2026. https://tinyurl.com/5n7xztrf

3. A Study of A166 Versus Trastuzumab Emtansine (T-DM1) in Patients With HER2-Positive Unresectable or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane Therapy (A166). ClinicalTrials.gov. Updated May 8, 2026. Accessed September 16, 2026. https://clinicaltrials.gov/study/NCT06968585