Background
For HER2-positive metastatic breast cancer progressing after trastuzumab and a taxane, HER2-directed antibody-drug conjugates (ADCs) are central to later-line therapy. Trastuzumab botidotin is a novel HER2-directed ADC (trastuzumab + cleavable GGFG tetrapeptide linker + a topoisomerase I inhibitor payload, SHR169265), mechanistically akin to trastuzumab deruxtecan. This phase 3, open-label, multicenter trial (57 centers, China; N=365) compared trastuzumab botidotin with trastuzumab emtansine (T-DM1) in HER2-positive unresectable/metastatic breast cancer previously treated with trastuzumab and a taxane.
Results
Interventions and follow up: Arm A: Trastuzumab botidotin (n=182).
Arm B: Trastuzumab emtansine (T-DM1) (n=183).
Primary endpoint: PFS by blinded independent central review (BICR), intention-to-treat.
mFollow up: 14.9 months.
Results: PFS: 11.1 vs 4.4 mo; HR 0.39 (95% CI 0.30–0.51); P<.0001.
ORR: 76.9% vs 53.0%.
OS (immature): medians not reached; HR 0.62 (95% CI 0.38–1.03).
Arm B: Trastuzumab emtansine (T-DM1) (n=183).
Primary endpoint: PFS by blinded independent central review (BICR), intention-to-treat.
mFollow up: 14.9 months.
Results: PFS: 11.1 vs 4.4 mo; HR 0.39 (95% CI 0.30–0.51); P<.0001.
ORR: 76.9% vs 53.0%.
OS (immature): medians not reached; HR 0.62 (95% CI 0.38–1.03).
Adverse events
Grade ≥3 TEAE: 69.8% vs 63.7%.
Ocular (botidotin): high incidence of corneal/ocular events (blurred vision, keratopathy); most recovered or resolved with a protocol-defined management algorithm.
Other (botidotin): low incidence of pulmonary (ILD), haematologic, hepatic, and GI toxicity.
Ocular (botidotin): high incidence of corneal/ocular events (blurred vision, keratopathy); most recovered or resolved with a protocol-defined management algorithm.
Other (botidotin): low incidence of pulmonary (ILD), haematologic, hepatic, and GI toxicity.
Conclusions
Trastuzumab botidotin more than doubled PFS versus T-DM1 (11.1 vs 4.4 mo; HR 0.39) with a higher objective response rate in previously treated HER2-positive advanced breast cancer. It is an active new HER2 ADC with a distinct ocular-toxicity profile requiring proactive monitoring; OS data are immature.
Key Limitations
Open-label design and China-only enrolment limit generalisability. The comparator (T-DM1) is no longer the preferred second-line standard where trastuzumab deruxtecan (T-DXd) is available, so superiority over T-DM1 does not establish a role versus T-DXd. OS is immature, and ocular toxicity may affect quality of life and adherence. The median T-DM1 PFS (4.4 mo) is lower than in some prior trials, raising questions about the population.
Clinical Context
The result positions trastuzumab botidotin as a potential HER2 ADC option in the second-line-and-beyond setting, particularly where access to T-DXd is limited. Globally, DESTINY-Breast03 established T-DXd over T-DM1 as the second-line standard (NCCN/ESMO), so trastuzumab botidotin's ultimate place depends on head-to-head data versus T-DXd and OS maturation. Trastuzumab botidotin is not FDA-approved.