Trastuzumab Botidotin Prolongs PFS vs T-DM1 in HER2+ Advanced Breast Cancer

Trastuzumab botidotin significantly prolonged progression-free survival (PFS) compared with trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab (Herceptin) and a taxane, according to the prespecified final PFS analysis of the phase 3 KL166-III-06 trial (NCT06968585) published in the Journal of Clinical Oncology.¹

What were the efficacy results for trastuzumab botidotin in the KL166-III-06 trial?

At a median follow-up of 14.9 months, the median PFS by blinded independent central review (BICR) was 11.1 months (95% CI, 9.7-13.8) with trastuzumab botidotin vs 4.4 months (95% CI, 4.2-5.7) with T-DM1 (HR, 0.39; 95% CI, 0.30-0.51; nominal P <.0001). The 6-month PFS rates were 69.7% vs 39.7%, respectively, and the 12-month rates were 46.0% vs 15.3%. Investigator-assessed PFS was consistent with the BICR assessment, and the benefit was consistent across all prespecified subgroups, including those defined by number of prior lines of anti-HER2 therapy, visceral metastases, prior pertuzumab (Perjeta), and prior anti-HER2 tyrosine kinase inhibitor (TKI) therapy.

The objective response rate (ORR) by BICR was 76.9% (95% CI, 70.1%-82.8%) with trastuzumab botidotin vs 53.0% (95% CI, 45.5%-60.4%) with T-DM1. Complete responses occurred in 2 patients (1.1%) receiving trastuzumab botidotin and in none receiving T-DM1. The disease control rate (DCR) was 91.8% (95% CI, 86.8%-95.3%) vs 79.2% (95% CI, 72.6%-84.9%), the clinical benefit rate (CBR) was 80.8% (95% CI, 74.3%-86.2%) vs 56.3% (95% CI, 48.8%-63.6%), and the median duration of response (DOR) was 12.2 months vs 5.7 months, respectively.

Overall survival (OS) data were immature at 17.5% maturity, with medians not reached in either arm, but the investigators noted a trend favoring trastuzumab botidotin (HR, 0.62; 95% CI, 0.38-1.03). The 12-month OS rates were 90.6% with trastuzumab botidotin vs 85.0% with T-DM1. Among patients who experienced disease progression, new-onset brain metastases occurred in 9.2% (n = 9/98) in the trastuzumab botidotin arm vs 11.7% (n = 18/154) in the T-DM1 arm.

Investigators wrote that the results “supported trastuzumab botidotin as a new treatment option for HER2-positive [breast cancer].”

Trastuzumab botidotin, formerly known as A166, is a HER2-directed antibody-drug conjugate (ADC) in which an antibody sharing the amino acid sequence of trastuzumab is site-specifically conjugated to the anti-microtubule agent duostatin-5, a monomethyl auristatin F analog, via a protease-cleavable valine-citrulline linker, yielding a drug-to-antibody ratio of 2. The investigators noted that prior pharmacokinetic studies indicated lower circulating levels of free payload with trastuzumab botidotin than with other approved HER2-targeted ADCs.

What was the trial design for KL166-III-06?

The open-label, multicenter KL166-III-06 trial was conducted at 57 centers in China. Between July 18, 2023, and April 26, 2024, 365 adults aged 18 to 75 years with HER2-positive unresectable or metastatic breast cancer who had experienced disease progression after at least 1 trastuzumab-based regimen and prior taxane therapy were randomly assigned 1:1 to receive trastuzumab botidotin at 4.8 mg/kg (n = 182) or T-DM1 at 3.6 mg/kg (n = 183), both intravenously once every 3 weeks until disease progression or unacceptable toxicity. Crossover was not permitted. Stratification factors included number of prior lines of anti-HER2 therapy (1 vs 2 or more), presence of visceral metastasis, and prior pertuzumab treatment.

HER2 positivity was defined as an immunohistochemistry score of 3+ or 2+ with confirmation by fluorescence in situ hybridization. Key exclusion criteria included prior HER2-targeted ADCs with a microtubule inhibitor payload, severe corneal epithelial disease, known active central nervous system metastases, and clinically active interstitial lung disease (ILD).

The primary end point was PFS by BICR. Secondary end points included OS, investigator-assessed PFS, ORR, DCR, CBR, DOR, and safety. At a prespecified interim analysis with a data cutoff of September 4, 2024, trastuzumab botidotin met the prespecified superiority boundary for PFS (one-sided P <.0001). Because the final PFS analysis, with a data cutoff of April 26, 2025, was descriptive, the investigators noted that its P values are nominal.

Baseline characteristics were balanced between the arms. The median age was 55.0 years (range, 23-74) in the trastuzumab botidotin arm and 54.0 years (range, 32-75) in the T-DM1 arm, and 99.7% of patients were female. Overall, 73.4% of patients had visceral metastases, 53.4% had received 2 or more prior lines of anti-HER2 therapy, 46.0% had received prior pertuzumab, and 59.5% had received a prior anti-HER2 TKI, most commonly pyrotinib (Irene; 55.9%). One patient in each arm had received prior fam-trastuzumab deruxtecan-nxki (Enhertu). At data cutoff, 33.0% of patients in the trastuzumab botidotin arm remained on treatment vs 7.7% in the T-DM1 arm.

What adverse effects were noted with trastuzumab botidotin?

In the safety analysis set of 182 patients per arm, the median treatment duration was 7.5 months with trastuzumab botidotin and 5.3 months with T-DM1. Treatment-emergent adverse events (TEAEs) occurred in 99.5% of patients in both arms; grade 3 or higher TEAEs occurred in 69.8% vs 63.7%, respectively. Serious adverse events (SAEs) occurred in 15.9% vs 28.0% of patients, treatment-related SAEs in 11.5% vs 20.3%, and treatment-related adverse events (TRAEs) leading to discontinuation in 1.1% vs 3.8%. There were no on-treatment deaths with trastuzumab botidotin vs 3 (1.6%) with T-DM1, all of which were considered unrelated to treatment.

The most common TRAEs with trastuzumab botidotin were ocular, including corneal disorder (92.9%; grade 3 or higher, 37.9%), dry eye (61.5%; grade 3 or higher, 30.2%), and blurred vision (28.6%; grade 3 or higher, 20.9%), as well as hypoesthesia (34.1%; grade 3 or higher, 2.2%). T-DM1 was primarily associated with hematologic and hepatic toxicities, including decreased platelet count (87.9%; grade 3 or higher, 45.6%), increased aspartate aminotransferase (82.4%), and increased alanine aminotransferase (65.4%).

None of the most common ocular TRAEs led to treatment discontinuation or were SAEs, although some resulted in dose modifications. The median time to onset of grade 3 or higher ocular TRAEs was 46 to 47 days, and 94.5% to 98.6% of these events recovered to grade 2 or lower in a median of 16 days with a protocol-defined management algorithm that included proactive monitoring, prophylactic lubricating eye drops, dose modifications, and temporary treatment interruptions. Among patients with ocular events, limitations in instrumental and self-care activities of daily living were reported in 20.3% and 7.1%, respectively; these had recovered or resolved in 86.5% and 92.3% of affected patients by data cutoff.

Treatment-related ILD or pneumonitis occurred in 1.1% of patients receiving trastuzumab botidotin, all grade 2 or lower, vs 2.7% of those receiving T-DM1, including grade 3 or higher events in 1.6%. Treatment-related decreases in left ventricular ejection fraction occurred in 1.6% vs 3.8%, respectively, and all were asymptomatic and reversible.

The investigators noted that trastuzumab botidotin required additional ocular examinations, such as regular slit-lamp examinations, particularly during the initial 4 cycles, and that the feasibility of this monitoring in settings without ready access to specialized ophthalmologic care warrants further evaluation. Other limitations included the trial’s enrollment of an exclusively Chinese population, its comparison against T-DM1 rather than trastuzumab deruxtecan, which became the standard of care after the trial was designed in early 2022, and its open-label design, which was mitigated by the use of BICR.

Reference

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