Trastuzumab Botidotin Triples Median PFS Versus T-DM1 in Phase III HER2-Positive Breast Cancer Trial Published in JCO
核心洞察
Kelun-Biotech's HER2 (搜索)-directed ADC trastuzumab botidotin extended median progression-free survival to 11.1 months versus 4.4 months with T-DM1 (HR, 0.39; 95% CI, 0.30-0.51; nominal P <.0001).
The phase III KL166-III-06 trial randomized 365 patients with HER2 (搜索)-positive unresectable or metastatic breast cancer after prior trastuzumab and taxane therapy, and results were published in the Journal of Clinical Oncology.
Trastuzumab botidotin produced an objective response rate of 76.9% versus 53.0% and a median duration of response of 12.2 months versus 5.7 months, with immature overall survival data favoring the ADC.
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. announced that results from the phase III registrational study of its HER2 (搜索)-targeted antibody–drug conjugate (ADC) trastuzumab botidotin (舒泰莱®) in HER2-positive unresectable or metastatic breast cancer have been published in the Journal of Clinical Oncology (JCO, impact factor 44.7). The findings had previously been selected as a Late-Breaking Abstract and presented as an oral presentation at the 2025 European Society for Medical Oncology (ESMO) Congress.
The publication marks the first phase III trial in China of a HER2 (搜索) ADC compared head-to-head with trastuzumab emtansine (T-DM1) to report positive results, according to the company.
KL166-III-06 Trial Design and Patient Population
The randomized, open-label, multicenter phase III KL166-III-06 trial (NCT06968585) was conducted at 57 centers in China. Between July 18, 2023, and April 26, 2024, 365 adults aged 18 to 75 years with HER2 (搜索)-positive unresectable or metastatic breast cancer who had experienced disease progression after at least one 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 administered intravenously once every three weeks until disease progression or unacceptable toxicity. Crossover was not permitted.
Stratification factors included the number of prior lines of anti-HER2 (搜索) 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 (搜索) (ILD).
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 two or more prior lines of anti-HER2 (搜索) therapy, 46.0% had received prior pertuzumab, and 59.5% had received a prior anti-HER2 tyrosine kinase inhibitor, most commonly pyrotinib (55.9%). One patient in each arm had received prior fam-trastuzumab deruxtecan-nxki. At data cutoff, 33.0% of patients in the trastuzumab botidotin arm remained on treatment versus 7.7% in the T-DM1 arm.
The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), duration of response (DoR), and safety.
Progression-Free Survival and Response Outcomes
At a median follow-up of 14.9 months and a data cutoff of April 26, 2025, median PFS by BICR was 11.1 months (95% CI, 9.7–13.8) with trastuzumab botidotin versus 4.4 months (95% CI, 4.2–5.7) with T-DM1 (HR, 0.39; 95% CI, 0.30–0.51; nominal P < .0001), meeting the study's primary endpoint. The 6-month PFS rates were 69.7% versus 39.7%, and the 12-month rates were 46.0% versus 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 (搜索) therapy, visceral metastases, prior pertuzumab, and prior anti-HER2 tyrosine kinase inhibitor therapy.
ORR by BICR was 76.9% (95% CI, 70.1%–82.8%) with trastuzumab botidotin versus 53.0% (95% CI, 45.5%–60.4%) with T-DM1. Complete responses occurred in two patients (1.1%) receiving trastuzumab botidotin and in none receiving T-DM1. The DCR was 91.8% (95% CI, 86.8%–95.3%) versus 79.2% (95% CI, 72.6%–84.9%), the CBR was 80.8% (95% CI, 74.3%–86.2%) versus 56.3% (95% CI, 48.8%–63.6%), and the median DoR was 12.2 months versus 5.7 months, respectively.
OS data were immature at 17.5% maturity, with medians not reached in either arm, but investigators noted a trend favoring trastuzumab botidotin (HR, 0.62; 95% CI, 0.38–1.03), corresponding to a 38% reduction in the risk of death. The 12-month OS rates were 90.6% with trastuzumab botidotin versus 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 versus 11.7% (n = 18/154) in the T-DM1 arm.
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 was descriptive, the investigators noted that its P values are nominal.
Safety Profile and Ocular Toxicity Management
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 occurred in 99.5% of patients in both arms, and grade 3 or higher events occurred in 69.8% versus 63.7%, respectively. Serious adverse events occurred in 15.9% versus 28.0% of patients, treatment-related serious adverse events in 11.5% versus 20.3%, and treatment-related adverse events leading to discontinuation in 1.1% versus 3.8%. There were no on-treatment deaths with trastuzumab botidotin versus three (1.6%) with T-DM1, all considered unrelated to treatment.
The most common treatment-related adverse events 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 treatment-related adverse events led to treatment discontinuation or were serious adverse events, although some resulted in dose modifications. The median time to onset of grade 3 or higher ocular events 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, versus 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% versus 3.8%, respectively, and all were asymptomatic and reversible.
ADC Design and Regulatory Status
Trastuzumab botidotin, formerly known as A166, is a HER2 (搜索)-directed ADC in which an antibody sharing the amino acid sequence of trastuzumab is site-specifically conjugated to the anti-microtubule agent duostatin-5 (搜索), a monomethyl auristatin F analog, via a protease-cleavable valine-citrulline linker, yielding a drug-to-antibody ratio of 2. The company describes the payload as a highly cytotoxic tubulin inhibitor, Duo-5 (搜索). Trastuzumab botidotin binds HER2 on the surface of tumor cells and is internalized, releasing the toxin molecule intracellularly; Duo-5 induces tumor cell cycle arrest in the G2/M phase, leading to apoptosis. After targeting HER2, the ADC can also inhibit the HER2 signaling pathway and has antibody-dependent cell-mediated cytotoxicity activity. Investigators noted that prior pharmacokinetic studies indicated lower circulating levels of free payload with trastuzumab botidotin than with other approved HER2-targeted ADCs.
Based on the results of the KL166-III-06 study, trastuzumab botidotin was approved by China's National Medical Products Administration (搜索) for adult patients with unresectable or metastatic HER2-positive breast cancer (搜索) who have received one or more prior anti-HER2 (搜索) therapies, becoming the first domestically developed HER2 ADC approved for this indication in China. At the prespecified interim analysis, trastuzumab botidotin monotherapy demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of PFS by BICR compared with T-DM1, with a beneficial trend for OS also observed.
Kelun-Biotech has also initiated an open, multicenter phase II clinical study of trastuzumab botidotin in patients with HER2 (搜索)-positive unresectable or metastatic breast cancer who previously received a topoisomerase inhibitor payload ADC.
Trial Limitations
The investigators noted that trastuzumab botidotin required additional ocular examinations, such as regular slit-lamp examinations, particularly during the initial four 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.
Kelun-Biotech (6990.HK) is a holding subsidiary of Kelun Pharmaceutical focused on R&D, manufacturing, commercialization and global collaboration of innovative biological and small molecule drugs, with more than 30 ongoing key innovative drug projects and a proprietary ADC and novel DC platform, OptiDC.