Breast Cancer | Image Credit: © Sebastian Kaulitzki – stock.adobe.com
The biparatopic HER2-targeting antibody-drug conjugate (ADC) JSKN003 displayed a manageable safety profile and produced antitumor activity in patients with heavily pretreated HER2-positive advanced breast cancer, according to pooled data from the phase 1 JSKN003-101 trial (NCT05494918) conducted in Australia and the phase 1/2 JSKN003-102 trial (NCT05744427) conducted in China.
Findings from the pooled analysis presented at the 2025 ASCO Annual Meeting demonstrated that efficacy-evaluable patients from both studies (n = 75) who were naive to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) achieved a confirmed objective response rate (ORR) of 54.7% (95% CI, 42.7%-66.2%), a disease control rate (DCR) or 94.7% (95% CI, 86.9%-98.5%), and a clinical benefit rate (CBR) of 66.7% (95% CI, 54.8%-77.1%). Patients treated at the recommended phase 2 dose (RP2D) of 6.3 mg/kg (n = 30) experienced a confirmed ORR of 73.3% (95% CI, 54.1%-87.7%), a DCR of 93.3% (95% CI, 77.9%-99.2%), and a CBR of 83.3% (95% CI, 65.3%-94.4%). Notably, all responses were partial.
Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 94.3% of patients (n = 88), and any-grade treatment-related AEs (TRAEs) occurred in 93.2% of patients. Grade 3 or higher TEAEs were reported at a rate of 21.6%, including 15.9% of patients who experienced grade 3 or higher TRAEs. The rates of serious AEs and serious TRAEs were 11.4% and 5.7%, respectively. TRAEs led to dose reductions in 12.5% of patients, and 1 patient discontinued treatment due to TRAEs. TRAEs did not lead to any deaths.
“A pivotal phase 3 trial [NCT06846437] is ongoing to compare JSKN003 with ado-trastuzumab emtansine [T-DM1; Kadcyla] in patients with HER2-positive advanced breast cancer who [were] previously treated with trastuzumab [Herceptin],” lead study author Yiqun Du, MD, of the Department of Medical Oncology at Fudan University Shanghai Cancer Center in China, and colleagues wrote in a poster presentation of the data.
JSKN003 Background and Trial Overviews
The biparatopic ADC targets HER2 and is conjugated with a topoisomerase I inhibitor via a tetrapeptide linker, with the intention of enhancing serum stability and antitumor activity.
JSKN003-101 was a first-in-human dose-escalation and -expansion study, while the JSKN003-102 further investigated the agent in China. Both studies included patients with advanced solid tumors. This pooled analysis included patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization+) breast cancer treated across the 2 studies.
Among the 88 patients with breast cancer between the 2 studies, the majority were treated with JSKN003 at a dose of 6.3 mg/kg or 8.4 mg/kg. The median follow-up was 6.08 months (range, 5.45-6.31).
In the safety population, the median age was 55.0 years (range, 32-79). Most patients were female (97.7%), were Asian (94.3%), had an ECOG performance status of 1 (77.3%), had IHC 3+ disease (71.6%), had stage IV disease (100%), had visceral metastases (76.1%), received prior surgery for their tumors (87.5%), received prior radiotherapy (100%), received at least 3 prior lines of therapy (55.7%), and received prior HER2-targeted therapy (100%). Prior HER2 therapies included a monoclonal antibody (97.7%), an ADC, including T-DXd (61.4%), and a TKI (64.8%). Additionally, 39.8% of patients received prior endocrine therapy.
Additional Efficacy and Safety
Pooled data also showed that in efficacy-evaluable patients who previously received T-DXd (n = 7), 1 partial response was recorded, and 4 patients had stable disease. Tumor shrinkage was noted in 4 patients.
In patients who received 1 prior line of therapy (n =15) or 2 prior lines of therapy (n = 19), the confirmed ORRs were 66.7% (95% CI, 38.4%-88.2%) and 63.2% (95% CI, 38.4%-83.7%), respectively.
For the overall population, the median duration of response was 18.4 months (95% CI, 9.9-not evaluable). Progression-free survival (PFS) data were immature at data cutoff; the 3- and 6-month PFS rates were 88.4% (95% CI, 78.8%-93.8%) and 75.4% (95% CI, 62.3%-84.4%), respectively.
The most common TRAEs reported in at least 20% of patients included nausea (grade 1/2, 37.5%; grade ≥3, 1.1%), increased alanine aminotransferase levels (34.1%; 2.3%), decreased white blood cell count (34.1%; 0%), vomiting (31.6%; 0%), anemia (29.5%; 2.3%), decreased appetite (27.2%; 2.3%), decreased platelet count (25.0%; 1.1%), fatigue (23.9%; 1.1%), decreased neutrophil count (23.9%; 0%), and diarrhea (22.8%; 1.1%).
Reference
Du Y, Zhang J, Liu J, et al. JSKN003, a biparatopic HER2-targeting ADC, in heavily pretreated HER2-positive breast cancer: A pooled analysis of early-phase studies. J Clin Oncol. 2025;43(suppl 16):1028. doi:10.1200/JCO.2025.43.16_suppl.1028