FDA Grants Breakthrough Therapy Status to JSKN003 for Advanced Ovarian Cancer

The FDA has granted breakthrough therapy designation (BTD) to JSKN003, an investigational biparatopic HER2-targeting antibody-drug conjugate (ADC), for the treatment of adult patients with advanced or metastatic platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancers (PROC).¹ The designation specifically applies to patients with HER2-expressing tumors (IHC 1+, 2+, or 3+) who have previously received bevacizumab (Avastin).

The FDA’s decision is supported by pooled clinical data presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. This data originated from 2 early-phase trials: a phase 1 study in Australia (JSKN003-101; NCT05494918) and a phase 1/2 study in China (JSKN003-102; NCT05744427). The BTD is intended to expedite the development and regulatory review of drugs that demonstrate substantial improvement over existing therapies for serious conditions.

Clinical Efficacy in Platinum-Resistant Disease

In a pooled analysis of 46 patients with PROC, JSKN003 monotherapy demonstrated a confirmed objective response rate (ORR) of 63.0% (95% CI, 47.5%–76.8%), including 2 complete responses and 27 partial responses. The disease control rate reached 93.5%. With a median follow-up of 9.3 months, the median progression-free survival (PFS) was 7.7 months, and the 9-month overall survival (OS) rate was 89.9%.²

Response rates were particularly robust among patients with confirmed HER2 expression (IHC 1+/2+/3+). In this subgroup (n = 18), the ORR rose to 72.2% and the median PFS reached 9.4 months. Notably, clinical activity was also observed in patients with HER2 IHC 0 status, where the ORR was 52.4% and median PFS was 6.6 months, suggesting that the agent's mechanism may transcend traditional HER2-high definitions.

Mechanism of Action and Study Design

JSKN003 is an ADC engineered through site-specific conjugation to the Fc glycans of anbenitamab (KN026), a recombinant humanized anti-HER2 bispecific antibody. The resulting conjugate has a drug-to-antibody ratio of approximately 4. By binding to 2 distinct epitopes on the HER2 receptor (extracellular domains II and IV), JSKN003 facilitates efficient internalization and delivers a topoisomerase I inhibitor payload directly into tumor cells.¹

Preclinical and early clinical data suggest that JSKN003 offers improved serum stability and a potent bystander effect compared to first-generation ADCs. These characteristics potentially widen the therapeutic window by reducing off-target toxicity while maintaining efficacy in tumors with heterogeneous HER2 expression.

Safety and Tolerability

The safety profile observed in the pooled analysis was manageable, with most treatment-related adverse events (TRAEs) being grade 1 or 2. Grade 3 or 4 TRAEs occurred in 19.6% of patients. The most common toxicities included anemia (39.1%), increased aspartate aminotransferase (39.1%), diarrhea (37.0%), and nausea (37.0%). Serious TRAEs were reported in 13.0% of patients, and no deaths were attributed to the study drug. Interstitial lung disease , a known risk with topoisomerase I-inhibitor ADCs, was observed but typically remained low-grade (grade 1 or 2) and manageable with standard protocols.

Addressing an Urgent Clinical Need

Platinum-resistant ovarian cancer remains a significant therapeutic challenge. Standard-of-care options, which typically involve single-agent nonplatinum chemotherapy (such as pegylated liposomal doxorubicin, paclitaxel, or topotecan) with or without bevacizumab, offer limited benefit. Historical data for these regimens show an ORR of only 10% to 15%, a median PFS of 3 to 4 months, and a median OS of approximately 12 months.

The clinical data for JSKN003 suggest it may more than double the median PFS and significantly improve response rates compared to current benchmarks. Alphamab Oncology is currently conducting a confirmatory phase 3 trial in China (JSKN003-306; NCT06751485) and has received FDA clearance to initiate a phase 2 study (JSKN003-202) in the US to further validate these findings.

REFERENCES

1. Alphamab Oncology announces biparatopic HER2-targeting ADC JSKN003 was granted breakthrough therapy designation by the FDA for the treatment of PROC. News release. Alphamab Oncology. December 19, 2025. Accessed December 22, 2025. https://tinyurl.com/wh34nc6x

2. Wu X, Chen Y, Rao Q, et al. JSKN003, a biparatopic anti-HER2 antibody drug conjugate (ADC), in the treatment of platinum-resistant ovarian cancer (PROC): Updated findings from two clinical trials. J Clin Oncol. 2025;43(suppl 16):5557. doi:10.1200/JCO.2025.43.16_suppl.5557