Editor's Note: On June 27, 2024, Nature Communications published the results of a phase 1 clinical trial conducted by Professor Binghe Xu, an academician of the Chinese Academy of Engineering, and his joint team. The study focuses on a novel HER2 antibody-drug conjugate (ADC), FS-1502, which offers a potential new treatment option for HER2-positive breast cancer patients.

Breast cancer, one of the most common malignant tumors in women worldwide, is particularly concerning for its HER2-positive subtype due to its high invasiveness and poor prognosis. Research indicates that HER2-positive breast cancer accounts for approximately 20% of all breast cancer cases, with a higher mortality rate among these patients. While traditional chemotherapy and targeted therapies have shown some efficacy, there remains an urgent need for more effective treatment options.

FS-1502 comprises a selective cleavable β-glucuronide linker, an anti-HER2 antibody, and the anti-microtubule payload monomethyl auristatin F (MMAF). Using a unique site-specific chemical enzymatic method, the linker-payload is attached to the antibody, enhancing the stability of the linker and improving its physicochemical properties compared to traditional methods. The β-glucuronide cleavable linker technology enables tumor-selective release and activation of the payload while minimizing toxicity to normal tissues. Preclinical studies have already demonstrated the promising antitumor activity and safety of this novel ADC. This reported study is a multicenter, single-arm, dose-escalation, and expansion phase 1 clinical trial, marking the first human clinical trial for FS-1502. A total of 150 patients were enrolled to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of FS-1502.

The study results showed that FS-1502 was generally well-tolerated among patients, with 34% experiencing grade 3 or higher drug-related adverse events and 9.3% reporting serious adverse events related to the study drug.

In terms of antitumor activity, FS-1502 demonstrated encouraging efficacy. Among HER2-positive breast cancer patients, 3.0% achieved complete response (CR), 50.7% achieved partial response (PR), with an objective response rate (ORR) of 53.7%. The disease control rate (DCR) and clinical benefit rate (CBR) at ≥24 weeks were 88.1% and 59.7%, respectively. Additionally, the median duration of response (DoR) was 2.7 months, and the median progression-free survival (PFS) reached 15.5 months.

According to Academician Binghe Xu, the innovation of FS-1502 lies in its unique drug design, which uses site-specific chemical enzymatic methods to precisely conjugate the cytotoxin to the antibody, ensuring the uniformity and stability of the drug. This design not only enhances the efficacy of the drug but also reduces systemic toxicity, making FS-1502 a potentially safer and more effective treatment for HER2-positive breast cancer. The success of the phase 1 clinical trial lays a solid foundation for the future development of FS-1502. As research progresses, the team will continue to explore the efficacy and safety of FS-1502 in a broader patient population and its potential for combination with other treatment modalities.