GSK5764227, an investigational B7-H3-targeted antibody-drug conjugate (ADC), has been granted Breakthrough Therapy Designation by the FDA for the treatment of extensive-stage small cell lung cancer (ES-SCLC) in patients who have progressed on or after platinum-based chemotherapy. This designation aims to expedite the development and review of GSK5764227, recognizing its potential to offer significant improvements over existing therapies for this aggressive cancer. The decision is supported by promising early clinical evidence from the Phase 1 ARTEMIS-001 trial.
Clinical Efficacy and Safety Data
The Breakthrough Therapy Designation is primarily based on data from the ARTEMIS-001 Phase 1 trial (NCT05276609), an open-label, multi-center study evaluating the safety, tolerability, and preliminary anti-tumor activity of GSK5764227 in patients with locally advanced or metastatic solid tumors. Notably, the trial included patients with relapsed or refractory ES-SCLC.
Data presented at the 2023 ASCO Annual Meeting highlighted that GSK5764227, composed of a fully humanized anti-B7-H3 monoclonal antibody covalently linked to a topoisomerase inhibitor payload, demonstrated a manageable safety profile and early signs of efficacy. In a cohort of 11 SCLC patients, the objective response rate (ORR) was 63.6% (95% CI, 30.8%-89.1%), and the disease control rate (DCR) reached 81.8% (95% CI, 48.2%-97.7%). The median progression-free survival (PFS) was 4.7 months (95% CI, 1.4-not applicable), with a 3-month PFS rate of 72.7% (95% CI, 37.1%-90.3%).
Additional data from the ARTEMIS-001 trial will be presented at the 2024 World Conference on Lung Cancer.
The Need for New Treatments in ES-SCLC
Small cell lung cancer accounts for approximately 15% of all lung cancers in the United States, with about 70% of these cases diagnosed at the extensive stage. ES-SCLC is characterized by rapid progression and poor prognosis, with a 5-year survival rate of only around 3%. Relapse is common following initial treatment, and the median overall survival for relapsed ES-SCLC patients treated with current standard-of-care regimens is limited to 5-6 months.
Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, emphasized the urgency for new treatments, stating, “Extensive-stage small-cell lung cancer is aggressive with poor prognosis and significant need for new treatments. Today’s breakthrough therapy designation supports our ambition to accelerate GSK’227 for these patients as part of our broader ADC program focused on developing new treatment options with transformational and first-to-market potential.”
Ongoing and Future Clinical Development
The ARTEMIS-001 trial enrolled patients with various advanced or metastatic solid tumors, irrespective of B7-H3 expression. The dose-escalation phase followed an accelerated titration plus i3+3 design, with GSK5764227 administered intravenously every 3 weeks at escalating doses. The primary endpoint for the dose-escalation phase was to determine the maximum tolerated dose (MTD), while the primary endpoint for the expansion phase is ORR per RECIST 1.1 criteria.
As of March 10, 2023, 53 patients had been enrolled and treated with GSK5764227 across different dose levels. The overall ORR was 30% (95% CI, 17.9%-44.6%), and the DCR was 86% (95% CI, 73.3%-94.2%). The median PFS was 5.4 months (95% CI, 4.3-7.0).
GSK plans to initiate global Phase 1/2 trials in the second half of 2024 to support a registrational pathway for GSK5764227. These trials will further evaluate the safety and efficacy of the ADC in ES-SCLC and other solid tumors.
About GSK5764227
GSK5764227, also known as HS-20093, is a novel investigational ADC that targets B7-H3, a protein frequently expressed in various solid tumors. It comprises a fully humanized anti-B7-H3 monoclonal antibody covalently linked to a topoisomerase inhibitor payload. GSK acquired exclusive worldwide rights to GSK5764227 from Hansoh Pharma, excluding mainland China, Hong Kong, Macau, and Taiwan.
