Despite significant progress in immunotherapy for oncology, the majority of patients treated with approved checkpoint inhibitors either fail to respond to therapy or develop resistance. Recent work has demonstrated that immune checkpoints work primarily by inhibiting CD28, a critical costimulatory receptor in T cells. Anti-PD-1 and anti-CTLA-4 treatments inhibit the brakes on CD28, but do not provide activating “gas” signals to CD28 required to induce an anti-tumor response.
Davoceticept is an Fc fusion protein of a modified CD80, vIgD designed to block the inhibitory immune checkpoints PD-L1 and CTLA-4, and to provide PD-L1-dependent T cell activation via CD28 costimulatory receptor. Localized to the tumor by high-affinity binding to PD-L1, davoceticept activates T cells by clustering and agonism of CD28 only in the presence of PD-L1. Additionally, davoceticept binds CTLA-4 expressed on T cells and blocks CTLA4-CD80/CD86 interactions, further potentiating T cell activity.
Results from the dose-escalation portion of NEON-1 (NCT04186637), a first-in-human, dose-escalation and expansion study of davoceticept monotherapy in participants with advanced malignancies, were presented as a poster at the 2022 ASCO Annual Meeting. These data demonstrated that davoceticept was well tolerated, with no reported events of cytokine release syndrome. Despite a highly heterogeneous, heavily pretreated, advanced solid tumor population – the majority classically considered to be unresponsive to immunotherapy – 11 (23%) of 48 evaluable participants demonstrated tumor volume reduction; 25 (52%) achieved clinical benefit as defined as a best response of stable disease or better; Four (8%) remained on treatment beyond 6 months. Two partial responses were observed in colorectal and renal cell carcinoma. Initial data from NEON-1 were presented at 2021 ASCO Virtual Meeting.
NEON-2 is a Phase 1 study of davoceticept in combination with KEYTRUDA® (pembrolizumab) in patients with advanced malignancies. A collaboration and supply agreement with Merck to evaluate the safety and efficacy of davoceticept in combination with KEYTRUDA® (pembrolizumab) was announced in June 2021. Initial data from NEON-2 study were shared during our inaugural R&D Day in September 2022. Preliminary analyses demonstrate encouraging outcomes, which include a patient with clear cell renal cell carcinoma (ccRCC) with prior primary resistance to nivolumab who achieved a durable confirmed partial response (30% tumor volume reduction). Two additional subjects showed evidence of tumor reduction: a 37.8% reduction in prostate-specific antigen (PSA; 622.9 to 387.7 ng/mL) in a subject with castrate-resistant prostate cancer, and a 25.5% tumor volume reduction in a subject with poorly differentiated renal cell carcinoma (RCC) with prior primary resistance to pembrolizumab and axitinib.
Dose escalation in NEON-2 is ongoing. In NEON-1, expansion cohorts in RCC, melanoma, and PD-L1-positive tumors are also ongoing.
For more information on our ongoing clinical trials please refer to the clinical trials portion of our website.