Dose escalation of davoceticept, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1)
Meeting Abstract | 2022 ASCO Annual Meeting I
oregon; portland; chiles
Background: Strong preclinical rationale supports combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly of CD28, a critical T cell costimulatory molecule recognized as a key target of checkpoint inhibition. Davoceticept (ALPN-202) is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in multiple tumor models in vitro and in vivo, while demonstrating favorable preclinical safety. Methods: This is an open-label dose escalation and expansion study of davoceticept in adults with advanced solid tumors or lymphoma (NCT04186637). Patients with cancers refractory to standard therapies including CPIs, or cancers without available standard or curative therapy are eligible. Dose escalation studied two dose schedules, Q1W and Q3W. Objectives include safety and tolerability, PK, PD and preliminary anticancer activity. Disease assessments are evaluated by RECIST v1.1 for solid tumors. A prior presentation discussed the first 5 cohorts of the Q1W schedule; this presentation updates progress in dose escalation, including the Q3W schedule. Results: As of January 2022, 57 adults with various advanced solid tumors, most commonly colorectal and pancreatic, received davoceticept monotherapy, which was well tolerated through 10 mg/kg Q3W. It demonstrated dose-dependent PK and target saturation. Immune-related AEs (irAEs), occurred in 20/57 (35%), mostly of the skin, endocrine and gastrointestinal systems. All but 4 of the irAE were grade 1-2. Only one DLT (chronic active gastritis grade 3) was observed at 3 mg/kg Q3W. Among 48 evaluable patients, unconfirmed partial responses were observed in 2 (colorectal and renal cell). Stable disease, at first scan at 6 weeks, was observed in 23 (48%); 11 (23%) demonstrated volume reduction (target lesion ΔSLD < 0%); 2 had SD for > 6 months, and 1 had an ongoing SD at 8 months. At doses above 0.1 mg/kg, ex vivo analyses showed agonism of T cell CD28, and flow cytometry demonstrated increased circulating activated (ICOS+), proliferating (Ki-67+) and central memory T cells, and reduced regulatory T cells, consistent with CD28 engagement. Conclusions: Davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity and peripheral immune activation in a largely treatment-refractory, non-immunogenic tumor population. These findings support an additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and provide further rationale for combination study. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned, and a combination study with pembrolizumab has initiated (NCT04920383). Clinical trial information: NCT04186637.
Earle A. Chiles Research Institute
Davar, Diwakar; Sanborn, Rachel E; and See full list of authors in comments, "Dose escalation of davoceticept, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1)" (2022). Articles, Abstracts, and Reports. 6220.