Diwakar Davar, MBBS, M.Sc, Assistant Professor, Phase I Therapeutics and Melanoma at UPMC. In this video, he speaks about the ASCO 2022 Abstract - Dose Escalation of Davoceticept, a conditional CD28 Costimulator and Dual Checkpoint Inhibitor, in Advanced Malignancies (NEON-1).
Combining checkpoint inhibition (CPI) with T cell costimulatory agonists, notably CD28, a major T cell costimulatory ligand recognized as a significant target of checkpoint inhibition, has a strong preclinical rationale. Davoceticept (ALPN-202) is a PD-L1-dependent CD80 vIgD-Fc fusion that mediates CD28 costimulation and suppresses the PD-L1 and CTLA-4 checkpoints. It has outperformed CPI-only therapy in vitro and in vivo in various tumor types, while also displaying favorable preclinical safety.
This is an open-label davoceticept dose escalation and expansion trial in individuals with advanced solid tumors or lymphoma (NCT04186637). Patients with malignancies that have resisted traditional therapies, including CPIs, or cancers for which no standard or curative therapy is available, are eligible. Dosing escalation was investigated using two dose schedules, Q1W and Q3W. Safety and tolerability, PK, PD, and preclinical anticancer activity are all goals. For solid tumors, RECIST v1.1 is used to determine disease severity. A previous presentation covered the first five cohorts of the Q1W plan; this presentation provides an update on dose escalation progress, including the Q3W schedule.
By January 2022, 57 adults with advanced solid tumors, most commonly colorectal and pancreatic, had received davoceticept monotherapy, which had been well tolerated at 10 mg/kg Q3W. It exhibited dose-dependent PK as well as target saturation. Immune-related adverse events (irAEs) occurred in 20/57 (35%) of the patients, primarily in the skin, endocrine, and gastrointestinal systems. Except for four irAE, all were grade 1-2. At 3 mg/kg Q3W, only one DLT (chronic active gastritis grade 3) was seen. Unconfirmed partial responses were seen in two of the 48 evaluable patients (colorectal and renal cell). At the first scan at 6 weeks, 23 (48 percent) had stable disease; 11 (23 percent) had volume decrease (target lesion SLD 0%); 2 had SD for more than 6 months, and 1 had continued SD at 8 months. Ex vivo investigations revealed T cell CD28 agonism at dosages greater than 0.1 mg/kg, and flow cytometry revealed increased circulating activated (ICOS+), proliferative (Ki-67+), and central memory T cells, as well as decreased regulatory T cells, consistent with CD28 engagement.
In a predominantly treatment-refractory, non-immunogenic tumor population, davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signals of activity and peripheral immune activation. These data indicate the additive effect of combining CD28 agonism with checkpoint inhibition, identify biologically active dose regimens of davoceticept for future single agent development, and provide additional justification for combination research. Expansion cohorts are being planned, including cutaneous melanoma and PD-L1-positive tumors, and a combo study with pembrolizumab has begun (NCT04920383). NCT04186637 is the clinical trial number.