Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2)

Abstract

Background: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively.

Methods: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers.

Results: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease).

Conclusions: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated.

Trial registration number: NEON-1 (NCT04186637) and NEON-2 (NCT04920383).

Keywords: Combination therapy; Immune Checkpoint Inhibitor; Immunotherapy; co-inhibitory molecule.

Figure 1. Pharmacokinetics and drug saturation in the NEON studies pharmacokinetics of davoceticept during monotherapy (NEON-1, solid lines) and pembrolizumab combination (NEON-2, dashed lines) by dose (●, 0.1 mg/kg davoceticept; ●, 0.3 mg/kg davoceticept) and regimen; once weekly, Q1W (A) and once every 3 weeks, Q3W (B); dose-dependent drug saturation in NEON-1 (C) and NEON-2 (D). Drug saturation of CD28 on circulating CD4+T cells by davoceticept was determined by flow cytometry pre-dose and following infusion using an antibody specific for davoceticept bound to CD28. Per cent saturation was calculated using a ratio of test article to saturated control and normalized to cycle 1 pre-dose.

Figure 2. Antitumor efficacy of davoceticept monotherapy (NEON-1) or davoceticept+pembrolizumab combination (NEON-2). Per cent change in the sum of the longest diameters during davoceticept monotherapy (NEON-1) are shown over time (panel B) and by the best change from baseline and overall response (panel C). The PRs in NEON-1 and NEON-2 were confirmed with repeat scans. BoR, best overall response; CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; Q1W, once weekly; Q3W, once every 3 weeks; SD, stable disease; SLD, sum of the longest diameters.

Figure 3. Peripheral T-cell modulation in patients who received davoceticept monotherapy (NEON-1). Flow cytometric analyses of Ki67+CD4+ (A, B) and CD8+ (C, D) during treatment with davoceticept monotherapy Q1W (A, C) or Q3W (B, D). ***p=0.0005, **p=0.0017, *p=0.0313, not significant (ns). Error bars indicate stable disease where applicable. Q1W, once weekly; Q3W, once every 3 weeks.