UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Immunother Cancer. 2024 Aug 3;12(8):e009474. doi: 10.1136/jitc-2024-009474.
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.
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.
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).
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.
NEON-1 (NCT04186637) and NEON-2 (NCT04920383).
Davoceticept（ALPN-202）是一种 CD80 变体免疫球蛋白结构域的 Fc 融合物，旨在介导程序性死亡配体 1（PD-L1）依赖性 CD28 共刺激，同时抑制 PD-L1 和细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）检查点。Davoceticept 单药治疗和 Davoceticept 联合 pembrolizumab 治疗在晚期实体瘤成人患者中的安全性和疗效分别在 NEON-1 和 NEON-2 中进行了研究。
在 NEON-1（n=58）中，Davoceticept 以 0.001-10mg/kg 的静脉剂量每周一次（Q1W）或每 3 周一次（Q3W）给药。在 NEON-2（n=29）中，Davoceticept 以 0.1 或 0.3mg/kg 的静脉剂量每周一次或每 3 周一次给药，联合 pembrolizumab（每 6 周 400mg 一次）。在这两项研究中，主要终点包括剂量限制毒性（DLT）的发生率；不良事件（AE）和实验室异常的类型、发生率和严重程度；以及 AE 的严重程度。次要终点包括使用 RECIST v1.1 评估的抗肿瘤疗效、药代动力学、抗药物抗体和药效学生物标志物。
Davoceticept 单药治疗的治疗相关 AE（TRAEs）和免疫相关不良事件（irAEs）发生率分别为 67%（39/58）和 36%（21/58），Davoceticept 联合 pembrolizumab 治疗的发生率分别为 62%（18/29）和 31%（9/29）。≥Gr3 TRAEs 和≥Gr3 irAEs 的发生率分别为 12%（7/58）和 5%（3/58），Davoceticept 联合 pembrolizumab 治疗的发生率分别为 24%（7/29）和 10%（3/29）。Davoceticept 单药 3mg/kg Q3W 时发生 1 例 Gr3 免疫相关性胃炎的 DLT。在 Davoceticept 联合 pembrolizumab 治疗期间，发生 2 例 Gr5 心脏 DLT；其中 1 例为心源性休克（0.3mg/kg Q3W，转移至肝脏的脉络膜黑色素瘤），1 例为免疫介导性心肌炎（0.1mg/kg Q3W，微卫星稳定转移性结直肠癌），导致这两项研究提前终止。在这两项研究中，5 例肾细胞癌（RCC）患者有临床获益的证据（2 例部分缓解，3 例病情稳定）。
Davoceticept 作为静脉内单药治疗，最高剂量达 10mg/kg 时一般耐受性良好。Davoceticept 单药治疗和 Davoceticept 联合 pembrolizumab 治疗均观察到临床活性，尤其是在 RCC 中。然而，Davoceticept 联合低剂量 pembrolizumab 治疗时发生了两例致命性心脏事件。在更全面阐明其安全性特征之前，Davoceticept 的未来临床研究不应考虑与程序性死亡 1 抑制剂抗癌机制联合。
NEON-1（NCT04186637）和 NEON-2（NCT04920383）。
