Davoceticept (ALPN-202) 是 CD80 变异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。分别在 NEON-1 和 NEON-2 中探讨了达沃西普单药治疗以及达沃西普和派姆单抗联合治疗在晚期实体瘤成人患者中的安全性和有效性。在 NEON-1 (n=58) 中，达沃西普 0.001-10mg/kg每周一次（Q1W）或每三周一次（Q3W）静脉注射。在 NEON-2 (n=29) 中，达沃西普以 2 个剂量水平（0.1 或 0.3mg/kg）Q1W 或 Q3W 与 pembrolizumab（400mg 每 6 周一次）一起静脉内给药。在这两项研究中，主要终点包括剂量限制性毒性（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 的严重性。次要终点包括使用 RECIST v1.1、药代动力学、抗药物抗体和药效生物标志物评估的抗肿瘤疗效。治疗相关 AE (TRAE) 和免疫相关不良事件 (irAE) 的发生率为 67% (39/58)达沃西普单药治疗的发生率分别为 62% (18/29) 和 36% (21/58)，达沃西普与派姆单抗联合治疗的发生率分别为 62% (18/29) 和 31% (9/29)。达沃西普单药治疗中≥3级TRAE和≥Gr3 irAE的发生率分别为12% (7/58)和5% (3/58)，达沃西普单药治疗时≥3级(Gr)3 TRAE和≥Gr3 irAE的发生率分别为24% (7/29)和10% (3/29)分别与达沃西普和派姆单抗组合。在达沃西普单药治疗 3 mg/kg Q3W 期间，发生了 1 例 Gr3 免疫相关性胃炎 DLT。在达沃西普与派姆单抗联合治疗期间，发生了两次 Gr5 心脏 DLT；心源性休克（0.3mg/kg Q3W，脉络膜黑色素瘤转移至肝脏）和免疫介导的心肌炎（0.1mg/kg Q3W，微卫星稳定转移性结直肠腺癌）各一个实例，促使两项研究提前终止。在这两项研究中，5 名肾细胞癌 (RCC) 患者表现出临床获益的证据（2 名部分缓解，3 名疾病稳定）。达沃西普作为单一疗法，静脉注射剂量高达 10 mg/kg 时总体耐受性良好。观察到达沃西普单药治疗和达沃西普与派姆单抗联合治疗的临床活性证据，特别是在肾细胞癌中。然而，低剂量达沃西普和派姆单抗联合使用时发生了两起致命的心脏事件。达沃西普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使用，直到其安全性得到更充分的阐明。NEON-1 (NCT04186637) 和 NEON-2 (NCT04920383)。© 作者（或其作者）雇主）2024。CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

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).© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.