Purpose: Simlukafusp alfa (FAP-IL2v), a tumor-targeted immunocytokine, comprising an interleukin-2 variant moiety with abolished CD25 binding fused to human immunoglobulin G1, is directed against fibroblast activation protein-α. This phase I, open-label, multicenter, dose-escalation and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors. Methods: Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intra-participant up-titration regimens (15/20 mg, 20/25 mg, 20/20/35 mg, 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended expansion dose, and pharmacokinetics. Results: Sixty-one participants were enrolled. DLTs included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (up-titration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). Up-titration regimen 15/20 mg was the MTD and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses (natural killer cells, 13-fold; CD4+ T cells [including Tregs], 2-fold; CD8+ T cells, 3.5-fold), but without any percentage change in Tregs. Clinical activity was observed from 5 mg (objective response rate, 5.1% [n = 3]; disease control rate, 27.1% [n = 16]). Responses were durable (n = 3; 2.8 [censored], 6.3, and 43.4 months). Conclusions: FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.

中文翻译：

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Simlukafusp Alfa (FAP-IL2v) 在晚期/转移性实体瘤中的 I 期研究的安全性、药代动力学、药效学和抗肿瘤活性

目的：Simlukafusp alfa (FAP-IL2v) 是一种肿瘤靶向免疫细胞因子，包含与人免疫球蛋白 G1 融合的已废除 CD25 结合的白细胞介素 2 变体部分，针对成纤维细胞活化蛋白-α。这项 I 期、开放标签、多中心、剂量递增和扩展研究 (NCT02627274) 评估了 FAP-IL2v 在晚期/转移性实体瘤患者中的安全性、药代动力学、药效学和抗肿瘤活性。方法：参与者每周一次静脉注射 FAP-IL2v。剂量从 5 mg 开始递增；评估了固定剂量（≤25 mg）和参与者内滴定方案（15/20 mg、20/25 mg、20/20/35 mg、20/35/35 mg）。主要目标是剂量限制毒性 (DLT)、最大耐受剂量 (MTD)、推荐扩展剂量和药代动力学。结果：登记了 61 名参与者。 DLT 包括疲劳（固定剂量 20 mg：n = 1）、乏力（25 mg：n = 1）、药物引起的肝损伤（上调方案 20/25 mg：n = 1）、转氨酶升高（20/25 mg：n = 1）和肺炎（20/35/35 mg：n = 1）。向上滴定方案 15/20 mg 是 MTD，并被选为推荐的扩展剂量。所有测试剂量的外周血绝对免疫细胞计数均增加（自然杀伤细胞，13 倍；CD4+ T 细胞[包括 Tregs]，2 倍；CD8+ T 细胞，3.5 倍），但没有任何百分比变化特雷格。从 5 mg 开始观察临床活性（客观缓解率，5.1% [n = 3]；疾病控制率，27.1% [n = 16]）。反应是持久的（n = 3；2.8 [审查]、6.3 和 43.4 个月）。结论：FAP-IL2v 具有可控的安全性，并且在晚期/转移性实体瘤中显示出抗肿瘤活性的初步迹象。