肿瘤细胞治疗研究
英文原题：Phase 1/2 study of pegenzileukin, a pegylated recombinant non-alpha IL-2, with cemiplimab for the treatment of advanced unresectable or metastatic skin cancers.
pegenzileukin 联合 cemiplimab 在 16 g/kg 的 RP2D 下显示出可控的安全性特征，以及支持其作用机制的有前景的转化数据。
背景：Pegenzileukin（SAR444245）是一种聚乙二醇化、非α型重组人白细胞介素2（IL-2）变体，可避免与IL-2受体亚基γ链结合及相关毒性，同时保留与IL-2Rβ链结合的能力，以激活效应T细胞和自然杀伤（NK）细胞。首次人体研究显示，pegenzileukin联合帕博利珠单抗治疗晚期和转移性实体瘤初显疗效且安全性可耐受。本研究评估pegenzileukin联合西米普利单抗治疗晚期或转移性黑色素瘤（MM）和皮肤鳞状细胞癌（CSCC）的效果。 方法：这项1/2期、开放标签、多中心研究评估了MM（队列A）和CSCC（队列B）患者的药物联合方案。剂量递增阶段，pegenzileukin按两个剂量水平给药（16 μg/kg：队列A1和B1；24 μg/kg：队列A2和B2）；剂量扩展阶段采用推荐的2期剂量（RP2D）。西米普利单抗剂量为350 mg；两种药物均每3周静脉输注一次，每次30分钟。主要终点为客观缓解率（ORR）；次要终点包括剂量限制性毒性（DLT）、无进展生存期（PFS）、安全性及探索性生物标志物终点。 结果：共入组46例患者。在pegenzileukin RP2D（16 μg/kg；队列A1 n=20，队列B1 n=16）下，队列A1和B1的ORR分别为40%和56.3%。队列A1中，1例完全缓解，7例部分缓解（PR）；队列B1中，9例达到PR。在RP2D下，队列A1和B1的应答者中分别有75.0%和85.7%应答持续时间达到12个月。6个月PFS率在队列A1为55.0%，队列B1为70.7%。4例患者共发生5次DLT：队列A有1例3级血小板减少和1例2级细胞因子释放综合征；队列B有1例3级丙氨酸转氨酶/天冬氨酸转氨酶升高和1例输注相关反应（IRR）。1级或2级IRR是最常见的不良事件。治疗显著扩增NK细胞和CD8 T细胞，未增加调节性T细胞。 结论：在RP2D 16 μg/kg下，pegenzileukin联合西米普利单抗的安全性可管理，并显示出支持其作用机制的有前景转化研究数据。 试验注册号：NCT04913220。
BACKGROUND: Pegenzileukin (SAR444245), a pegylated non-alpha recombinant human interleukin (IL)-2 variant, avoids engagement of the IL-2 receptor subunit (IL-2R ) chain and associated toxicities, while retaining engagement of IL-2R , for activation of effector T cell and natural killer (NK) cell. The first-in-human study of pegenzileukin with pembrolizumab showed initial efficacy and tolerable safety in advanced and metastatic solid tumors. In this study, we evaluate pegenzileukin with cemiplimab for advanced or metastatic melanoma (MM) and cutaneous squamous cell carcinoma (CSCC). METHODS: This phase 1/2, open-label, multicenter study evaluated drug combinations in patients with MM (Cohort A) and CSCC (Cohort B). Pegenzileukin was given at two dose levels (16 g/kg: Cohort A1 and B1 and 24 g/kg: Cohort A2 and B2) during dose escalation and recommended phase 2 dose (RP2D) during dose expansion, while cemiplimab was given at a dose of 350 mg; both drugs were administered every 3 weeks as a 30-minute intravenous infusion. The primary endpoint was the objective response rate (ORR); secondary endpoints included dose-limiting toxicities (DLTs), progression-free survival (PFS), safety, and exploratory biomarker endpoints. RESULTS: A total of 46 patients were enrolled. At the RP2D of pegenzileukin (16 g/kg, n=20 in Cohort A1 and n=16 in Cohort B1), the ORR was 40% in Cohort A1 and 56.3% in Cohort B1. In Cohort A1, one patient achieved a complete response, and seven achieved a partial response (PR). In Cohort B1, nine patients achieved a PR. At the RP2D, 75.0% and 85.7% responders, respectively, in Cohort A1 and Cohort B1 had a duration of response of 12 months. The PFS rate at 6 months was 55.0% in Cohort A1 and 70.7% in Cohort B1. Five DLTs occurred in four patients: Cohort A had one case of 3 Grade thrombocytopenia and one of Grade 2 cytokine release syndrome, while Cohort B had one case of 3 Grade alanine transaminase/aspartate transaminase increases and one infusion-related reaction (IRR). Grade 1 or 2 IRRs were the most common adverse events. Treatment led to robust expansion of NK and CD8 T-cells, without an increase of regulatory T cells. CONCLUSION: Pegenzileukin in combination with cemiplimab at the RP2D of 16 g/kg showed a manageable safety profile and promising translational data supporting its mechanism of action. TRIAL REGISTRATION NUMBER: NCT04913220.
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