Retifanlimab is a humanized, hinge-stabilized immunoglobulin G4κ monoclonal antibody against human programmed cell death protein 1 (PD-1). This first-in-human, phase I study assessed the safety and efficacy of retifanlimab in patients with advanced solid tumors and identified optimal dosing. POD1UM-101 was conducted in two parts: (i) dose escalation—evaluated retifanlimab [1 mg/kg every 2 weeks (q2w), 3 or 10 mg/kg q2w or every 4 weeks (q4w)] in patients with relapsed/refractory, unresectable, locally advanced or metastatic solid tumors; (ii) cohort expansion—biomarker-unselected tumor-specific cohorts [endometrial, cervical, sarcoma, non-small-cell lung cancer (NSCLC)] received retifanlimab 3 mg/kg q2w, and tumor-agnostic cohorts received flat dosing [375 mg every 3 weeks (q3w), or 500 and 750 mg q4w]. Primary objectives were safety and tolerability; secondary objective was efficacy in selected tumor types. Thirty-seven patients were enrolled in dose escalation, 134 in PD-1 therapy-naïve tumor-specific cohort expansion (endometrial, = 29; cervical, NSCLC, soft tissue sarcoma, each = 35), and 45 in flat dosing (375 mg q3w, 500 and 750 mg q4w, each = 15). No dose-limiting toxicities occurred during dose escalation; maximum tolerated dose was not reached and 3-mg/kg q2w expansion dose was selected based on safety and pharmacokinetic data. Immune-related adverse events were experienced by 40 patients (30%) in tumor-specific cohorts (most frequently hypothyroidism, hyperthyroidism, colitis, nephritis) and 6 (13%) in flat dosing (most frequently hypothyroidism, hyperthyroidism). Objective response rate (95% confidence interval) was 14% (4.8 to 30.3), 14% (3.9 to 31.7), 20% (8.4 to 36.9), and 3% (0.1 to 14.9) in advanced NSCLC, endometrial, cervical, and sarcoma tumor-specific cohorts that progressed after multiple prior systemic therapies. Retifanlimab demonstrated clinical pharmacology, safety, and antitumor activity consistent with the programmed death (ligand)-1 inhibitor class. POD1UM-101 results support further exploration of retifanlimab as monotherapy and backbone immunotherapy in combination treatments, with recommended doses of 500 mg q4w and 375 mg q3w.

中文翻译：

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PD-1 抑制剂 retifanlimab (INCMGA00012) 在晚期实体瘤 (POD1UM-101) 患者中的首次人体 I 期研究

Retifanlimab 是一种针对人程序性细胞死亡蛋白 1 (PD-1) 的人源化、铰链稳定的免疫球蛋白 G4κ 单克隆抗体。这项首次人体 I 期研究评估了 retifanlimab 对晚期实体瘤患者的安全性和有效性，并确定了最佳剂量。POD1UM-101 分两部分进行：(i) 剂量递增——在复发/难治性患者中评估 retifanlimab [每 2 周 1 mg/kg (q2w)、3 或 10 mg/kg q2w 或每 4 周 (q4w)] ，不可切除的局部晚期或转移性实体瘤；(ii) 队列扩展——未选择生物标志物的肿瘤特异性队列[子宫内膜癌、宫颈癌、肉瘤、非小细胞肺癌 (NSCLC)] 接受瑞替凡利单抗 3 mg/kg 每两周一次，肿瘤不可知队列接受固定剂量 [375 mg]每 3 周一次 (q3w)，或 500 和 750 mg q4w]。主要目标是安全性和耐受性；次要目标是对选定肿瘤类型的疗效。37 名患者参加了剂量递增试验，134 名患者参加了未经 PD-1 治疗的肿瘤特异性队列扩展（子宫内膜，= 29；宫颈癌、非小细胞肺癌、软组织肉瘤，各 = 35），45 名患者参加了固定剂量（375 mg）每 3 周一次，每 4 周一次 500 和 750 毫克，各 = 15)。剂量递增期间未发生剂量限制性毒性；未达到最大耐受剂量，根据安全性和药代动力学数据选择 3 mg/kg q2w 扩展剂量。肿瘤特异性队列中有 40 名患者 (30%) 经历了免疫相关不良事件（最常见的是甲状腺功能减退、甲状腺功能亢进、结肠炎、肾炎），固定剂量组中有 6 名患者 (13%) 经历了免疫相关不良事件（最常见的是甲状腺功能减退、甲状腺功能亢进）。晚期非小细胞肺癌、子宫内膜癌、宫颈癌、宫颈癌的客观缓解率（95%置信区间）分别为14%（4.8至30.3）、14%（3.9至31.7）、20%（8.4至36.9）和3%（0.1至14.9）。以及在多次先前的全身治疗后进展的肉瘤肿瘤特异性队列。Retifanlimab 的临床药理学、安全性和抗肿瘤活性与程序性死亡（配体）-1 抑制剂类别一致。POD1UM-101结果支持进一步探索retifanlimab作为单一疗法和联合治疗中的骨干免疫疗法，推荐剂量为500 mg q4w和375 mg q3w。