背景:Retifanlimab是一种人性化的,铰链稳定的免疫球蛋白G4κ单克隆抗体抗人程序性细胞死亡蛋白1(PD-1)。这个第一个人类,I期研究评估了retifanlimab在晚期实体瘤患者中的安全性和有效性,并确定了最佳给药.
方法:POD1UM-101分两个部分进行:(i)剂量递增评估的retifanlimab[每2周1mg/kg(q2w),3或10mg/kgq2w或每4周(q4w)]复发/难治性患者,不可切除,局部晚期或转移性实体瘤;(ii)队列扩展-生物标志物-未选择的肿瘤特异性队列[子宫内膜,子宫颈,肉瘤,非小细胞肺癌(NSCLC)]接受retifanlimab3mg/kgq2w,和肿瘤无关的队列接受了平坦的剂量[375毫克每3周(q3w),或500和750毫克q4w]。主要目标是安全性和耐受性;次要目标是选定肿瘤类型的疗效。
结果:37例患者纳入剂量递增,134在PD-1治疗初治肿瘤特异性队列扩展(子宫内膜,n=29;子宫颈,NSCLC,软组织肉瘤,每个n=35),和45在平板给药(375毫克q3w,500和750毫克q4w,每个n=15)。在剂量递增过程中没有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/kgq2w扩展剂量。在肿瘤特异性队列中,有40名患者(30%)发生了免疫相关的不良事件(最常见的是甲状腺功能减退,甲状腺功能亢进,结肠炎,肾炎)和6(13%)在平坦的剂量(最常见的甲状腺功能减退,甲状腺功能亢进)。客观反应率(95%置信区间)为14%(4.8至30.3),14%(3.9至31.7),20%(8.4至36.9),在晚期非小细胞肺癌中占3%(0.1至14.9),子宫内膜,子宫颈,和在多次系统治疗后进展的肉瘤肿瘤特异性队列。
结论:Retifanlimab具有临床药理学,安全,和抗肿瘤活性与程序性死亡(配体)-1抑制剂类一致。POD1UM-101结果支持进一步探索retifanlimab作为联合治疗中的单一疗法和骨干免疫疗法,推荐剂量为500毫克q4w和375毫克q3w。
BACKGROUND: 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.
METHODS: 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.
RESULTS: Thirty-seven patients were enrolled in dose escalation, 134 in PD-1 therapy-naïve tumor-specific cohort expansion (endometrial, n = 29; cervical, NSCLC, soft tissue sarcoma, each n = 35), and 45 in flat dosing (375 mg q3w, 500 and 750 mg q4w, each n = 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.
CONCLUSIONS: 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.