沙司利单抗替代给药方案在晚期非小细胞肺癌及其他恶性肿瘤患者中的药代动力学、安全性和疗效。
Pharmacokinetics, safety, and efficacy of an alternative dosing regimen of sasanlimab in participants with advanced NSCLC and other malignancies.
作者信息
Penkov Konstantin, Bondarenko Igor, Saenko Daria Viktorovna, Kulyaba Yaroslav, Guo Jun, Gong Yi, Yamamoto Noboru, Hotko Yevhen Stepanovych, Boyko Vasyl, Fadeeva Natalya Vladimirovna, Ursol Grygorii Mykolaiovych, Ahn Hee Kyung, Kislov Nikolay Viktorovich, Shen Chia-I, Davis Craig, Kowalski Karey, Michelon Elisabete, Pavlov Dmitri, Hirohashi Tomoko, Cho Byoung Chul
机构信息
Private Medical Institution "Euromedservice," Saint-Petersburg, Russia.
Dnipro State Medical University, Dnipro, Ukraine.
出版信息
Ther Adv Med Oncol. 2024 Sep 11;16:17588359241274592. doi: 10.1177/17588359241274592. eCollection 2024.
BACKGROUND
Sasanlimab (PF-06801591), a humanized immunoglobulin G4 monoclonal antibody, binds to programmed cell death protein-1 (PD-1), preventing ligand (PD-L1) interaction.
OBJECTIVES
To evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of two subcutaneous sasanlimab dosing regimens.
DESIGN
An open-label study consisting of phases Ib and II. Phase Ib: non-randomized, dose escalation, and expansion study in Asian participants with advanced malignancies.
PHASE II
conducted globally in participants with non-small-cell lung cancer with PD-L1 positive or PD-L1 status unknown tumors; participants were randomized 1:2 to receive subcutaneous sasanlimab 300 mg once every 4 weeks (300 mg-Q4W) or 600 mg once every 6 weeks (600 mg-Q6W).
METHODS
Primary endpoint in phase Ib: dose-limiting toxicity (DLT) occurring in first treatment cycle; in phase II: and AUC.
RESULTS
A total of 155 participants (phase Ib, = 34; phase II, = 121) received sasanlimab. Phase Ib: no DLT reported. Phase II: ratio of adjusted geometric mean for AUC was 231.2 (90% CI, 190.1-281.2) and was 111.5 (90% CI, 86.3-144.0) following 600 mg-Q6W (test) versus 300 mg-Q4W (reference). Phase Ib: grade 3 treatment-related adverse events (TRAEs) occurred in 1/4 (25%) and 3/12 (25%) participants treated in 300 mg-Q4W dose escalation and expansion cohorts, respectively. Phase II: grade 3 TRAEs occurred in 3/41 (7.3%) and 3/80 (3.8%) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively; no grade 4/5 TRAEs. Phase II: confirmed objective response was observed in 11/41 (26.8% (95% CI, 14.2-42.9)) and 12/80 (15.0% (95% CI, 8.0-24.7)) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively.
CONCLUSIONS
Phase Ib regimens were considered safe with no DLTs reported. In phase II, 600 mg-Q6W regimen criteria were met for AUC and metrics to support PK-based extrapolation of efficacy of alternative regimen. Regimens were well tolerated, showing anti-tumor activity in participants with advanced solid tumors. Administration of sasanlimab at a dose of 600 mg-Q6W subcutaneously may serve as a convenient alternative to 300 mg-Q4W administration.
TRIAL REGISTRATION
NCT04181788 (ClinicalTrials.gov); 2019-003818-14 (EudraCT).
背景
Sasanlimab（PF-06801591）是一种人源化免疫球蛋白G4单克隆抗体，可与程序性细胞死亡蛋白1（PD-1）结合，阻止其与配体（PD-L1）相互作用。
目的
评估两种皮下注射sasanlimab给药方案的药代动力学（PK）、安全性、耐受性和疗效。
设计
一项由Ib期和II期组成的开放标签研究。Ib期：在患有晚期恶性肿瘤的亚洲参与者中进行的非随机、剂量递增和扩展研究。
II期：在患有PD-L1阳性或PD-L1状态未知肿瘤的非小细胞肺癌参与者中全球范围内开展；参与者按1:2随机分组，接受皮下注射sasanlimab，每4周一次，每次300mg（300mg-Q4W）或每6周一次，每次600mg（600mg-Q6W）。
方法
Ib期的主要终点：在第一个治疗周期中出现的剂量限制性毒性（DLT）；在II期： 和AUC。
结果
共有155名参与者（Ib期，n = 34；II期，n = 121）接受了sasanlimab治疗。Ib期：未报告DLT。II期：与300mg-Q4W（对照）相比，600mg-Q6W（试验）后的AUC调整几何均值比为231.2（90%CI，190.1-281.2）， 为111.5（90%CI，86.3-144.0）。Ib期：在300mg-Q4W剂量递增和扩展队列中接受治疗的参与者中，分别有1/4（25%）和3/12（25%）出现3级治疗相关不良事件（TRAEs）。II期：接受300mg-Q4W和600mg-Q6W治疗的参与者中，分别有3/41（7.3%）和3/80（3.8%）出现3级TRAEs；无4/5级TRAEs。II期：接受300mg-Q4W和600mg-Q6W治疗的参与者中，分别有11/41（26.8%（95%CI，14.2-42.9））和12/80（15.0%（95%CI，8.0-24.7））观察到确认的客观缓解。
结论
Ib期方案被认为是安全的，未报告DLT。在II期，600mg-Q6W方案符合AUC和 指标标准，以支持基于PK的替代方案疗效外推。这些方案耐受性良好，在晚期实体瘤参与者中显示出抗肿瘤活性。皮下注射600mg-Q6W剂量的sasanlimab可能是300mg-Q4W给药的一种方便替代方案。
试验注册
NCT04181788（ClinicalTrials.gov）；2019-003818-14（EudraCT）。
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