一项多中心II期试验，评估四联方案(派姆单抗、曲妥珠单抗和双联化疗)作为不可切除或转移性人表皮生长因子受体2 (HER2)阳性晚期胃癌(AGC)一线治疗的有效性和安全性。

主要终点是Ib期的2期推荐剂量(RP2D)和II期的客观缓解率(ORR)。次要终点包括无进展生存期(PFS)、总生存期(OS)、缓解持续时间、缓解时间和安全性。

在无剂量限制或意外毒性的情况下，Ib期试验的起始剂量选择为RP2D剂量。43例患者达到了主要终点:客观缓解率为76.7%(95%可信区间[CI]: 61.4-88.2)，完全缓解率为14%，部分缓解率为62.8%。中位无进展生存期、总生存期和缓解时间分别为8.6个月、19.3个月和10.8个月。无患者因免疫相关不良事件停用派姆单抗。PD-L1与存活率无关。通过靶向测序对肿瘤标本进行预处理后的分析表明，ERBB2扩增、RTK/RAS通路改变和HLA-B校正的高新抗原负荷与生存率呈正相关。目前的四联方案对HER-2阳性AGC患者显示出持久的疗效和安全性。

Abstract

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4-88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC

原文链接

pubmed.ncbi.nlm.nih.gov/36224176/

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