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Efficacy, safety and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase Ib trial.

Toripalimab 在复发或转移性神经内分泌肿瘤患者中的疗效、安全性和生物标志物: 一项多中心 Ib 期试验。

  • 影响因子:8.32
  • DOI:10.1158/1078-0432.CCR-19-4000
  • 作者列表:"Lu M","Zhang P","Zhang Y","Li Z","Gong JF","Li J","Li J","Li Y","Zhang X","Lu Z","Wang X","Zhou J","Peng Z","Wang W","Feng H","Wu H","Yao S","Shen L
  • 发表时间:2020-02-21
Abstract

PURPOSE:Patients with recurrent or metastatic neuroendocrine neoplasms (NENs) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat 2nd line metastatic melanoma in China in 2018. EXPERIMENTAL DESIGN:The multiple-center phase Ib trial enrolled patients with NENs (Ki-67≥10%) after failures of 1st line therapy to received 3 mg/kg toripalimab once every two weeks. The primary objective was objective response rate (ORR) and safety. PD-L1 expression and whole exome sequencing were performed on tumor biopsies. Secondary objectives included duration of response (DOR), disease control rate (DCR), progression free survival and overall survival. RESULTS:Of 40 patients included from April 2017 to December 2018, 8 partial responses and 6 stable diseases were observed, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months. Patients with PD-L1 expression (≥10%) or high tumor mutational burden (TMB) had better ORR than PD-L1 <10% (50.0% vs 10.7%, p=0.019) and TMB low patients (75.0% vs 16.1%, p=0.03). 3/8 (37.5%) responders harbored ARID1A mutations while only 1/27 non-responder was mutated (p=0.03). Of note, 1 exceptional responder with TMB-L, MSS and PD-L1 negative had multiple genomic arrangements with high prediction score for neoantigens. CONCLUSIONS:Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%) and/or MSI-H might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit.

摘要

目的: 复发或转移性神经内分泌肿瘤 (NENs) 患者预后差,治疗选择少。Toripalimab 是一种针对人 PD-1 受体特异性的人源化 IgG4 抗体,2018年在中国首次被批准用于治疗第2 线转移性黑色素瘤。 实验设计: 多中心 Ib 期试验入组了 10% 线治疗失败后的 NENs (Ki-67 ≥ 第1) 患者,每两周接受一次 3 mg/kg toripalimab。主要目标是客观缓解率 (ORR) 和安全性。对肿瘤活检进行 PD-L1 表达和全外显子组测序。次要目标包括缓解时间 (DOR) 、疾病控制率 (DCR) 、无进展生存期和总生存期。 结果: 在 2017年4月至 2018年12月纳入的 40 例患者中,观察到 8 例部分缓解和 6 例疾病稳定,ORR 为 20%,DCR 为 35%。中位 DOR 为 15.2 个月。PD-L1 表达 (≥ 10%) 或高肿瘤突变负荷 (TMB) 的患者 ORR 优于 PD-L1

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