Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
Harbin Medical University Cancer Hospital, Harbin, China.
Clin Cancer Res. 2020 May 15;26(10):2337-2345. doi: 10.1158/1078-0432.CCR-19-4000. Epub 2020 Feb 21.
Patients with recurrent or metastatic neuroendocrine neoplasms (NEN) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat second-line metastatic melanoma in China in 2018.
The multiple-center phase Ib trial enrolled patients with NENs (Ki-67 ≥ 10%) after failure of first-line therapy 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), and progression-free survival and overall survival.
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%, = 0.019) and TMB-low patients (75.0% vs. 16.1%, = 0.03). Three of 8 (37.5%) responders harbored mutations, whereas only 1 of 27 nonresponders had mutations ( = 0.03). Of note, 1 exceptional responder with TMB-L, microsatellite stable (MSS), and PD-L1-negative had multiple genomic arrangements with high prediction score for neoantigens.
Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%), and/or microsatellite instable (MSI-H) might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit.
复发性或转移性神经内分泌肿瘤（NEN）患者预后较差，治疗选择有限。特瑞普利单抗是一种针对人 PD-1 受体的人源化 IgG4 抗体，于 2018 年在中国首次被批准用于二线转移性黑色素瘤的治疗。
这项多中心 Ib 期临床试验招募了一线治疗失败后 Ki-67≥10%的 NEN 患者，接受 3mg/kg 特瑞普利单抗每两周一次的治疗。主要终点为客观缓解率（ORR）和安全性。对肿瘤活检进行 PD-L1 表达和全外显子组测序。次要终点包括缓解持续时间（DOR）、疾病控制率（DCR）、无进展生存期和总生存期。
2017 年 4 月至 2018 年 12 月期间共纳入 40 例患者，观察到 8 例部分缓解和 6 例稳定疾病，ORR 为 20%，DCR 为 35%。DOR 中位数为 15.2 个月。PD-L1 表达（≥10%）或高肿瘤突变负荷（TMB）患者的 ORR 优于 PD-L1<10%患者（50.0% vs. 10.7%， = 0.019）和 TMB 低患者（75.0% vs. 16.1%， = 0.03）。8 例缓解者中有 3 例（37.5%）携带 突变，而 27 例非缓解者中仅有 1 例（1/27，16.1%）携带突变（ = 0.03）。值得注意的是，1 例 TMB-L、微卫星稳定（MSS）和 PD-L1 阴性的例外缓解者具有高预测新抗原评分的多种基因组排列。
特瑞普利单抗治疗复发性或转移性 NEN 具有抗肿瘤活性和安全性。PD-L1 阳性、TMB-H（前 10%）和/或微卫星不稳定（MSI-H）的患者可能优先受益于该治疗。ARID1A 基因突变和高基因组重排可能与临床获益相关。
