戈沙妥珠单抗联合特瑞普利单抗对比特瑞普利单抗联合白蛋白结合型紫杉醇一线治疗不可切除的局部晚期或转移性三阴性乳腺癌：一项多中心、开放标签、随机II期试验的方案。
完整摘要 · 中文译文
背景：在近期III期研究之后，晚期三阴性乳腺癌（TNBC）的一线治疗格局已发生显著演变。在TORCHLIGHT试验中，与安慰剂联合白蛋白结合型紫杉醇相比，特瑞普利单抗联合白蛋白结合型紫杉醇在程序性死亡配体1（PD-L1）阳性疾病中改善了无进展生存期（PFS）。在ASCENT-03中，戈沙妥珠单抗单药治疗在不符合抗程序性死亡蛋白1（PD-1）/PD-L1治疗条件的未经治疗晚期TNBC患者中，显示出比化疗更长的PFS。ASCENT-04/KEYNOTE-D19报告，在PD-L1阳性肿瘤患者中，与化疗联合帕博利珠单抗相比，戈沙妥珠单抗联合帕博利珠单抗显著降低了疾病进展或死亡风险。然而，在中国相关的PD-L1阳性人群中，缺乏戈沙妥珠单抗联合特瑞普利单抗的前瞻性证据。 方法：这项多中心、开放标签、随机、探索性优效性、平行分组II期试验（NCT07040644；方案CO-US-979-7331）入组未经治疗、不可切除的局部晚期或转移性PD-L1阳性TNBC患者。患者按相等比例随机分配，接受戈沙妥珠单抗10 mg/kg静脉给药（IV；第1天和第8天）联合特瑞普利单抗240 mg IV（第1天），或特瑞普利单抗240 mg IV（第1天）联合白蛋白结合型紫杉醇125 mg/m2 IV（第1天和第8天），以3周为一个周期。主要终点是由研究者根据实体瘤疗效评价标准（RECIST）第1.1版评估的PFS。关键次要和探索性 探索性终点包括客观缓解率（ORR）、缓解持续时间（DoR）、至缓解时间（TTR）、总生存期（OS）、安全性以及亚组分析，其中包括内脏转移状态、既往根治性治疗背景下的抗PD-(L)1暴露、疾病状态、无病间期（DFI）以及既往紫杉烷治疗等。 讨论：这项II期试验旨在评估sacituzumab govitecan联合toripalimab相较于toripalimab联合白蛋白结合型紫杉醇在与中国的临床实践相关的治疗背景下的优效性。显著的设计特征包括在中国入组、使用toripalimab作为当地已批准的免疫检查点抑制剂联合药物、纳入更广泛的PD-L1阳性人群，以及允许在根治性治疗背景下既往接受过免疫检查点抑制剂暴露。该试验可能阐明sacituzumab govitecan联合toripalimab在中国PD-L1阳性晚期三阴性乳腺癌（TNBC）一线治疗中的作用。 试验注册：ClinicalTrials.gov，NCT07040644；网址：https://clinicaltrials.gov/study/NCT07040644。
完整摘要 · 英文原文
BACKGROUND: First-line therapeutic landscape for advanced triple-negative breast cancer (TNBC) has evolved significantly following recent phase III studies. In the TORCHLIGHT trial, toripalimab plus nab-paclitaxel improved progression-free survival (PFS) versus placebo combined with nab-paclitaxel in programmed death ligand 1 (PD-L1)-positive disease. In ASCENT-03, sacituzumab govitecan monotherapy demonstrated longer PFS than chemotherapy among untreated patients with advanced TNBC who were ineligible for anti-programmed cell death protein 1 (PD-1)/PD-L1 treatment. ASCENT-04/KEYNOTE-D19 reported a significant reduction in the risk of disease progression or death for sacituzumab govitecan plus pembrolizumab compared to chemotherapy plus pembrolizumab in patients with PD-L1-positive tumor. However, prospective evidence for sacituzumab govitecan plus toripalimab is lacking in a China-relevant PD-L1-positive population. METHODS: This multicenter, open-label, randomized, exploratory superiority, parallel-group phase II trial (NCT07040644; protocol CO-US-979-7331) enrolls patients with treatment-naïve unresectable locally advanced or metastatic PD-L1-positive TNBC. Patients are randomly assigned in equal proportions to receive either sacituzumab govitecan at 10 mg/kg intravenously (IV; days 1 and 8) plus toripalimab at 240 mg IV (day 1) or toripalimab at 240 mg IV (day 1) plus nab-paclitaxel at 125 mg/m2 IV (day 1 and 8) in a 3-week cycle. Primary endpoint is PFS assessed by investigators per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key secondary and exploratory endpoints encompass objective response rate (ORR), duration of response (DoR), time to response (TTR), overall survival (OS), safety, and subgroup analyses, including visceral metastasis status, prior curative-setting anti-PD-(L)1 exposure, disease status, disease-free interval (DFI), and prior taxane therapy, among others. DISCUSSION: This phase II trial is designed to evaluate the superiority of sacituzumab govitecan plus toripalimab over toripalimab plus nab-paclitaxel in a treatment setting relevant to Chinese practice. Notable design features include enrollment in China, use of toripalimab as the locally approved immune checkpoint inhibitor partner, inclusion of a broader PD-L1-positive population, and allowance for prior immune checkpoint inhibitor exposure in the curative setting. This trial may clarify the role of sacituzumab govitecan plus toripalimab in first-line PD-L1-positive advanced TNBC in China. TRIAL REGISTRATION: ClinicalTrials.gov, NCT07040644; URL: https://clinicaltrials.gov/study/NCT07040644.