International Breast Cancer Center, Quiron Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Princess Margaret Cancer Centre, Toronto, ON, Canada.
Lancet. 2020 Dec 5;396(10265):1817-1828. doi: 10.1016/S0140-6736(20)32531-9.
BACKGROUND: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing. FINDINGS: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25·9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26·3 months (22·7-29·7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9·7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0·65, 95% CI 0·49-0·86; one-sided p=0·0012 [primary objective met]). Median progression-free survival was 7·6 and 5·6 months (HR, 0·74, 0·61-0·90; one-sided p=0·0014 [not significant]) among patients with CPS of 1 or more and 7·5 and 5·6 months (HR, 0·82, 0·69-0·97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group. INTERPRETATION: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
背景：帕博利珠单抗单药治疗转移性三阴性乳腺癌患者具有持久的抗肿瘤活性和可管理的安全性。我们旨在研究在转移性三阴性乳腺癌患者中，帕博利珠单抗联合化疗是否会增强化疗的抗肿瘤活性。
方法：在这项在 29 个国家的 209 个地点进行的随机、安慰剂对照、双盲、3 期试验中，我们使用区块方法（区块大小为 6）和带有集成网络响应的交互式语音应答系统，以 2:1 的比例随机分配未经治疗的局部不可切除或转移性三阴性乳腺癌患者，接受帕博利珠单抗（200mg）每 3 周联合化疗（nab-紫杉醇；紫杉醇；或吉西他滨加卡铂）或安慰剂联合化疗。随机分组按研究化疗类型（紫杉烷类或吉西他滨-卡铂）、基线时 PD-L1 表达（综合阳性评分[CPS]≥1 或 <1）以及新辅助或辅助治疗中是否使用同一类化疗（是或否）分层。纳入标准包括年龄至少 18 岁，经中心确认为三阴性乳腺癌；至少有一个可测量的病变；提供新获得的肿瘤样本，由中心实验室通过免疫组织化学法确定三阴性乳腺癌状态和 PD-L1 状态；东部合作肿瘤学组体能状态评分为 0 或 1；以及有足够的器官功能。申办者、研究者、其他研究地点工作人员（未揭开面纱的药剂师除外）和患者对帕博利珠单抗与生理盐水安慰剂的给药情况均不知情。此外，申办者、研究者、其他研究地点工作人员和患者对患者水平肿瘤 PD-L1 生物标志物结果均不知情。主要疗效终点是在 PD-L1 CPS≥10、CPS≥1 和意向治疗人群中评估的无进展生存期和总生存期。无进展生存期的最终评估在此次中期分析中进行；正在继续随访以评估总生存期。对于无进展生存期，采用了分层检验策略，即首先在 CPS≥10 的患者中进行检验（本次中期分析的预设统计标准为α=0·00411），然后在 CPS≥1 的患者中进行检验（本次中期分析的α=0·00111，从 CPS≥10 的患者的无进展生存期中传递过来的部分α），最后在意向治疗人群中进行检验（本次中期分析的α=0·00111）。本研究在 ClinicalTrials.gov 注册，编号为 NCT02819518，正在进行中。
发现：2017 年 1 月 9 日至 2018 年 6 月 12 日，在筛选的 1372 名患者中，847 名患者被随机分配接受治疗，566 名患者接受帕博利珠单抗联合化疗，281 名患者接受安慰剂联合化疗。在第二次中期分析（数据截止日期为 2019 年 12 月 11 日）时，帕博利珠单抗联合化疗组的中位随访时间为 25.9 个月（IQR 22.8-29.9），安慰剂联合化疗组的中位随访时间为 26.3 个月（22.7-29.7）。在 CPS≥10 的患者中，帕博利珠单抗联合化疗组的中位无进展生存期为 9.7 个月，安慰剂联合化疗组为 5.6 个月（进展或死亡的风险比[HR]，0.65，95%CI 0.49-0.86；单侧 p=0.0012[主要目标达成]）。在 CPS≥1 的患者中，中位无进展生存期分别为 7.6 个月和 5.6 个月（HR，0.74，0.61-0.90；单侧 p=0.0014[不显著]），在意向治疗人群中，中位无进展生存期分别为 7.5 个月和 5.6 个月（HR，0.82，0.69-0.97[未测试]）。帕博利珠单抗治疗效果随 PD-L1 富集而增加。帕博利珠单抗联合化疗组和安慰剂联合化疗组 3-5 级治疗相关不良事件发生率分别为 68%和 67%，包括帕博利珠单抗联合化疗组死亡率<1%和安慰剂联合化疗组为 0%。
解释：帕博利珠单抗联合化疗在 PD-L1 CPS≥10 的转移性三阴性乳腺癌患者中与安慰剂联合化疗相比，显著改善了无进展生存期，具有显著的临床意义。这些发现表明，在转移性三阴性乳腺癌患者中，帕博利珠单抗联合标准化疗可能作为一线治疗方案。
资金来源：默克公司（Merck & Co., Inc. 的子公司）
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