From the International Breast Cancer Center, Pangaea Oncology, Quirónsalud Group, Barcelona (J.C., J.P.-G.), and the Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid (J.C.) - both in Spain; the Department of Medicine, University of California San Francisco Comprehensive Cancer Center, San Francisco (H.S.R.); Princess Margaret Cancer Centre, Toronto (D.W.C.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul (S.-A.I.); Cancer Center at Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia (M.M.Y.); the Oncology Institute, Arturo Lopez Perez Foundation, Santiago, Chile (C.G.); the Department of Oncology, Republican Clinical Oncology Dispensary, Ufa, Russia (O.L.); the Oncology Research Unit, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil (C.H.B.); the Department of Breast Oncology, Aichi Cancer Center Hospital (H.I.), and the Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine (N.M.) - both in Nagoya, Japan; the Department of Hematology and Oncology, Oncomedica, Montería, Colombia (M.T.O.); Ege University Medical Faculty, Izmir, Turkey (E.G.); the Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville - both in Australia (S.L.); Merck, Rahway, NJ (Z.G., X.Z., V.K., W.P.); and the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London (P.S.).
N Engl J Med. 2022 Jul 21;387(3):217-226. doi: 10.1056/NEJMoa2202809.
In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported.
We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed.
A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group.
Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.).
在这项 3 期试验的中期分析中，与接受化疗的患者相比，在肿瘤 PD-L1 表达（综合阳性评分[CPS]≥10）的晚期三阴性乳腺癌患者中，接受帕博利珠单抗联合化疗的患者无进展生存期更长（CPS 表示 PD-L1 染色的肿瘤细胞、淋巴细胞和巨噬细胞数量与总存活肿瘤细胞数量的比值乘以 100）。总生存的最终分析结果尚未报道。
我们将未经治疗的局部复发不可切除或转移性三阴性乳腺癌患者按 2:1 的比例随机分为两组，分别接受帕博利珠单抗（200mg）每 3 周一次联合研究者选择的化疗（纳米白蛋白结合紫杉醇、紫杉醇或吉西他滨-卡铂）或安慰剂联合化疗。主要终点为无进展生存期（此前报道）和肿瘤 PD-L1 表达 CPS≥10 的患者（CPS-10 亚组）、肿瘤 PD-L1 表达 CPS≥1 的患者（CPS-1 亚组）以及意向治疗人群的总生存期。还评估了安全性。
共有 847 例患者接受了随机分组：566 例患者被分配至帕博利珠单抗-化疗组，281 例患者被分配至安慰剂-化疗组。中位随访时间为 44.1 个月。在 CPS-10 亚组中，帕博利珠单抗-化疗组的中位总生存期为 23.0 个月，安慰剂-化疗组为 16.1 个月（死亡风险比，0.73；95%置信区间[CI]，0.55 至 0.95；双侧 P=0.0185[达到显著标准]）；在 CPS-1 亚组中，两组的中位总生存期分别为 17.6 和 16.0 个月（风险比，0.86；95%CI，0.72 至 1.04；双侧 P=0.1125[未达到显著标准]）；在意向治疗人群中，两组的中位总生存期分别为 17.2 和 15.5 个月（风险比，0.89；95%CI，0.76 至 1.05[未进行显著性检验]）。帕博利珠单抗-化疗组和安慰剂-化疗组分别有 68.1%和 66.9%的患者发生与试验方案相关的 3 级、4 级或 5 级不良事件，包括 0.4%的帕博利珠单抗-化疗组患者和无患者的安慰剂-化疗组死亡。
在肿瘤 PD-L1 表达 CPS≥10 的晚期三阴性乳腺癌患者中，与单独化疗相比，帕博利珠单抗联合化疗可显著延长总生存期。（由默克公司资助；KEYNOTE-355 临床试验.gov 编号，NCT02819518。）
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