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晚期三阴性乳腺癌一线免疫大结局
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2022.07.21 上海

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  免疫细胞程序性死亡受体PD-1及其配体PD-L1是重要的免疫检查点,可控制人体免疫细胞按照程序集体自杀。三阴性乳腺癌等恶性肿瘤细胞可刺激PD-1或PD-L1高表达,从而逃避人体免疫细胞攻击。593天前,国际四大医学期刊之一、英国《柳叶刀》正刊发表KEYNOTE-355研究中期分析结果,发现PD-1抑制剂帕博利珠单抗(可瑞达,俗称K药)显著改善PD-L1高表达晚期三阴性乳腺癌一线标准化疗患者的无进展生存。不过,当时尚未报告总生存最终分析结果。

KEYNOTE-355 (NCT02819518): A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer

  2022年7月21日,国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》发表西班牙巴塞罗那国际乳腺癌中心、马德里欧洲大学、美国默克、旧金山加利福尼亚大学综合癌症中心、加拿大多伦多大学玛格丽特公主癌症中心、韩国首尔大学医院癌症研究所、马来西亚吉隆坡班太医院癌症中心、智利阿图罗·洛佩兹·佩雷斯基金会肿瘤研究所、俄罗斯巴什科尔托斯坦共和国肿瘤医院、巴西南大河天主教大学圣卢卡斯医院、日本名古屋大学爱知癌症中心医院、哥伦比亚蒙特里亚肿瘤医院、土耳其埃格大学医学院、澳大利亚墨尔本大学彼得麦卡伦癌症中心、英国伦敦大学玛丽王后学院巴特癌症研究所的KEYNOTE-355研究最终分析结果,比较了晚期三阴性乳腺癌一线标准化疗±帕博利珠单抗的患者总生存和安全性。

  该国际多中心双盲安慰剂随机对照三期临床研究于2017年1月~2018年6月从29个国家地区209家医院入组局部复发不可手术或远处转移三阴性乳腺癌尚未治疗患者847例,按2∶1的比例随机分为两组:帕博利珠单抗+化疗组566例、安慰剂+化疗组281例,每3周给予帕博利珠单抗200毫克或安慰剂+研究者选择的化疗(白蛋白紫杉醇、紫杉醇或吉西他滨+卡铂)。主要终点为全部患者、肿瘤表达PD-L1且综合阳性评分≥10和≥1亚组患者的无进展生存(已报告)和总生存。综合阳性评分(CPS)定义为PD-L1染色阳性肿瘤细胞、淋巴细胞和巨噬细胞数量,除以存活肿瘤细胞总数,再乘以100。对实际治疗患者评定安全性。


  结果,中位随访44.1个月帕博利珠单抗+化疗组与安慰剂+化疗组相比,中位总生存:
  • CPS≥10亚组:23.0个月比16.1个月(死亡风险比:0.73,95%置信区间:0.55~0.95,双侧P=0.0185,满足统计学意义显著标准)
  • CPS≥1亚组:17.6个月比16.0个月(死亡风险比:0.86,95%置信区间:0.72~1.04,双侧P=0.1125,统计学意义不显著)
  • 全部患者:17.2个月比15.5个月(死亡风险比:0.89,95%置信区间:0.76~1.05,未检验统计学意义)


  对于实际治疗患者,帕博利珠单抗+化疗组562例与安慰剂+化疗组281例相比:
  • 不良事件发生率:98.6%比98.2%
  • 3~5级不良事件发生率:77.9%比73.7%
  • 治疗方案相关不良事件发生率:96.3%比95.0%
  • 3~5级治疗方案相关不良事件发生率:68.1%比66.9%
  • 免疫所致不良事件发生率:26.5%比6.4%
  • 3~5级免疫所致不良事件发生率:5.3%比0%
  • 治疗相关死亡率:0.4%比0%

  因此,该研究总生存最终分析结果表明,对于PD-L1高表达晚期三阴性乳腺癌,一线标准化疗±帕博利珠单抗相比,可显著延长患者总生存

  对此,法国斯特拉斯堡癌症研究所发表同期评论:帕博利珠单抗治疗乳腺癌的KEYNOTE-355研究结果不是渐进式的,而是颠覆式的,可以与2005年发表的曲妥珠单抗治疗HER2阳性乳腺癌结果相提并论。

相关链接


N Engl J Med. 2022 Jul 21;387(3):217-226.

Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer.

Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Perez-Garcia J, Iwata H, Masuda N, Torregroza Otero M, Gokmen E, Loi S, Guo Z, Zhou X, Karantza V, Pan W, Schmid P; KEYNOTE-355 Investigators.

International Breast Cancer Center, Pangaea Oncology, Quirónsalud Group, Barcelona; Universidad Europea de Madrid, Madrid, Spain; University of California San Francisco Comprehensive Cancer Center, San Francisco; Princess Margaret Cancer Centre, Toronto; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul; Cancer Center at Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; Oncology Institute, Arturo Lopez Perez Foundation, Santiago, Chile; Republican Clinical Oncology Dispensary, Ufa, Russia; Hospital Sao Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; Aichi Cancer Center Hospital; Nagoya University Graduate School of Medicine, Nagoya, Japan; Oncomedica, Montería, Colombia; Ege University Medical Faculty, Izmir, Turkey; Peter MacCallum Cancer Centre, Melbourne; University of Melbourne, Parkville, Australia; Merck, Rahway, NJ; Barts Cancer Institute, Queen Mary University of London, London.

Among patients with triple-negative breast cancer and high expression of PD-L1, pembrolizumab plus chemotherapy resulted in longer overall survival than chemotherapy alone.

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

FUNDING: Merck Sharp and Dohme

KEYNOTE-355 ClinicalTrials.gov number: NCT02819518

PMID: 35857659

DOI: 10.1056/NEJMoa2202809


N Engl J Med. 2022 Jul 21;387(3):273-274.

Pembrolizumab in the Treatment of Breast Cancer.

Pivot X.

Institute of Cancerology Strasbourg, Strasbourg, France.

PMID: 35857664

DOI: 10.1056/NEJMe2207532

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