Pembrolizumab

编者按：在2026年ESMO年会上，美国加利福尼亚州希望之城综合癌症中心Hope S. Rugo教授汇报了KEYNOTE-B49研究的IA（期中分析）与FA（最终分析）结果，结果显示，在PD-L1 CPS≥1的HR+/HER2-晚期乳腺癌（ABC）患者中，帕博利珠单抗联合化疗在无进展生存期（PFS）方面取得了统计学显著改善；在PD-L1 CPS≥10的患者亚组中，观察到该联合方案在PFS上的获益更为显著。此外，研究显示免疫联合组24个月时的PFS率实现了超三倍的提升，且整体安全性可控，这提示部分内分泌耐药且更具侵袭性的患者有望从免疫治疗中获益。基于此，肿瘤瞭望在ESMO年会现场特邀采访Hope S. Rugo教授，请她就KEYNOTE-B49研究的核心数据、特定亚组的临床获益以及PD-L1检测在临床实践中的指导意义进行了深入解读与分享。 《肿瘤瞭望》：您在本届ESMO年会上报告了KEYNOTE-B49研究的结果，请您就研究背景及研究数据进行介绍。 Hope S. Rugo 教授 美国加利福尼亚州希望之城综合癌症中心 我是美国加利福尼亚州希望之城综合癌症中心乳腺肿瘤内科医生，同时也是乳腺肿瘤内科主任。此次ESMO年会上，我汇报了KEYNOTE-B49研究的数据。这项研究在几年前启动，旨在评估帕博利珠单抗（pembro）+化疗（CT）对比安慰剂（pbo）+CT在PD-L1阳性HR+/HER2-ABC患者中的治疗疗效。研究入组了342例经中心检测的PD-L1 CPS≥1、既往接受过内分泌治疗（ET）且适合一线化疗的局部复发不可手术或转移性HR+/HER2-晚期乳腺癌患者。 在本研究人群中，PD-L1阳性定义为CPS≥1。由于入组缓慢且患者PD-L1阳性率较低，该试验的最终设计样本量从最初的800例修订为约340例。主要终点是盲态独立中心审查（BICR）评估的、PD-L1 CPS≥1患者的无进展生存期（PFS）。关键次要终点为CPS≥1患者总生存期（OS），其他次要终点包括CPS≥10患者的PFS/OS、ORR/DCR/DOR与安全性。 本次ESMO年会上我报告了该研究IA（期中）与FA（最终）两次分析结果，中位随访时间分别29.1个月（数据截止日期：2025年9月22日）与34.9个月（数据截止日期：2026年3月16日）。我们发现，该入组患者中大多数患者的PD-L1 CPS为1至9（占比78.9），而21.1%的患者CPS≥10，且PD-L1 CPS评分方面两组特征一致。 在PD-L1 CPS≥1的患者中，接受帕博利珠单抗联合化疗的患者，其PFS相比安慰剂联合化疗组取得了统计学显著的改善。期中分析（6.7 vs 6.0个月）和最终分析（6.7 vs 6.0个月）的风险比（HR）均为0.74，但中位PFS的绝对差异较短，仅为0.7个月。 在PD-L1 CPS≥10的人群中，我们看到了更大的差异，期中分析显示，两组中位PFS 为：7.5vs 4.4个月，HR 0.59（0.35-0.98），PFS获益更有利于帕博利珠单抗联合化疗组。不过，该亚组人群规模较小，仅占总体人群的21%，每组36例患者。 当我们观察PD-L1 CPS≥1患者的PFS时，可以明显看到有一部分患者的获益远超中位值所显示的水平。在PD-L1 CPS≥1的患者中，24个月时的PFS率提高了三倍以上（14.1% vs 3.5%），这确实非常引人注目。该亚组患者PFS率从不到5%提升到了约14%，即有14%的患者在24个月时仍未出现疾病进展，我们平时很少看到这样的数据。这确实表明，在HR阳性、内分泌难治性转移性疾病患者中，存在一部分PD-L1阳性（且在PD-L1≥10时更为显著）的患者，能够从标准化疗联合帕博利珠单抗中获益。 我们也评估了OS，但无论在PD-L1 CPS≥1还是PD-L1 CPS≥10的亚组中，均未观察到帕博利珠单抗+化疗组OS的显著获益。不过，当我们根据患者后续接受的挽救治疗进行校正后，HR确实降至了1以下（HR 0.94）。非常有趣的是，接受帕博利珠单抗的患者后续接受化疗或抗体偶联药物（ADC）的比例更低。在针对这一变量进行校正后，HR略有好转，但由于样本量极小，仍未达到统计学显著差异。 在副作用方面，甲状腺疾病是最常见的不良事件，包括免疫相关不良事件在内，我们并未观察到其他超出研究已知范围的不良反应。 因此，我认为这项研究就给我们带来的启示是：确实存在一部分能够获益的患者，尽管这是一个小亚组。这些患者必须是PD-L1阳性，并且在强阳性（即CPS≥10）患者中获益更为显著。我们尚不清楚ER表达低于10%的患者是否会有不同的反应，因为在本试验中该亚组人数极少。但我认为，对于那些看起来更具侵袭性、对内分泌治疗不太敏感的ER阳性、内分泌难治性转移性乳腺癌患者，评估其PD-L1状态非常重要，因为这些患者可能会从免疫治疗中获益。 上下滑动查看英文对话 I am Hope Rugo, a breast medical oncologist and director of the breast medical oncology division at the City of Hope Comprehensive Cancer Center in California, United States. Today I presented data from the Merck KEYNOTE-B49 trial. We started this trial some years ago to evaluate the benefit of adding pembrolizumab to treatment of physician's choice versus chemotherapy of physician's choice in patients with centrally defined PD-L1 positive, hormone receptor positive, endocrine-resistant, metastatic breast cancer who had not received previous chemotherapy for advanced disease. In this population, we found that the majority of patients—almost 80%—had a PD-L1 CPS of 1 to 9, whereas 21% had a PD-L1 CPS of 10 or more. We saw a statistically significant improvement in progression-free survival in patients with PD-L1 positive disease who received pembrolizumab plus chemotherapy versus chemotherapy and placebo. The hazard ratio was 0.74 in both the interim and final analyses, but the absolute difference in median PFS was short, at just 0.7 months (from 6 to 6.7 months). Pre-specified secondary endpoints, including the CPS population of 10 or more. There, we saw a greater difference with the hazard ratio down in the 0.5 range for progression-free survival, favoring pembrolizumab versus chemotherapy alone. However, this population was small, representing 21% of the overall population, with 36 patients in each arm. When we looked at the PD-L1≥1 patients and PFS, there was clearly a subset of patients who benefited more than what was indicated by the median. The PFS rate at 24 months more than tripled in patients with a PD-L1 CPS of one or greater, which is truly remarkable. The proportion of patients free from progression at 24 months went from under 5% to about 14%. We don't usually see that. This suggests that there is a subset of patients with PD-L1 positive disease—enhanced when the PD-L1 is 10 or more—who benefit from the addition of pembrolizumab to standard chemotherapy in HR-positive, endocrine-refractory, metastatic disease. We looked at overall survival, but there was no difference regardless of the subset evaluated. We did see a shift of the hazard ratio to less than one when we adjusted for subsequent therapy. It was interesting that patients who received pembrolizumab were less likely to get subsequent chemotherapy and less likely to get an antibody-drug conjugate. When we adjusted for that variable, the hazard ratio was a little better. Still, it was not statistically significant, given the very small numbers. There was no difference in side effects, including immune-related adverse events, compared to what we have seen in other studies. Thyroid disorders were the most common. So, I think what that leaves us with is the understanding that there is a small subset of patients who benefit. They must have PD-L1 defined disease, and the benefit is enhanced in patients with strongly PD-L1 positive disease, defined as a CPS of 10 or greater. We do not know whether patients with an ER of less than 10% would have responded differently, as this represented a very small subset in our trial. However, I think it is important for us to assess PD-L1 status in patients with ER-positive, endocrine-refractory, metastatic disease—patients who seem to have more aggressive, less endocrine-sensitive disease up front—because those patients may benefit from immunotherapy. Hope S. Rugo 教授 希望之城女性癌症项目主任、乳腺肿瘤内科主任、医学肿瘤学与治疗学研究系教授 美国临床肿瘤学会（ASCO) 委员 乳腺癌转化研究联盟 (TBCRC）成员 联盟（前CALGB）乳腺委员会成员 随机Ⅱ期I-SPY2药物实验安全委员会主席 乳腺癌研究基金会（BCRF）资助的多中心免疫治疗临床研究首席研究员 （来源：《肿瘤瞭望》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

■60例患者入组已完成；初步结果预计于2027年上半年公布，为3期试验给药方案提供依据。 ■天演药业继续保留Muzastotug的全球商业化权利。 天演药业昨日宣布， 其抗CTLA-4 SAFEbody ® 安全抗体Muzastotug（ADG126）联合默沙东抗PD-1疗法KEYTRUDA ® （帕博利珠单抗）， 用于治疗后线无肝转移的MSS CRC （微卫星稳定型结直肠癌） 患者的随机2期剂量优化临床试验已完成患者入组。