Defining Optimal Radiotherapy Dose and Fractionation in Combination with Preoperative Immuno-Chemotherapy in Early-Stage Triple Negative Breast Cancer

摘要 我们的目标是开发一种新的方法，合理地结合放射治疗(RT)，以改善 淋巴结阳性、三阴性乳腺癌(TNBC)患者的新辅助治疗成熟的 Keynote-522试验的结果，该试验测试了免疫检查点抑制剂(ICI)的添加， Pembrolizumab，到新辅助化疗(NAC)，定义了早期TNBC的新护理标准， 基于改善的病理完全应答率和无事件生存率。尽管取得了这一突破， 大约35%的患者对培溴利珠单抗和NAC没有反应。这些“无回应者”代表 患有生物侵袭性、免疫治疗耐药的TNBC的患者，对他们来说，新的策略可以克服 免疫治疗的抵抗力是迫切需要的。虽然试点研究已经证明了 Pembrolizumab的RT是安全的，并显示出对TNBC有效的早期信号(NCT02730130， NCT03366844)，RT与新标准Pembrolizomab/NAC方案联合使用的最佳剂量 仍然没有明确的定义，阻碍了设计更大的临床试验来测试这一令人信服的方法的进展。我们会 通过扩展我们正在进行的临床试验P-RAD：一项随机研究 术前化疗，Pembrolizumab和No，低或高剂量放射治疗结节阳性，HER2- 癌症；NCT04443348)。我们的多学科团队将确定要结合的最佳RT剂量 Pembrolizumab通过与新佐剂Pembrolizumab/NAC进行不同剂量的RT(0、9和24GyRT)试验 在早期TNBC患者中。这项研究的目的也是为了弥合知识差距方面的影响 RT联合免疫化疗对TNBC免疫反应的影响。这将是 通过相关研究中的系列TNBC组织和血液样本的免疫图谱研究实现。我们 建议对RT和Pembrolizumab/NAC之间的相互作用进行全面研究，以揭示差异 早期局部和新系统联合治疗的应答者和无应答者之间的关系 TNBC。我们希望证明，对TNBC的免疫微环境进行重新编程将导致更大的 有益于免疫治疗，并可能有助于选择可能从将RT添加到 培溴利珠单抗/NAC。基于诱人的假设和令人信服的初步数据，可用组织 样本和患者来自地理TNBC集水区和行业的支持，我们建议这两个 综合目标：1)建立放疗增强剂量(0Gy9Gy24Gy三种剂量)对原发乳腺的影响 肿瘤联合培溴利珠单抗和标准护理的培溴利珠单抗/NAC的病理学研究 结节阳性TNBC患者的完全应答率；以及；2)确定剂量依赖效应 培溴利珠单抗/NAC联合RT对TNBC免疫微环境和系统免疫的影响成功 这项研究的完成将直接为这一方法在大型III阶段随机试验中的测试提供信息 将通过转变术前放疗在新时代的作用来促进范式的转变 TNBC中的免疫化疗。

SUMMARY Our goal is to develop a novel approach to rationally incorporate radiotherapy (RT) to improve the outcome of neoadjuvant therapy in patients with lymph node positive, triple-negative breast cancer (TNBC). The mature results from the KEYNOTE-522 trial, which tested the addition of immune checkpoint inhibitor (ICI), pembrolizumab, to neoadjuvant chemotherapy (NAC), defined the new standard of care in early-stage TNBC, based on improved pathologic complete response rates and event-free survival. Despite this breakthrough, approximately 35% of patients will not respond to pembrolizumab and NAC. These “non-responders” represent patients with biologically aggressive, immunotherapy-resistant TNBC, for whom novel strategies to overcome immunotherapy resistance are desperately needed. While pilot studies have demonstrated the combination of RT with pembrolizumab to be safe and showed early signals of efficacy in TNBC (NCT02730130, NCT03366844), the optimal dose of RT to be combined with the new standard pembrolizomab/NAC regimen remains undefined, impeding progress in designing larger clinical trials to test this compelling approach. We will generate this knowledge through expanding our ongoing clinical trial, P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2– Cancer; NCT04443348). Our multidisciplinary team will define the optimal dose of RT to combine with pembrolizumab by testing the different doses of RT (0Gy, 9Gy and 24Gy) with neoadjuvant pembrolizumab/NAC in early-stage TNBC patients. The study is designed to also bridge the knowledge gap in terms of the effects of RT on immune responses in the context of combination with immuno-chemotherapy in TNBC. This will be achieved through immunoprofiling studies of serial TNBC tissue and blood samples in correlative studies. We propose comprehensive studies of the interplay between RT and pembrolizumab/NAC to reveal differences between responders and non-responders to this combined local and novel systemic therapy in early-stage TNBC. We expect to show that reprogramming the immune microenvironment of TNBC will result in greater benefit for immunotherapy and may help select patients that may optimally benefit from the addition of RT to pembrolizumab/NAC. Based on enticing hypotheses and compelling preliminary data, availability tissue specimens and patients from geographic TNBC catchment areas and industry support, we propose the two integrated aims: 1) To establish the effect of RT boost dose (0Gy, 9Gy or 24Gy) delivered to the primary breast tumor in combination with pembrolizumab followed by standard-of-care pembrolizumab/NAC on pathologic complete response (pCR) rates in node-positive TNBC patients, and; 2) To define the dose-dependent effects of RT with pembrolizumab/NAC on the TNBC immune microenvironment and systemic immunity. Successful completion of this study will directly inform the testing of this approach in a large, phase III randomized trial and will contribute to a paradigm shift by transforming the role of preoperative RT in the new era of immunochemotherapy in TNBC.