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

总结 我们的目标是开发一种新的方法，合理地结合放射治疗（RT），以改善预后， 在淋巴结阳性、三阴性乳腺癌（TNBC）患者中的新辅助疗法。成熟 来自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， 帕博利珠单抗，新辅助化疗（NAC），定义了早期TNBC的新护理标准， 基于病理完全缓解率和无事件生存率的改善。尽管取得了这一突破， 大约35%的患者对派姆单抗和NAC没有反应。这些“无应答者”代表 患有生物侵袭性、免疫治疗耐药TNBC的患者， 迫切需要免疫疗法的抵抗力。虽然试点研究表明， 用派姆单抗进行RT是安全的，并且在TNBC中显示出有效性的早期信号（NCT 02730130， NCT 03366844），RT与新标准派姆单抗/NAC方案联合的最佳剂量 仍然不明确，阻碍了设计更大的临床试验来测试这种引人注目的方法的进展。我们将 通过扩大我们正在进行的临床试验，P-RAD：一项随机研究， 术前化疗、派姆单抗和无、低或高剂量放射治疗淋巴结阳性、HER 2- 癌症; NCT 04443348）。我们的多学科团队将确定RT的最佳剂量，以联合收割机与 通过测试不同剂量的RT（0 Gy、9 Gy和24 Gy）与新辅助pembrolizumab/NAC 早期TNBC患者。这项研究的目的也是为了弥合知识差距方面的影响， RT在TNBC中与免疫化疗组合的背景下对免疫应答的影响。这将是 通过在相关研究中对系列TNBC组织和血液样品的免疫谱研究来实现。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 在早期阶段，这种联合局部和新型全身治疗的应答者和非应答者之间 TNBC。我们期望表明，重新编程TNBC的免疫微环境将导致更大的免疫应答。 有利于免疫治疗，并可能有助于选择可能最佳受益于RT的患者， 派姆单抗/NAC。基于诱人的假设和令人信服的初步数据， 标本和病人从地理TNBC集水区和行业的支持，我们建议这两个 综合研究目的：1）确定乳腺放疗加强剂量（0 Gy、9 Gy、24 Gy）的效果 肿瘤联合派姆单抗，随后标准治疗派姆单抗/NAC治疗病理学 淋巴结阳性TNBC患者的完全缓解（pCR）率; 2）定义剂量依赖性效应 RT与派姆单抗/NAC对TNBC免疫微环境和全身免疫的影响。成功 这项研究的完成将直接为在一项大型III期随机试验中测试这种方法提供信息， 将通过改变术前RT在新时代的作用， 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.