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

确定早期三阴性乳腺癌的最佳放疗剂量和分割与术前免疫化疗相结合

• 批准号: 10512391
• 负责人: Dan Gabriel Duda
• 金额: $ 35.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512391
• 关键词: Adjuvant Chemotherapy; Adjuvant Therapy; American College of Radiology Imaging Network; Antibodies; Axilla; Biological; Biological Markers; Biopsy Specimen; Blood; Blood Vessels; Blood specimen; Breast; Breast Cancer Model; Breast Cancer Patient; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL13 gene; CXCL9 gene; CXCR3 gene; Catchment Area; Chemotherapy-Oncologic Procedure; Clinical Data; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Correlative Study; Cytometry; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Disease-Free Survival; Dose; Dose Fractionation; ERBB2 gene; Early treatment; Eastern Cooperative Oncology Group; Geography; Goals; High Endothelial Venule; Human; Immune checkpoint inhibitor; Immune response; Immunity; Immuno-Chemotherapy; Immunosuppression; Immunotherapy; In complete remission; Industry; Infiltration; Interferon Type II; Interleukin-2; Knowledge; Ligands; Lymphocyte; Lymphopenia; Malignant Neoplasms; Mammary Neoplasms; Molecular; Myeloid Cells; Neoadjuvant Therapy; Operative Surgical Procedures; PD-1 blockade; Pathologic; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Population; Positive Lymph Node; Protein Array; Publishing; RANTES; Radiation Dose Unit; Radiation therapy; Randomized; Residual Neoplasm; Resistance; Role; Signal Transduction; Specimen; Systemic Therapy; T cell infiltration; T-Lymphocyte; TNF gene; Testing; Tissue Sample; Tissues; Tumor Immunity; Tumor Tissue; Tumor-Infiltrating Lymphocytes; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; checkpoint therapy; chemokine; chemotherapy; cytokine; design; effector T cell; experience; immune cell infiltrate; improved; improved outcome; inhibitor therapy; innovation; insight; malignant breast neoplasm; multidisciplinary; neoplastic cell; novel; novel strategies; pembrolizumab; phase 2 study; phase III trial; pre-clinical; primary endpoint; randomized trial; randomized, clinical trials; responders and non-responders; response; standard of care; synergism; tertiary lymphoid organ; trafficking; treatment response; triple-negative invasive breast carcinoma; tumor; tumor-immune system interactions

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.

概括 我们的目标是开发一种新颖的方法来合理地纳入放射治疗（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 Keynote-522试验的结果，该试验测试了添加了免疫粘液抑制剂（ICI），， pembrolizumab，新辅助化疗（NAC），定义了早期TNBC的新护理标准， 基于改善病理的完整反应率和无事件生存率。尽管有这个突破， 大约35％的患者不会对pembrolizumab和NAC反应。这些“非反应者”代表 具有生物学侵略性，免疫疗法的TNBC的患者，为之克服的新策略 迫切需要抵抗免疫疗法。试点研究证明了 带有pembrolizumab的RT是安全的，并显示了TNBC效率的早期信号（NCT02730130， NCT03366844），与新标准Pembrolizomab/NAC方案结合的RT的最佳剂量 仍然不确定，阻碍了设计更大的临床试验以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：一项随机研究来产生这些知识 术前化学疗法，pembrolizumab和NO，低剂量辐射或高剂量辐射 癌症; NCT04443348）。我们的多学科团队将定义RT的最佳剂量 pembrolizumab通过新辅助pembrolizumab/nac测试不同剂量的RT（0GY，9GY和24GY） 在早期TNBC患者中。该研究旨在根据 在TNBC中与免疫化学疗法结合的背景下，RT对免疫调查的RT。这将是 通过在相关研究中对串行TNBC组织和血液样本的免疫申请研究实现。我们 建议对RT和Pembrolizumab/NAC之间相互作用的综合研究以揭示差异 在早期的局部和新型全身疗法的反应者和无反应者之间 TNBC。我们期望表明，重编程TNBC的免疫微环境将导致更大 免疫疗法的好处，并可能有助于选择可能从添加RT中受益的患者 pembrolizumab/nac。基于诱人的假设和引人注目的初步数据，可用性组织 地理TNBC集水区和行业支持的标本和患者，我们提出了这两个 综合目的：1）建立递送到初级乳房的RT增强剂量（0gy，9gy或24gy）的效果 肿瘤与pembrolizumab联合使用，然后是护理标准的pembrolizumab/NAC在病理上 节点阳性TNBC患者的完全反应（PCR）率，并且； 2）定义剂量依赖性效果 TNBC免疫微环境和全身免疫力的pembrolizumab/nac的RT。成功的 这项研究的完成将直接在大型第三阶段随机试验中对该方法进行测试，并 将通过改变术前RT在新时代的作用来促进范式转变 TNBC中的免疫化学疗法。