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合理结合放射治疗（RT）的新方法，以改善放疗的结果 淋巴结阳性、三阴性乳腺癌 (TNBC) 患者的新辅助治疗。 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， 派姆单抗与新辅助化疗 (NAC) 定义了早期 TNBC 的新护理标准， 尽管取得了这一突破，但基于改善的病理完全缓解率和无事件生存率， 大约 35% 的患者对派姆单抗和 NAC 没有反应，这些“无反应者”代表。 患有生物侵袭性、免疫治疗耐药的 TNBC 患者，需要新的策略来克服 迫切需要免疫治疗耐药性，而试点研究已经证明了两者的结合。 使用派姆单抗进行放疗是安全的，并且在 TNBC 中显示出疗效的早期信号（NCT02730130， NCT03366844)，与新标准 pembrolizomab/NAC 方案相结合的最佳放疗剂量 仍未定义，阻碍了设计更大规模的临床试验来测试这种令人信服的方法的进展。 通过扩大我们正在进行的临床试验 P-RAD：一项随机研究来生成这些知识 术前化疗、派姆单抗和无、低或高剂量放射治疗淋巴结阳性、HER2– 癌症；NCT04443348)。我们的多学科团队将确定与之相结合的最佳放疗剂量。 通过使用新辅助派姆单抗/NAC 测试不同剂量的 RT（0Gy、9Gy 和 24Gy）来检测派姆单抗 该研究旨在弥补早期 TNBC 患者的影响方面的知识差距。 放疗与免疫化疗联合治疗 TNBC 时的免疫反应。 我们通过相关研究中对连续 TNBC 组织和血液样本的免疫分析研究来实现。 RT 和 pembrolizumab/NAC 之间相互作用的综合提案研究揭示差异 早期阶段对这种局部和新型全身治疗相结合的治疗有反应者和无反应者之间的比较 我们希望证明，重新编程 TNBC 的免疫微环境将带来更大的效果。 免疫疗法的益处，并可能有助于选择可能从添加 RT 中获得最佳益处的患者 基于诱人的假设和令人信服的初步数据，可用组织。 来自地理 TNBC 集水区的标本和患者以及行业支持，我们建议这两个 综合目标： 1) 确定对主乳进行放疗加强剂量（0Gy、9Gy 或 24Gy）的效果 与 pembrolizumab 联合治疗肿瘤，然后根据病理学情况采用标准护理 pembrolizumab/NAC 淋巴结阳性 TNBC 患者的完全缓解 (pCR) 率，以及；2) 确定剂量依赖性效应 派姆单抗/NAC 的 RT 对 TNBC 免疫微环境和全身免疫的成功。 这项研究的完成将直接为在大型 III 期随机试验中测试该方法提供信息，并且 将通过改变术前放疗在新时代的作用来促进范式转变 TNBC 中的免疫化疗。