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

Duke University, Durham NC

Investigators

Abstract

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.