A Phase II Study of Biomarker-Guided De-escalation Using Anthracycline-Free Neoadjuvant Chemoimmunotherapy in Early-Stage Triple Negative Breast Cancer (TNBC) Patients With High Tumor-Infiltrating Lymphocytes (TILs)

NeoTILs is a single-arm, single-institution phase II non-inferiority trial evaluating a 12-week neoadjuvant regimen of carboplatin, paclitaxel, and pembrolizumab (CPP) in patients with early-stage (anatomic Stage II to IIIB) triple negative breast cancer whose tumors show high tumor-infiltrating lymphocytes (TILs), defined as TILs of 30 percent or greater on a digitized hematoxylin and eosin slide from the diagnostic biopsy, assessed centrally. The trial tests whether the pathologic complete response (pCR) rate achieved with this anthracycline-free neoadjuvant regimen is not significantly inferior to the historical pCR rate of 65 percent reported with the KEYNOTE-522 regimen in a comparable TIL-enriched population. Following pre-screening consent and confirmation of high TIL status, eligible patients are formally consented and enrolled. All patients receive 12 weeks of neoadjuvant CPP, with anthracycline omitted entirely from the neoadjuvant phase, followed by definitive surgery. Treatment after surgery is determined by pathologic response, making this a response-adapted design. Patients who achieve pCR continue pembrolizumab alone to complete a total of nine doses and never receive anthracycline chemotherapy. Patients with residual invasive disease in the breast or axillary lymph nodes receive adjuvant doxorubicin and cyclophosphamide together with continued pembrolizumab for four cycles, consistent with current standard of care, and also complete the planned nine total doses of pembrolizumab. Additional adjuvant therapy, including olaparib for patients with germline BRCA1 or BRCA2 mutations and capecitabine for residual disease, may be given at the treating physician's discretion. The trial uses a group sequential design with a planned futility analysis at 50 percent information (n1 = 25) and a maximum sample size of 50 evaluable patients if the futility boundary is not crossed, out of an anticipated screening population of approximately 150 patients. Continuous safety monitoring begins with the sixth patient enrolled, with significant safety events defined as grade 3 or 4 adverse events or serious adverse events, or a surgical delay of more than 12 weeks, judged definitely or probably related to the neoadjuvant regimen. The primary endpoint is pCR rate. Secondary endpoints include three-year event-free survival, three- and five-year overall survival, treatment-related toxicity, incidence of chemotherapy-induced peripheral neuropathy, and patient-reported quality of life measured with the EORTC QLQ-C30 and QLQ-CIPN20 at baseline, end of neoadjuvant therapy, and 6 and 12 months post-treatment. Exploratory endpoints include near-pCR rate (residual cancer burden 0 or 1), radiographic response, and correlation of baseline and on-treatment TIL levels, PD-L1 expression, and circulating tumor DNA dynamics with pathologic response and long-term survival outcomes. Patients are followed for a minimum of five years for event-free and overall survival.