Tumor-Infiltrating Lymphocytes as a Predictor of Adjuvant Avelumab Efficacy in Patients with High-risk Triple-Negative Breast Cancer

Abstract Purpose: We aimed to investigate the prognostic and predictive value of tumor-infiltrating lymphocytes (TIL) for adjuvant immunotherapy in high-risk early triple-negative breast cancer (TNBC). Patients and Methods: The phase III A-BRAVE trial randomized 466 patients with high-risk early TNBC to adjuvant avelumab or observation after standard therapy. Inclusion criteria allowed 2 strata: stratum A (primary surgery followed by adjuvant chemotherapy, defined at high risk based on pathologic stage) and stratum B (neoadjuvant chemotherapy followed by surgery without pathologic complete response). TILs were centrally assessed on treatment-naïve tumor samples [baseline TILs (BSL-TIL)] and on residual disease (RD) after neoadjuvant chemotherapy (RD-TILs, stratum B). Residual cancer burden (RCB) was assessed in stratum B. Survival endpoints were disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS). Results: BSL-TILs were available for 387 patients and RD-TILs for 330 patients (290 with both BSL-TILs and RD-TILs). Higher BSL-TILs were independently associated with improved outcomes across all endpoints. In stratum B, higher RD-TILs showed a significant independent association with improved outcomes, outperforming BSL-TILs. RCB was also independently prognostic. Avelumab improved outcomes only for patients with BSL-TILs ≥30%, particularly in stratum B (3-year DDFS rates, 92% vs. 58.7%; HR, 0.20 in high BSL-TILs and 70.4% vs. 70.1%, HR, 0.92 in low BSL-TILs; interaction P = 0.019). Similar results were obtained for DFS and OS. RCB was not predictive for avelumab benefit. Conclusions: TILs may predict benefit from adjuvant immunotherapy in early TNBC. These findings warrant validation and support TIL-guided immunotherapy strategies in future trials.