Tumor infiltrating lymphocytes as a predictor of adjuvant avelumab efficacy in patients with high-risk triple negative breast cancer.

Purpose: We aimed to investigate the prognostic and predictive value of tumor infiltrating lymphocytes (TILs) for adjuvant immunotherapy in high-risk early 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 two strata: Stratum A (primary surgery followed by adjuvant chemotherapy, defined at high risk based on pathological stage) and Stratum B (neoadjuvant chemotherapy followed by surgery without pathological complete response). TILs were centrally assessed on treatment-naive tumor samples (BSL-TILs) and on residual disease after neoadjuvant chemotherapy (RD-TILs, Stratum B). Residual cancer burden (RCB) was assessed in Stratum B. Survival endpoints were: disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). Results: BSL-TILs were available for 387 patients, 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-yr DDFS rates 92.0% 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 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 TILs-guided immunotherapy strategies in future trials