Phase 3 trial of tumor-infiltrating lymphocytes as predictor of adjuvant avelumab efficacy in high-risk triple-negative breast cancer

The multicenter phase 3 A-BRAVE trial in Italy investigated the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs) for adjuvant avelumab in high-risk early triple-negative breast cancer (TNBC). The trial randomized 466 patients with high-risk early TNBC to adjuvant avelumab of 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) or stratum B (neoadjuvant chemotherapy followed by surgery without pathologic complete response). TILs were centrally assessed on treatment-naïve tumor samples (baseline TILs; BSL-TILs) an on residual disease after neoadjuvant chemotherapy (RD-TILs) in stratum B. Survival endpoints were disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS). 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. Residual cancer burden (RCB) in stratum B was also independently prognostic. Avelumab improved outcomes only for patient with BSL-TILs ≥ 30%, particularly in stratum B (3-year rates of DDFS 92% versus 58.7% in high BSL-TILs and 70.4% versus 70.1% low BSL TILs; interaction p=0.019). Similar results were obtained for DFS and OS. RCB was not predictive for avelumab benefit. The authors conclude that TILs may predict benefit from adjuvant avelumab in early TNBC.