Randomized trial of cemiplimab and fianlimab with neoadjuvant chemotherapy in early-stage high-risk HER2-negative breast cancer

Adding immune checkpoint inhibitors (ICIs) to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer. Dual checkpoint blockademight further enhance efficacy. In the randomized I-SPY2 trial, addition of cemiplimab (anti-PD-1) and fianlimab (anti-LAG-3) to neoadjuvant chemotherapy for stage II or III HER2-negative, high-risk breast cancer was evaluated. Patients received weekly paclitaxel for 12 weeks, then four cycles of doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, patients in the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks.The primary endpoint was pathologic complete response (pCR). A total of 78 participants were randomized to the intervention group, with 350 participants randomized to the historical control population. In all clinical signatures (defined by HR-status, TNBC, MammaPrint high and MammaPrint ultrahigh molecular risk) addition of PCF was associated with significantly improved pCR rates. PCF was highly effective in the subset of patients with immune signature positive status. The authors conclude that addition of PD-1 and LAG-3 inhibition to neoadjuvant chemotherapy warrant further investigation in HER2-negative breast cancer.