Multicenter phase 1b-2 biomarker study of adding radiotherapy to pembrolizumab before neoadjuvant chemotherapy for HER2-negative breast cancer

The multicenter phase 1b-2 PEARL trial in the United States assessed safety and immune biomarkers after preoperative radiation therapy (RT) and anti-PD1 therapy in stage I-III triple-negative breast cancer (TNBC, n=54) or HR-positive/HER2-negative breast cancer (n=12). All patients received one cycle of pembrolizumab followed by a second cycle plus RT and then neoadjuvant chemotherapy (NAC). The safety endpoint was met. The incidence of grade ≥ 3 toxicities was 41%. The pCR rate was 59.2%, 33.3%, and 54.4% for the TNBC, HR+/HER2-, andentire cohort, respectively. A total of 77.8% of TNBC and 41.6% of HR+/HER2- had a near pCR (RCB 0-1). The 3-year event-free survival (EFS) rate was 80%. In the entire cohort, PD-L1 expression increased after anti-PD1 (p=0.044) and anti-PD1/RT (p=0.009)) compared with baseline. In TNBC, adding RT to anti-PD1 significantly decreased tumor-infiltrating lymphocytes (TILs; p=0.014). Baseline TILs correlated with PD-L1 expression and TNFα. The authors conclude that preoperative RT with pembrolizumab is safe and results in high pCR rates and 3-year EFS. PD-L1 and TILs may be predictive biomarkers for preoperative anti-PD1/RT response.