PEARL: A Phase Ib/II Biomarker Study of Adding Radiation Therapy to Pembrolizumab Before Neoadjuvant Chemotherapy in Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer

PURPOSE To assess safety and immune biomarkers after preoperative radiation therapy (RT) and anti-PD1 therapy in breast cancer. MATERIALS AND METHODS A phase I/IIb trial of pembrolizumab with RT was conducted in patients with triple-negative breast cancer (TNBC) and hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer. All received pembrolizumab followed by a second cycle + RT (anti-PD1/RT) of 24 Gy/three daily fractions delivered to the breast tumor and then neoadjuvant chemotherapy (NAC). Blood and tumor biopsies were obtained at baseline, after anti-PD1, and after anti–PD-RT. Coprimary end points were safety and change in tumor-infiltrating lymphocytes (TILs). Secondary end points were pathologic complete response (pCR), residual cancer burden (RCB) rates, and event-free survival (EFS). RESULTS Sixty-six patients with stage I-III breast cancer (54 TNBC, 12 HR+/HER2–) were enrolled. The median follow-up was 32 months. Safety end point was met. Incidence of grade ≥3 toxicities was 41%. The pCR rate was 59.2%, 33.3%, and 54.5% for the TNBC, HR+/HER2–, and entire 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 EFS was 80%. In the entire cohort, PD-L1 expression increased after anti-PD1 (median Combined Positive Score CPS, 7.49-23.20; 95% CI, –41.88 to –6.30; P = .044) and anti-PD1/RT (median CPS, 7.49-23.41; 95% CI, –41.88 to –6.30; P = .009), compared with baseline. In TNBC, adding RT to anti-PD1 significantly decreased TILs (28.9%-17.1%; 95% CI, 2.46 to 21.09; P = .014). Baseline TILs correlated with PD-L1 expression and TNF-a. CONCLUSION Preoperative RT with pembrolizumab is safe and results in high pCR rates and 3-year EFS, despite the lack of pembrolizumab during NAC. PD-L1 and TILs may be predictive biomarkers for preoperative anti-PD1/RT response. Reduction in TILs after adding RT to anti-PD1 highlights the importance of treatment sequencing.