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.
Trial registration: ClinicalTrials.gov NCT03366844.