ABSTRACT

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 RTwas conducted in patientswith triplenegative breast cancer (TNBC) and hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR1/HER2–) breast cancer. All received pembrolizumab followed by a second cycle 1 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 tumorinfiltrating 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 HR1/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, HR1/HER2–, and entire cohort, respectively. A total of 77.8% of TNBC and 41.6% of HR1/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 5 .044) and anti-PD1/RT (median CPS, 7.49-23.41; 95% CI, –41.88 to –6.30; P 5.009), 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 5 .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.