Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma

Preclinical data indicate that radiotherapy works synergistically with pembrolizumab, but the effect and toxicity of this combination may depend on radiotherapy timing. We conducted a randomized phase 1 trial combining pembrolizumab with either sequential (A) or concomitant (B) stereotactic body radiotherapy (SBRT) in metastatic urothelial carcinoma (mUC). No dose-limiting toxicity occurred. Treatment-related adverse events (trAEs; Common Terminology Criteria for Adverse Events v4.0) of grade 1–2 occurred in six of nine and all nine patients in arms A and B, respectively. One grade 3 trAE occurred in arm B. No grade 4–5 trAEs occurred. Overall response rates of 0% and 44.4% were noted in arms A and B, respectively, as per Response Evaluation Criteria in Solid Tumors v1.1. The trial was not powered to compare efficacy between arms. Targeted sequencing of tissue DNA and circulating tumor DNA (ctDNA) revealed high genomic concordance. Treatment response was associated with ctDNA fraction decline. We conclude that sequential and concomitant SBRT can be safely combined with pembrolizumab in mUC and that the effect of SBRT timing on efficacy is worth exploring further. This study assessed the safety of pembrolizumab combined with radiotherapy at two different time points in metastatic bladder cancer. We conclude that the combination treatment was well tolerated. Pembrolizumab can safely be combined with stereotactic body radiotherapy (SBRT) both sequentially and concomitantly. With an objective response rate of 44.4%, concomitant SBRT seems most promising. Circulating tumor DNA fraction could serve as a surrogate for monitoring disease evolution.