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Eur Urol. 2019 Jan 19. pii: S0302-2838(19)30010-7. doi: 10.1016/j.eururo.2019.01.009. [Epub ahead of print]

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

Author information

1
Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium. Electronic address: nora.sundahl@ugent.be.
2
Vancouver Prostate Centre, University of British Columbia, British Columbia, Canada; Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
3
Department of Urology, Ghent University Hospital, Ghent, Belgium.
4
Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Dermatology Research Unit, Ghent University Hospital, Ghent, Belgium.
5
Department of Radiology and Nuclear Medicine, Ghent University Hospital, Ghent, Belgium.
6
Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
7
Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
8
Department of Applied Mathematics, Computer Science and Statistics & Stat-Gent CRESCENDO Consortium, Ghent University, Ghent, Belgium.
9
Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Pathology, Ghent University Hospital, Ghent, Belgium.
10
Department of Pathology, Ghent University Hospital, Ghent, Belgium.
11
Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.

Abstract

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. PATIENT SUMMARY: 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.

KEYWORDS:

Checkpoint inhibitor; Circulating tumor DNA; Immunotherapy; Metastatic urothelial carcinoma; Precision oncology; Stereotactic body radiotherapy

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