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

Radiotherapy has the potential to sensitize tumors to immune checkpoint blockade. A recent article published by Sundahl et al. in European Urology assessed the toxicity and efficacy of stereotactic body radiotherapy (SBRT) at different time points to patients who receive pembrolizumab for mUC.1 In this randomized phase 1 trial, the investigators enrolled 18 patients who received at least one dose of SBRT and at least one dose of pembrolizumab. Patients were randomly divided into two groups, arm A included patients who received SBRT before the first cycle of pembrolizumab and arm B who received SBRT before the third cycle of pembrolizumab.

The study showed that combining pembrolizumab and SBRT is safe. In arm A, 6/9 patients experienced grade 1-2 treatment-related adverse events. In arm B, all patients experienced grade 1-2 treatment-related adverse events, and one patient experienced grade 3 treatment-related lymphopenia. They were not able to assess the efficacy based on the timing of SBRT. The overall objective response in arm A was 0% and 44% in arm B, but the trial was not powered to detect efficacy between arms.

The investigators also examined the changes in circulating tumor DNA (ctDNA). They found that treatment response was associated with a decline in ctDNA fraction compared to the baseline in patients who experienced a response. This important study establishes the safety of combining pembrolizumab and SBRT. Additional studies are ongoing to define the optimal sequence, radiation doses, and drug combination to achieve maximal anti-tumor efficacy in metastatic UC patients. 

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

Reference:

1. Sundahl N, Vandekerkhove G, Decaestecker K, Meireson A, De Visschere P, Fonteyne V, De Maeseneer D, Reynders D, Goetghebeur E, Van Dorpe J, Verbeke S, Annala M, Brochez L, Van der Eecken K, Wyatt AW, Rottey S, Ost P. Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma. Eur Urol. 2019 May;75(5):707-711. doi: 10.1016/j.eururo.2019.01.009. Epub 2019 Jan 19.

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