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

Abstract

Background: Preclinical data indicates that stereotactic body radiotherapy (SBRT) works synergistically with pembrolizumab, but the effect and potential toxicity might depend on the timing of SBRT. The current study assessed the safety of two different SBRT schedules in combination with pembrolizumab for metastatic urothelial carcinoma (mUC), and explored correlative biomarkers including circulating tumor DNA (ctDNA). Methods: An open-label phase 1 trial was conducted at Ghent University Hospital in patients with mUC to assess the dose-limiting toxicity (DLT) of the combination of pembrolizumab (200mg intravenously, 3-weekly) and SBRT (3x8Gy to the largest lesion). Patients were randomized (1:1) to receive SBRT either prior to the first (arm A) or the third (arm B) cycle of pembrolizumab. Blood was collected throughout the trial for biomarker analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoints included best overall response measured per Response Evaluation Criteria in Solid Tumors v1.1 (RECISTv1.1). Findings: Between November 14, 2016 and January 2, 2018, eighteen patients were randomized (nine to each arm) and started trial treatment. No DLT occurred. Treatment-related AEs grade 1-2 occurred in 6/9 and 9/9 patients in arm A and B respectively. One patient in arm B experienced lymphopenia grade 3, unrelated to SBRT. No treatment-related AEs grade 4- 5 occurred. An objective response rate as per RECISTv1.1 of 0% and 44·4% was noted in arm A and B respectively. Targeted sequencing of tissue DNA and ctDNA revealed high genomic concordance. A decline in ctDNA was observed in responding patients. Interpretation Neo-adjuvant and concomitant SBRT combined with pembrolizumab is safe, with potentially superior responses in the latter. ctDNA monitoring is feasible during disease evolution. Clinical Trial Number: The trial is registered on ClinicalTrials.gov (NCT02826564), and is complete. Funding Statement: This trial was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. Declaration of Interests: NS reports travel grants from Merck Sharpe & Dohme, Astellas, Bayer and Bristol-Myers Squibb. KD reports travel grants from Ipsen, Astellas, and Ferring; and honorarium from Ipsen, Astellas, Intuitive Surgical, and Medtronic Belgium. VF report travel grants and honorarium from Ipsen and Astellas. DDM reports a research grant from Roche; travel grants from Roche, Pfizer, and Astellas; and honorarium from Bristol-Myers Squibb, Pfizer, Janssen, and Bayer. LB reports a travel grant and honorarium from Incyte Biosciences. AWW reports honorarium from Sanofi and Janssen and research grants from Janssen. SR reports a research grant from Roche; travel grants from Merck Sharpe & Dohme, Roche, Pfizer, Bristol-Myers Squibb; and honorarium from Merck Sharpe & Dohme, Bristol-Myers Squibb, Roche, and Pfizer. PO reports research grants from Merck Sharpe & Dohme, Astellas and Janssen; travel grants from Ipsen and Ferring Pharmaceuticals; and honorarium from Ferring and Bayer. All other authors declare no competing interests. Merck Sharpe & Dohme provided financial support and pembrolizumab for the present study. Ethics Approval Statement: The study protocol was approved by the Ethics Committee of Ghent University Hospital (EC2016/0661).