lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

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

85 Pages Posted: 11 Oct 2018

See all articles by Nora Sundahl

Nora Sundahl

Ghent University - Department of Radiation Oncology and Experimental Cancer Research

Gillian Vandekerkhove

University of British Columbia (UBC)

Karel Decaestecke

Ghent University

Annabel Meireson

Ghent University - Ghent University Hospital

Pieter De Visschere

Ghent University - Ghent University Hospital

Valérie Fonteyne

Ghent University - Department of Radiation Oncology and Experimental Cancer Research

Daan De Maeseneer

Ghent University - Ghent University Hospital

Dries Reynders

Ghent University - Department of Applied Mathematics and Computer Science

Els Goetghebeur

Ghent University - Department of Applied Mathematics and Computer Science

Jo Van Dorpe

Ghent University - Ghent University Hospital

Sofie Verbeke

Ghent University - Ghent University Hospital

Matti Annala

University of British Columbia (UBC)

Lieve Brochez

Ghent University - Ghent University Hospital

Kim Van der Eecken

Ghent University - Ghent University Hospital

Alexander W. Wyatt

University of British Columbia (UBC)

Sylvie Rottey

Ghent University - Ghent University Hospital

Piet Ost

Ghent University - Department of Radiation Oncology and Experimental Cancer Research

More...

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).

Keywords: metastatic urothelial carcinoma, checkpoint inhibitors, stereotactic body radiotherapy, phase 1 trial, pembrolizumab

Suggested Citation

Sundahl, Nora and Vandekerkhove, Gillian and Decaestecke, Karel and Meireson, Annabel and De Visschere, Pieter and Fonteyne, Valérie and De Maeseneer, Daan and Reynders, Dries and Goetghebeur, Els and Van Dorpe, Jo and Verbeke, Sofie and Annala, Matti and Brochez, Lieve and Van der Eecken, Kim and Wyatt, Alexander W. and Rottey, Sylvie and Ost, Piet, Randomized Phase 1 Trial of Pembrolizumab with Neo-Adjuvant Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma (July 10, 2018). Available at SSRN: https://ssrn.com/abstract=3263670 or http://dx.doi.org/10.2139/ssrn.3263670

Nora Sundahl (Contact Author)

Ghent University - Department of Radiation Oncology and Experimental Cancer Research ( email )

Belgium

Gillian Vandekerkhove

University of British Columbia (UBC)

2329 West Mall
Vancouver, British Columbia BC V6T 1Z4
Canada

Karel Decaestecke

Ghent University

Coupure Links 653
Gent, 9000
Belgium

Annabel Meireson

Ghent University - Ghent University Hospital

Belgium

Pieter De Visschere

Ghent University - Ghent University Hospital

Belgium

Valérie Fonteyne

Ghent University - Department of Radiation Oncology and Experimental Cancer Research

Belgium

Daan De Maeseneer

Ghent University - Ghent University Hospital

Belgium

Dries Reynders

Ghent University - Department of Applied Mathematics and Computer Science

Gent, 9000
Belgium

Els Goetghebeur

Ghent University - Department of Applied Mathematics and Computer Science

Gent, 9000
Belgium

Jo Van Dorpe

Ghent University - Ghent University Hospital

Belgium

Sofie Verbeke

Ghent University - Ghent University Hospital

Belgium

Matti Annala

University of British Columbia (UBC)

2329 West Mall
Vancouver, British Columbia BC V6T 1Z4
Canada

Lieve Brochez

Ghent University - Ghent University Hospital

Belgium

Kim Van der Eecken

Ghent University - Ghent University Hospital

Belgium

Alexander W. Wyatt

University of British Columbia (UBC)

2329 West Mall
Vancouver, British Columbia BC V6T 1Z4
Canada

Sylvie Rottey

Ghent University - Ghent University Hospital

Belgium

Piet Ost

Ghent University - Department of Radiation Oncology and Experimental Cancer Research

Belgium

Click here to go to TheLancet.com

Paper statistics

Abstract Views
192
Downloads
14