A Randomized Phase 2 Trial of Pembrolizumab versus Pembrolizumab and Acalabrutinib in Patients with Platinum-Resistant Metastatic Urothelial Cancer - Beyond the Abstract

Pembrolizumab as a monotherapy PD-1 inhibitor for metastatic platinum-refractory urothelial cancer has a low objective response rate (ORR) of 21% (Keynote 045), and it was previously unclear to what extent myeloid-derived suppressor cells (MDSCs) suppressed T-cell activation to impact clinical responses in metastatic urothelial cancer. Preclinical studies inhibiting Bruton tyrosine kinase (BTK) in murine xenograft models inhibited MDSC growth and tumor growth, suggesting that BTK inhibition may reduce T-cell suppression.

We, therefore, conducted a randomized phase 2 clinical trial investigating the efficacy of concurrent administration of pembrolizumab and acalabrutinib, a highly selective and potent BTK inhibitor, compared to pembrolizumab alone. Our primary objectives were safety and ORR according to the RECIST 1.1 criteria, and our secondary endpoints included progression-free survival (PFS) and overall survival (OS). Of note, immune profiling was performed to analyze circulating monocytic MDSCs and T-cells in baseline and on-treatment specimens. A total of 75 patients were enrolled; 40 were treated with pembrolizumab (200mg intravenously every 3 weeks) plus acalabrutinib (100mg orally twice daily) and 35 were treated with pembrolizumab alone. The primary objective of ORR was not improved (20% for pembrolizumab-acalabrutinib versus 26% for pembrolizumab monotherapy).

Furthermore, the median PFS and median OS were 2.2 months (95% CI, 1.4-3.5 months) and 6.3 months (95% CI 3.6-12.3) with the combination cohort and 1.6 months (95% CI, 1.4-4.2 months) and 11.4 months (95% CI 5.7-21.1), respectively, with pembrolizumab alone. Regarding the observed adverse events (AEs), all patients but one experienced any grade AEs, and grade 3/4 occurring in ≥15% of patients included anemia (20%) with pembrolizumab and fatigue (23%), increased ALT (23%), UTI (18%), and anemia (18%) with combination treatment. Importantly, correlative studies evaluating circulating MDSCs showed that baseline MDSCs could not be associated directly with treatment response. However, one patient who had a complete response to treatment with pembrolizumab and acalabrutinib had high MDSCs at baseline that decreased on treatment, showing proof of principle of biomarker selection for potential future studies in metastatic urothelial cancer.

Written by: Tian Zhang, Michael R Harrison, Peter H O'Donnell, Ajjai S Alva, Noah M Hahn, Leonard J Appleman, Jeremy Cetnar, John M Burke, Mark T Fleming, Matthew I Milowsky, Amir Mortazavi, Neal Shore, Guru P Sonpavde, Emmett V Schmidt, Bojena Bitman, Veerendra Munugalavadla, Raquel Izumi, Priti Patel, Janet Staats, Cliburn Chan, Kent J Weinhold, Daniel J George
Duke Cancer Institute, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina., University of Chicago, Chicago, Illinois., University of Michigan Medical Center, Ann Arbor, Michigan., Johns Hopkins University, Baltimore, Maryland., University of Pittsburgh, Pittsburgh, Pennsylvania., Oregon Health and Science University Center for Health, Portland, Oregon., Rocky Mountain Cancer Centers, Aurora, Colorado., Virginia Oncology Associates, Norfolk, Virginia., Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina., Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Carolina Urologic Research Center, Myrtle Beach, South Carolina., Dana-Farber Cancer Institute, Boston, Massachusetts., Merck & Co, Inc, North Wales, Pennsylvania., Acerta Pharma (a member of the AstraZeneca group), South San Francisco, California., Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina., Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.


  1. Zhang T, Harrison MR, O'Donnell PH, et al. A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer [published online ahead of print, 2020 Aug 5]. Cancer. 2020;10.1002/cncr.33067. 
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