PMID- 32757302 OWN - NLM STAT- MEDLINE DCOM- 20210611 LR - 20210611 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 126 IP - 20 DP - 2020 Oct 15 TI - A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer. PG - 4485-4497 LID - 10.1002/cncr.33067 [doi] AB - BACKGROUND: Inhibition of the programmed cell death protein 1 (PD-1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation. METHODS: The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE-ST-005) was a randomized phase 2 trial evaluating the PD-1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum-refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells. RESULTS: Seventy-five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response [CR]) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in >/=15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment. CONCLUSIONS: Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on-treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T-cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue-based immune cell infiltration. CI - (c) 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. FAU - Zhang, Tian AU - Zhang T AUID- ORCID: 0000-0001-8914-3531 AD - Duke Cancer Institute, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina. FAU - Harrison, Michael R AU - Harrison MR AD - Duke Cancer Institute, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina. FAU - O'Donnell, Peter H AU - O'Donnell PH AUID- ORCID: 0000-0003-2650-0049 AD - University of Chicago, Chicago, Illinois. FAU - Alva, Ajjai S AU - Alva AS AD - University of Michigan Medical Center, Ann Arbor, Michigan. FAU - Hahn, Noah M AU - Hahn NM AD - Johns Hopkins University, Baltimore, Maryland. FAU - Appleman, Leonard J AU - Appleman LJ AD - University of Pittsburgh, Pittsburgh, Pennsylvania. FAU - Cetnar, Jeremy AU - Cetnar J AD - Oregon Health and Science University Center for Health, Portland, Oregon. FAU - Burke, John M AU - Burke JM AD - Rocky Mountain Cancer Centers, Aurora, Colorado. FAU - Fleming, Mark T AU - Fleming MT AD - Virginia Oncology Associates, Norfolk, Virginia. FAU - Milowsky, Matthew I AU - Milowsky MI AUID- ORCID: 0000-0002-8965-8129 AD - Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina. FAU - Mortazavi, Amir AU - Mortazavi A AD - Ohio State University Comprehensive Cancer Center, Columbus, Ohio. FAU - Shore, Neal AU - Shore N AD - Carolina Urologic Research Center, Myrtle Beach, South Carolina. FAU - Sonpavde, Guru P AU - Sonpavde GP AD - Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Schmidt, Emmett V AU - Schmidt EV AD - Merck & Co, Inc, North Wales, Pennsylvania. FAU - Bitman, Bojena AU - Bitman B AD - Acerta Pharma (a member of the AstraZeneca group), South San Francisco, California. FAU - Munugalavadla, Veerendra AU - Munugalavadla V AD - Acerta Pharma (a member of the AstraZeneca group), South San Francisco, California. FAU - Izumi, Raquel AU - Izumi R AD - Acerta Pharma (a member of the AstraZeneca group), South San Francisco, California. FAU - Patel, Priti AU - Patel P AD - Acerta Pharma (a member of the AstraZeneca group), South San Francisco, California. FAU - Staats, Janet AU - Staats J AD - Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina. FAU - Chan, Cliburn AU - Chan C AD - Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina. FAU - Weinhold, Kent J AU - Weinhold KJ AD - Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina. FAU - George, Daniel J AU - George DJ AD - Duke Cancer Institute, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina. AD - Duke Clinical Research Institute, Durham, North Carolina. LA - eng GR - Acerta Pharma, a member of the AstraZeneca group/ PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200805 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Benzamides) RN - 0 (Pyrazines) RN - DPT0O3T46P (pembrolizumab) RN - I42748ELQW (acalabrutinib) SB - IM CIN - Cancer. 2020 Oct 15;126(20):4446-4450. PMID: 32757318 MH - Aged MH - Antibodies, Monoclonal, Humanized/pharmacology/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use MH - Benzamides/pharmacology/*therapeutic use MH - Female MH - Humans MH - Immunotherapy MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Pyrazines/pharmacology/*therapeutic use MH - Urologic Neoplasms/*drug therapy PMC - PMC7590121 OTO - NOTNLM OT - immunotherapy OT - programmed cell death receptor 1 OT - protein kinase inhibitor OT - urologic neoplasms COIS- Tian Zhang reports research funding (to Duke) from AbbVie, Acerta, AstraZeneca, Janssen, Merck & Co, Inc, Merrimack, Novartis, OmniSeq, Pfizer, PGDx, Mirati, Regeneron, and Seattle Genetics; consulting/speaking for Exelixis, Genentech/Roche, Sanofi Aventis, and Genomic Health; consulting for AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Janssen, Merck, Pfizer, Pharmacyclics, Amgen, Seattle Genetics, MJH Life Sciences, and Sanofi Aventis; and stock ownership in/employment by Archimmune Therapeutics and Capio Biosciences (spouse). Michael R. Harrison reports research funding (to Duke) from Acerta Pharma, Astellas Pharma, Bristol-Myers Squibb, Clovis Oncology, Exelixis, Genentech, Janssen, Merck & Co, Inc, and Pfizer; personal fees from Bristol-Myers Squibb and Pfizer; and consulting/speaking for AstraZeneca, Bayer, Exelixis, Fujifilm, Genentech, and Janssen. Peter H. O'Donnell reports stock and other ownership interest in Allergan and PrescriptIQ; honoraria from Astellas Pharma, AstraZeneca, Atheneum Partners, Genentech/Roche, the Harrison Consulting Group, the Dedham Group, Schlesinger Associates, FirstWorld Publication, Health Advances, Inovio Pharmaceuticals, Janssen Biotech, Kantar Health, Merck & Co, Inc, OncLive, Parexel, Quintiles, and Seattle Genetics; a consulting or advisory role with Merck; research funding (to the University of Chicago) from Acerta Pharma, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, Janssen, Merck & Co, Inc, and Seattle Genetics; being named a coinventor on a pending patent for a genomic prescribing system for medication; travel/accommodation expenses from Genentech/Roche, Janssen, Merck & Co, Inc, and Seattle Genetics/Astellas Pharma; and other from Advance Medical, Janssen, Nektar, and the National Institutes of Health. Ajjai S. Alva reports consulting/advisory roles for Merck & Co, Inc, and AstraZeneca and research funding (to the University of Michigan Medical Center) from Clovis Oncology, Merck & Co, Inc, Bristol-Myers Squibb, AstraZeneca, Bayer, Progenics, Janssen, Genentech, Esanik, Ionis, and Prometheus. Noah M. Hahn reports research funding (to Johns Hopkins) from Acerta Pharma, Astex Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Incyte, Inovio, Merck & Co, Inc, Pieris, Principia Biopharma, and Seattle Genetics; consulting for AstraZeneca, Bristol-Myers Squibb, Champions Oncology, CicloMed, Ferring, Genentech/Roche, GlaxoSmithKline, Health Advances, Incyte, Inovio, Janssen, Merck & Co, Inc, Mirati Therapeutics, Pieris, Principia Biopharma, Seattle Genetics, TARIS Biomedical, and TransMed/Inteliquet; and honoraria from Bladder Cancer Academy and PierView. Leonard J. Appleman reports research funding (to the University of Pittsburgh) from Acerta Pharma, Agensys, Astellas Pharma, AVEO, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Eisai, Exelixis, Genentech/Roche, Inovio Pharmaceuticals, Lilly, Merck & Co, Inc, Novartis, Peloton Therapeutics, Pfizer, Amgen, Tokai, and Seattle Genetics. John M. Burke reports consulting for AbbVie, AstraZeneca, Bayer, Celgene/Juno, Gilead/Kite, Roche/Genentech, Seattle Genetics, and Tempus Labs; speaking for Seattle Genetics; and personal fees from Adaptive Biotechnologies, Verastem, and Bristol-Myers Squibb. Matthew I. Milowsky reports a consulting or advisory role for BioClin Therapeutics; has received research funding from Acerta Pharma, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Incyte, Inovio, Merck & Co, Inc, Pfizer, Roche/Genentech, Seattle Genetics, Mirati Pharmaceuticals, Boehringer Ingelheim, Constellation Pharmaceuticals, Jounce Therapeutics, Syndax, Innocrin Pharma, Medimmune, Cerulean Pharma, and X4 Pharmaceuticals; has received an honorarium (paid to his institution) from Asieris; and has received travel expenses from Roche/Genentech. Amir Mortazavi reports working on advisory boards for Debiopharm Group and Seattle Genetics and research funding from Acerta Pharma, Astellas Pharma, Bristol-Myers Squibb, Genentech, Merck & Co, Inc, Mirati Therapeutics, Novartis, Roche, and Seattle Genetics. Neal Shore reports research funding/consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Dendreon, Ferring, Genentech, Janssen, Merck & Co, Inc, Myovant, Nymox, Pfizer, Sanofi-Genzyme, and Tolmar. Guru P. Sonpavde is on advisory boards for Amgen, Astellas/Agensys, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech, Janssen, Merck & Co, Inc, Novartis, Pfizer, and Sanofi; reports consulting for Bicycle Therapeutics, the National Comprehensive Cancer Network, and Dava Oncology; has received research support for his institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Janssen, Merck & Co, Inc, Onyx-Amgen, Pfizer, and Sanofi; reports lecture fees for continuing medical education from Clinical Care Options; is an author for UpToDate; is on steering committees for AstraZeneca, Astellas, Bristol-Myers Squibb, Bavarian Nordic, QED, and Debiopharm Group; reports travel support for investigator meetings from Bristol-Myers Squibb; and is a speaker for OncLive, Physician Education Resource, and Research to Practice. Emmett V. Schmidt is an employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, and is a stockholder in Merck & Co, Inc. Bojena Bitman is an employee of Acerta Pharma, a member of the AstraZeneca group. Veerendra Munugalavadla is an employee of Acerta Pharma, a member of the AstraZeneca group, and owns stock in AstraZeneca and Gilead Sciences. Raquel Izumi is an employee of Acerta Pharma, a member of the AstraZeneca group; owns stock in AstraZeneca; and has a patent for acalabrutinib. Priti Patel is an employee of Acerta Pharma, a member of the AstraZeneca group, and owns stock in AstraZeneca. Daniel J. George reports research funding (to Duke) from Acerta Pharma, Astellas Pharma, Bayer, Bristol-Myers Squibb, Calithera, Dendreon, Exelixis, Innocrin, Janssen, Novartis, Pfizer, Sanofi, and Seattle Genetics; consulting and speaking for Bayer, Exelixis, and Sanofi; consulting for Astellas, AstraZeneca, Bristol-Myers Squibb, Capio Biosciences, Flatiron, Innocrin, Janssen, Merck & Co, Inc, Merck, Sharp & Dohme, Michael J Hennessey Associates, Modra Pharmaceuticals, Myovant Sciences, Vizuri Health Sciences, Physician Education Resource, and Pfizer; honoraria from Ipsen and UroGPO; honoraria and travel support from UroToday; membership on steering committees for Bristol-Myers Squibb, Nektar Therapeutics, and the National Cancer Institute; and other from American Association for Cancer Research, Axess Oncology, and Millennium Medical Publishing. The other authors made no disclosures. EDAT- 2020/08/07 06:00 MHDA- 2021/06/12 06:00 PMCR- 2020/10/27 CRDT- 2020/08/07 06:00 PHST- 2019/11/20 00:00 [received] PHST- 2020/02/17 00:00 [revised] PHST- 2020/03/24 00:00 [accepted] PHST- 2020/08/07 06:00 [pubmed] PHST- 2021/06/12 06:00 [medline] PHST- 2020/08/07 06:00 [entrez] PHST- 2020/10/27 00:00 [pmc-release] AID - CNCR33067 [pii] AID - 10.1002/cncr.33067 [doi] PST - ppublish SO - Cancer. 2020 Oct 15;126(20):4485-4497. doi: 10.1002/cncr.33067. Epub 2020 Aug 5.