PMID- 34428076
OWN - NLM
STAT- MEDLINE
DCOM- 20211129
LR  - 20221207
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 39
IP  - 28
DP  - 2021 Oct 1
TI  - Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as 
      Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive 
      Bladder Cancer.
PG  - 3140-3148
LID - 10.1200/JCO.21.01003 [doi]
AB  - PURPOSE: To evaluate the safety and efficacy of gemcitabine and cisplatin in 
      combination with the immune checkpoint inhibitor pembrolizumab as neoadjuvant 
      therapy before radical cystectomy (RC) in muscle-invasive bladder cancer. 
      METHODS: Patients with clinical T2-4aN0/XM0 muscle-invasive bladder cancer 
      eligible for RC were enrolled. The initial six patients received lead-in 
      pembrolizumab 200 mg once 2 weeks prior to pembrolizumab 200 mg once on day 1, 
      cisplatin 70 mg/m(2) once on day 1, and gemcitabine 1,000 mg/m(2) once on days 1 
      and 8 every 21 days for four cycles. This schedule was discontinued for toxicity 
      and subsequent patients received cisplatin 35 mg/m(2) once on days 1 and 8 
      without lead-in pembrolizumab. The primary end point was pathologic downstaging 
      (< pT2N0) with null and alternative hypothesis rates of 35% and 55%, 
      respectively. Secondary end points were toxicity including patient-reported 
      outcomes, complete pathologic response (pT0N0), event-free survival, and overall 
      survival. Association of pathologic downstaging with programmed cell death ligand 
      1 staining was explored. RESULTS: Thirty-nine patients were enrolled between June 
      2016 and March 2020 (72% cT2, 23% cT3, and 5% cT4a). Patients received a median 
      of four cycles of therapy. All patients underwent RC except one who declined. 
      Twenty-two of 39 patients (56% [95% CI, 40 to 72]) achieved < pT2N0 and 14 of 39 
      (36% [95% CI, 21 to 53]) achieved pT0N0. Most common adverse events (AEs) of any 
      grade were thrombocytopenia (74%), anemia (69%), neutropenia (67%), and 
      hypomagnesemia (67%). One patient had new-onset type 1 diabetes mellitus with 
      ketoacidosis related to pembrolizumab and no patients required steroids for 
      immune-related AEs. Clinicians consistently under-reported AEs when compared with 
      patients. CONCLUSION: Neoadjuvant gemcitabine and cisplatin plus pembrolizumab 
      met its primary end point for improved pathologic downstaging and was generally 
      safe. A global study of perioperative chemotherapy plus pembrolizumab or placebo 
      is ongoing.
FAU - Rose, Tracy L
AU  - Rose TL
AUID- ORCID: 0000-0003-1411-2487
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Division of Oncology, Department of Medicine, University of North Carolina at 
      Chapel Hill, Chapel Hill, NC.
FAU - Harrison, Michael R
AU  - Harrison MR
AUID- ORCID: 0000-0003-3776-8892
AD  - Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke 
      University, Durham, NC.
FAU - Deal, Allison M
AU  - Deal AM
AUID- ORCID: 0000-0003-3526-3938
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
FAU - Ramalingam, Sundhar
AU  - Ramalingam S
AD  - Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke 
      University, Durham, NC.
FAU - Whang, Young E
AU  - Whang YE
AUID- ORCID: 0000-0002-1621-6661
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Division of Oncology, Department of Medicine, University of North Carolina at 
      Chapel Hill, Chapel Hill, NC.
FAU - Brower, Blaine
AU  - Brower B
AD  - Division of Oncology, Department of Medicine, University of North Carolina at 
      Chapel Hill, Chapel Hill, NC.
FAU - Dunn, Mary
AU  - Dunn M
AD  - Division of Oncology, Department of Medicine, University of North Carolina at 
      Chapel Hill, Chapel Hill, NC.
AD  - Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, 
      NC.
FAU - Osterman, Chelsea K
AU  - Osterman CK
AUID- ORCID: 0000-0001-7101-7262
AD  - Division of Oncology, Department of Medicine, University of North Carolina at 
      Chapel Hill, Chapel Hill, NC.
FAU - Heiling, Hillary M
AU  - Heiling HM
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
FAU - Bjurlin, Marc A
AU  - Bjurlin MA
AUID- ORCID: 0000-0003-3500-8849
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, 
      NC.
FAU - Smith, Angela B
AU  - Smith AB
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, 
      NC.
FAU - Nielsen, Matthew E
AU  - Nielsen ME
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, 
      NC.
FAU - Tan, Hung-Jui
AU  - Tan HJ
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, 
      NC.
FAU - Wallen, Eric
AU  - Wallen E
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, 
      NC.
FAU - Woods, Michael E
AU  - Woods ME
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Department of Urology, Loyola University Medical Center, Maywood, IL.
FAU - George, Daniel
AU  - George D
AUID- ORCID: 0000-0003-1499-7203
AD  - Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke 
      University, Durham, NC.
FAU - Zhang, Tian
AU  - Zhang T
AUID- ORCID: 0000-0001-8914-3531
AD  - Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke 
      University, Durham, NC.
FAU - Drier, Anthony
AU  - Drier A
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
FAU - Kim, William Y
AU  - Kim WY
AUID- ORCID: 0000-0001-7922-2156
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Division of Oncology, Department of Medicine, University of North Carolina at 
      Chapel Hill, Chapel Hill, NC.
FAU - Milowsky, Matthew I
AU  - Milowsky MI
AUID- ORCID: 0000-0002-8965-8129
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC.
AD  - Division of Oncology, Department of Medicine, University of North Carolina at 
      Chapel Hill, Chapel Hill, NC.
LA  - eng
SI  - ClinicalTrials.gov/NCT02690558
GR  - K08 CA248967/CA/NCI NIH HHS/United States
GR  - R01 CA241810/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20210824
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0W860991D6 (Deoxycytidine)
RN  - DPT0O3T46P (pembrolizumab)
RN  - Q20Q21Q62J (Cisplatin)
RN  - 0 (Gemcitabine)
SB  - IM
CIN - J Urol. 2022 Nov;208(5):1158-1159. PMID: 35984094
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal, Humanized/*administration & dosage/adverse effects
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse 
      effects
MH  - Chemotherapy, Adjuvant
MH  - Cisplatin/*administration & dosage/adverse effects
MH  - *Cystectomy/adverse effects/mortality
MH  - Deoxycytidine/administration & dosage/adverse effects/*analogs & derivatives
MH  - Disease Progression
MH  - Female
MH  - Humans
MH  - Immune Checkpoint Inhibitors/*administration & dosage/adverse effects
MH  - Male
MH  - Middle Aged
MH  - *Neoadjuvant Therapy/adverse effects
MH  - Neoplasm Invasiveness
MH  - Neoplasm Staging
MH  - Progression-Free Survival
MH  - Time Factors
MH  - Urinary Bladder Neoplasms/mortality/pathology/*therapy
MH  - Gemcitabine
PMC - PMC8478388
COIS- Tracy L. RoseResearch Funding: Roche/Genentech, GeneCentric, Bristol Myers 
      Squibb, Merck, AstraZeneca Michael R. HarrisonConsulting or Advisory Role: Bayer, 
      Exelixis, Genentech, Fujifilm, Janssen Oncology, AstraZeneca, Pfizer, Bristol 
      Myers SquibbSpeakers' Bureau: Genentech, ExelixisResearch Funding: Bristol Myers 
      Squibb, Genentech, Pfizer, Merck, Clovis Oncology, Acerta Pharma, AstraZeneca, 
      Astellas Pharma, Bayer, Exelixis, Seattle Genetics Sundhar RamalingamHonoraria: 
      Bayer Young E. WhangResearch Funding: Astellas Pharma, Clovis Oncology, 
      Constellation Pharmaceuticals, Amgen, Regeneron, Arvinas Blaine BrowerConsulting 
      or Advisory Role: Seattle Genetics/AstellasTravel, Accommodations, Expenses: 
      Seattle Genetics/Astellas Marc A. BjurlinHonoraria: Intuitive Surgical Angela B. 
      SmithConsulting or Advisory Role: Merck, Photocure, Urogen Pharma, Fergene, Ambu 
      Matthew E. NielsenStock and Other Ownership Interests: Grand Rounds Health Eric 
      WallenStock and Other Ownership Interests: MDxHealth Daniel GeorgeLeadership: 
      Capio BioSciencesHonoraria: Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, 
      UroToday, Acceleron Pharma, American Association for Cancer Research, Axess 
      Oncology, Janssen Oncology, Millennium Medical PublishingConsulting or Advisory 
      Role: Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol 
      Myers Squibb, Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, 
      AstraZeneca, Michael J. Hennessy Associates, Constellation Pharmaceuticals, 
      Physicans' Education Resource, Propella Therapeutics, RevHealth LLCSpeakers' 
      Bureau: Sanofi, Bayer, ExelixisResearch Funding: Exelixis, Janssen Oncology, 
      Novartis, Pfizer, Astellas Pharma, Bristol Myers Squibb, Acerta Pharma, Bayer, 
      Dendreon, Innocrin Pharma, Calithera Biosciences, Sanofi/AventisTravel, 
      Accommodations, Expenses: Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen 
      Oncology, UroToday Tian ZhangLeadership: Capio BioSciences, Archimmune 
      TherapeuticsStock and Other Ownership Interests: Capio Biosciences, Archimmune 
      Therapeutics, NanoroboticsHonoraria: Exelixis, Genentech/Roche, MJH Life 
      Sciences, Pacific GenuityConsulting or Advisory Role: Janssen, Genentech/Roche, 
      Sanofi, Exelixis, AstraZeneca, Pfizer, Bristol Myers Squibb, Foundation Medicine, 
      Pharmacyclics, Amgen, Merck, Seattle Genetics, Dendreon, Calithera 
      BiosciencesSpeakers' Bureau: Exelixis, Genentech/Roche, Genomic Health, 
      Sanofi/AventisResearch Funding: Janssen, Acerta Pharma, Pfizer, Merrimack, Stem 
      CentRx, Novartis, OmniSeq, Personal Genome Diagnostics, Regeneron, Merck, Mirati 
      Therapeutics, Astellas PharmaPatents, Royalties, Other Intellectual Property: 
      Circulating tumor cell novel capture by c-MET technology, Prochelators as 
      Targeted Prodrugs for Prostate CancerTravel, Accommodations, Expenses: Acerta 
      Pharma, Genomic Health, AstraZeneca Anthony DrierEmployment: Docs Global William 
      Y. KimLeadership: Advanced Chemotherapy TechnologiesStock and Other Ownership 
      Interests: Johnson & Johnson, Bristol Myers Squibb, Kura Oncology, BeiGene, 
      FibroGen, Amgen, AbbVie, G1 Therapeutics, Spectrum Pharmaceuticals, Illumina, 
      Arvinas, Fibrogen, NantWorks, Oramed, Natera, ZentalisHonoraria: Takeda, H3 
      BiomedicineConsulting or Advisory Role: GeneCentric, Foundation MedicineResearch 
      Funding: Merck, GeneCentric, Foundation MedicinePatents, Royalties, Other 
      Intellectual Property: BASE47 bladder cancer subtype classifier, PurIST (Purity 
      Independent Subtyping of Tumors)Travel, Accommodations, Expenses: Takeda, H3 
      Biomedicine Matthew I. MilowskyResearch Funding: Merck, Roche/Genentech, Bristol 
      Myers Squibb, Astellas Pharma, Clovis Oncology, Inovio Pharmaceuticals, Mirati 
      Therapeutics, Constellation Pharmaceuticals, Syndax, Incyte, Amgen, Regeneron, 
      Arvinas, Seagen, Pfizer, Johnson & Johnson/JanssenNo other potential conflicts of 
      interest were reported.
EDAT- 2021/08/25 06:00
MHDA- 2021/11/30 06:00
PMCR- 2022/10/01
CRDT- 2021/08/24 17:13
PHST- 2021/08/25 06:00 [pubmed]
PHST- 2021/11/30 06:00 [medline]
PHST- 2021/08/24 17:13 [entrez]
PHST- 2022/10/01 00:00 [pmc-release]
AID - JCO.21.01003 [pii]
AID - 10.1200/JCO.21.01003 [doi]
PST - ppublish
SO  - J Clin Oncol. 2021 Oct 1;39(28):3140-3148. doi: 10.1200/JCO.21.01003. Epub 2021 
      Aug 24.