PMID- 32915679
OWN - NLM
STAT- MEDLINE
DCOM- 20210309
LR  - 20240403
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 38
IP  - 31
DP  - 2020 Nov 1
TI  - Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced 
      or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.
PG  - 3672-3684
LID - 10.1200/JCO.20.01652 [doi]
AB  - PURPOSE: We assessed the safety and efficacy of cabozantinib and nivolumab 
      (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic 
      urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND 
      METHODS: Patients received escalating doses of CaboNivo or CaboNivoIpi. The 
      primary objective was to establish a recommended phase II dose (RP2D). Secondary 
      objectives included objective response rate (ORR), progression-free survival 
      (PFS), duration of response (DoR), and overall survival (OS). RESULTS: Fifty-four 
      patients were enrolled at eight dose levels with a median follow-up time of 44.6 
      months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse 
      events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and 
      CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), 
      diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); 
      grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and 
      colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus 
      nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and 
      ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for 
      all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR 
      was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for 
      patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all 
      patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. 
      Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 
      months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION: CaboNivo 
      and CaboNivoIpi demonstrated manageable toxicities with durable responses and 
      encouraging survival in patients with mUC and other GU tumors. Multiple phase II 
      and III trials are ongoing for these combinations.
FAU - Apolo, Andrea B
AU  - Apolo AB
AUID- ORCID: 0000-0001-9409-1836
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Nadal, Rosa
AU  - Nadal R
AUID- ORCID: 0000-0002-6836-9731
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Girardi, Daniel M
AU  - Girardi DM
AUID- ORCID: 0000-0002-7903-8217
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Niglio, Scot A
AU  - Niglio SA
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Ley, Lisa
AU  - Ley L
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Cordes, Lisa M
AU  - Cordes LM
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Steinberg, Seth M
AU  - Steinberg SM
AUID- ORCID: 0000-0002-8280-551X
AD  - Biostatistics and Data Management Section, Office of the Clinical Director, 
      Center for Cancer Research, National Cancer Institute, National Institutes of 
      Health, Bethesda, MD.
FAU - Sierra Ortiz, Olena
AU  - Sierra Ortiz O
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Cadena, Jacqueline
AU  - Cadena J
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Diaz, Carlos
AU  - Diaz C
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Mallek, Marissa
AU  - Mallek M
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Davarpanah, Nicole N
AU  - Davarpanah NN
AUID- ORCID: 0000-0003-3948-5319
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Costello, Rene
AU  - Costello R
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Trepel, Jane B
AU  - Trepel JB
AD  - Developmental Therapeutics Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Lee, Min-Jung
AU  - Lee MJ
AD  - Developmental Therapeutics Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Merino, Maria J
AU  - Merino MJ
AD  - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Bagheri, Mohammad Hadi
AU  - Bagheri MH
AUID- ORCID: 0000-0002-9273-5359
AD  - Clinical Image Processing Service, Clinical Center, National Institutes of 
      Health, Bethesda, MD.
FAU - Monk, Paul
AU  - Monk P
AD  - Division of Medical Oncology, Department of Internal Medicine, College of 
      Medicine, The Ohio State University, and the Comprehensive Cancer Center, 
      Columbus, OH.
FAU - Figg, William D
AU  - Figg WD
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Gulley, James L
AU  - Gulley JL
AUID- ORCID: 0000-0002-6569-2912
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Agarwal, Piyush K
AU  - Agarwal PK
AD  - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Valera, Vladimir
AU  - Valera V
AD  - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Chalfin, Heather J
AU  - Chalfin HJ
AD  - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Jones, Jennifer
AU  - Jones J
AUID- ORCID: 0000-0002-9488-7719
AD  - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Streicher, Howard
AU  - Streicher H
AD  - Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer 
      Institute, National Institutes of Health, Rockville, MD.
FAU - Wright, John J
AU  - Wright JJ
AD  - Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer 
      Institute, National Institutes of Health, Rockville, MD.
FAU - Ning, Yangmin M
AU  - Ning YM
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Parnes, Howard L
AU  - Parnes HL
AD  - Division of Cancer Prevention, National Cancer Institute, National Institutes of 
      Health, Bethesda, MD.
FAU - Dahut, William L
AU  - Dahut WL
AUID- ORCID: 0000-0002-2766-9703
AD  - Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD.
FAU - Bottaro, Donald P
AU  - Bottaro DP
AUID- ORCID: 0000-0002-5057-5334
AD  - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Lara, Primo N Jr
AU  - Lara PN Jr
AD  - University of California Davis Comprehensive Cancer Center, Sacramento, CA.
FAU - Saraiya, Biren
AU  - Saraiya B
AD  - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
FAU - Pal, Sumanta K
AU  - Pal SK
AUID- ORCID: 0000-0002-1712-0848
AD  - City of Hope Comprehensive Cancer Center, Duarte, CA.
FAU - Stein, Mark N
AU  - Stein MN
AD  - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
FAU - Mortazavi, Amir
AU  - Mortazavi A
AUID- ORCID: 0000-0002-2122-6805
AD  - Division of Medical Oncology, Department of Internal Medicine, College of 
      Medicine, The Ohio State University, and the Comprehensive Cancer Center, 
      Columbus, OH.
LA  - eng
SI  - ClinicalTrials.gov/NCT02496208
GR  - P30 CA093373/CA/NCI NIH HHS/United States
GR  - UM1 CA186712/CA/NCI NIH HHS/United States
GR  - UM1 CA186717/CA/NCI NIH HHS/United States
GR  - ZIA BC011351/ImNIH/Intramural NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20200911
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 (Anilides)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (EPCAM protein, human)
RN  - 0 (Epithelial Cell Adhesion Molecule)
RN  - 0 (Ipilimumab)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, CXCR4)
RN  - 1C39JW444G (cabozantinib)
RN  - 31YO63LBSN (Nivolumab)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anilides/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - B7-H1 Antigen/metabolism
MH  - Carcinoma, Transitional Cell/*drug therapy/secondary
MH  - Colitis/chemically induced
MH  - Diarrhea/chemically induced
MH  - Epithelial Cell Adhesion Molecule/metabolism
MH  - Fatigue/chemically induced
MH  - Female
MH  - Hepatitis/etiology
MH  - Humans
MH  - Hypertension/chemically induced
MH  - Ipilimumab/administration & dosage
MH  - Male
MH  - Middle Aged
MH  - Neoplastic Cells, Circulating/metabolism
MH  - Nivolumab/administration & dosage
MH  - Progression-Free Survival
MH  - Proto-Oncogene Proteins c-met/metabolism
MH  - Pyridines/administration & dosage
MH  - Receptors, CXCR4/metabolism
MH  - Response Evaluation Criteria in Solid Tumors
MH  - Survival Rate
MH  - Urogenital Neoplasms/*drug therapy
MH  - Young Adult
PMC - PMC7605393
EDAT- 2020/09/12 06:00
MHDA- 2021/03/10 06:00
PMCR- 2021/11/01
CRDT- 2020/09/11 17:11
PHST- 2020/09/12 06:00 [pubmed]
PHST- 2021/03/10 06:00 [medline]
PHST- 2020/09/11 17:11 [entrez]
PHST- 2021/11/01 00:00 [pmc-release]
AID - 2001652 [pii]
AID - 10.1200/JCO.20.01652 [doi]
PST - ppublish
SO  - J Clin Oncol. 2020 Nov 1;38(31):3672-3684. doi: 10.1200/JCO.20.01652. Epub 2020 
      Sep 11.