title: Phase 2 Study of Bevacizumab and Temsirolimus After VEGFR TKI in Metastatic Renal Cell Carcinoma.
abstract: Inhibiting VEGF and mammalian target of rapamycin (mTOR) pathways are standard treatment approaches for patients with metastatic renal cell carcinoma (mRCC). Here we report the activity and safety of the VEGF ligand inhibitor bevacizumab and the mTOR inhibitor temsirolimus combination in patients with clear cell (CC) and non-clear cell (NCC) mRCC whose disease had failed to respond to prior VEGF blockade.
  
  
  
  In this phase 2 investigator-initiated multicenter study, patients received bevacizumab and temsirolimus. The primary end point was 4-month progression-free survival (PFS) rate. Secondary end points included overall response rate, median overall survival (OS), toxicity, and correlative studies of biomarkers downstream of mTOR.
  
  
  
  Forty patients received at least 1 dose of therapy. Thirty-three (82.5%) had favorable/intermediate risk disease according to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 13 (32.5%) with nccRCC histology. Nineteen (48.7%) had primary vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-refractory disease. The 4-month PFS rate was 65%. Overall median PFS and OS were 5.6 and 12.2 months. Median PFS and OS were 6.5 and 9.6 months in patients with primary VEGFR TKI-refractory disease, and 5.6 months and 13.1 months in patients with nccRCC. Dose reductions were needed in 80% of patients. Most frequent toxicities included fatigue, hypertension, dyslipidemia, and proteinuria. Dose discontinuation due to adverse events occurred in 27.5% of patients. Baseline tumor immunohistochemistry for phospho-S6 protein was not associated with clinical benefit.
  
  
  
  Combining bevacizumab and temsirolimus in patients previously treated with VEGFR TKI was possible but with dose reductions and treatment discontinuations. This combination resulted in modest activity, including in patients with primary VEGF-refractory disease and NCC histology.
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Mahoney
authors.affiliation: Department of Statistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Jacobus
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Rupal S
authors.initials: RS
authors.lastname: Bhatt
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Carvo
authors.affiliation: Department of Statistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Su-Chun
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Mekailah
authors.initials: M
authors.lastname: Simpson
authors.affiliation: PUCRS School of Medicine, Porto Alegre, Brazil.
authors.forename: André P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: M Dror
authors.initials: MD
authors.lastname: Michaelson
authors.affiliation: Department of Medical Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address: toni_choueiri@dfci.harvard.edu.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D000068258:Bevacizumab; C401859:temsirolimus; D020123:Sirolimus
keywords: Bevacizumab; Renal cell carcinoma; TKI-refractory disease; Temsirolimus