title: Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial.
abstract: Sunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC).
  
  
  
  To conduct a randomized phase 2 trial comparing sunitinib and everolimus in non-clear cell RCC (non-ccRCC).
  
  
  
  Patients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive sunitinib or everolimus with crossover at disease progression.
  
  
  
  Primary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with sunitinib to 20 wk with everolimus.
  
  
  
  Interim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with sunitinib and 4.1 mo with everolimus (p=0.6); median overall survival (mOS) was not reached with sunitinib and was 10.5 mo with everolimus, respectively (p=0.014). At final analysis, mOS was 16.2 and 14.9 mo with sunitinib and everolimus, respectively (p=0.18). There were four partial responses (PRs) in first-line therapy (sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors (n=49), mOS was 31.6 mo with sunitinib and 10.5 mo with everolimus (p=0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation.
  
  
  
  In this trial, everolimus was not superior to sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non-ccRCC.
  
  
  
  This randomized phase 2 trial provides the first head-to-head comparison of everolimus and sunitinib in patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC.
authors.affiliation: Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ntannir@mdanderson.org.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.affiliation: Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Emre
authors.initials: E
authors.lastname: Altinmakas
authors.affiliation: Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chaan S
authors.initials: CS
authors.lastname: Ng
authors.affiliation: Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Surena F
authors.initials: SF
authors.lastname: Matin
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zita
authors.initials: Z
authors.lastname: Dubauskas Lim
authors.affiliation: Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pheroze
authors.initials: P
authors.lastname: Tamboli
authors.affiliation: Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Rao
authors.affiliation: Pathology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
authors.affiliation: Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Beth-Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D015996:Survival Rate; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077210:Sunitinib
keywords: Everolimus; Non–clear cell renal cell carcinoma; Renal cell carcinoma; Sunitinib