title: Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4).
abstract: BACKGROUND
  RECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting.
  
  
  METHODS
  Patients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis.
  
  
  RESULTS
  Enrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7-11.0]; in the cohorts, it was 5.7 months (95% CI 3.7-11.3) with previous sunitinib, 7.8 months (95% CI 5.7-11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6-not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0-NE) and, in the cohorts, it was 23.8 months (95% CI 13.7-NE) with previous sunitinib, 17.2 months (95% CI 11.9-NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9-NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug).
  
  
  CONCLUSIONS
  These results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience.
  Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA motzerr@mskcc.org.
authors.forename: R J
authors.initials: RJ
authors.lastname: Motzer
authors.affiliation: Prevoljskiy Region Medical Centre, Novgorod, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Alyasova
authors.affiliation: Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: D
authors.initials: D
authors.lastname: Ye
authors.affiliation: Leningrad Regional Oncologic Dispensary, Saint-Petersburg, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Karpenko
authors.affiliation: Peking Union Medical College Hospital, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Moscow Hertzen Oncology Institute, Moscow, Russia.
authors.forename: B
authors.initials: B
authors.lastname: Alekseev
authors.affiliation: First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Xie
authors.affiliation: Center of Oncology, Sofia, Bulgaria.
authors.forename: G
authors.initials: G
authors.lastname: Kurteva
authors.affiliation: Centro de Investigaciones Clinicas Clinica Viedma, Viedma, Argentina.
authors.forename: R
authors.initials: R
authors.lastname: Kowalyszyn
authors.affiliation: Department of Oncology, Medical Radiological Research Center, Obninsk, Russia.
authors.forename: O
authors.initials: O
authors.lastname: Karyakin
authors.affiliation: Centro de Pesquisas Oncológicas-CEPON, Florianopolis-SC, Brazil.
authors.forename: Y
authors.initials: Y
authors.lastname: Neron
authors.affiliation: Crescent City Research Consortium, Marrero, Louisiana.
authors.forename: T
authors.initials: T
authors.lastname: Cosgriff
authors.affiliation: Novartis Oncology, East Hanover, USA.
authors.forename: L
authors.initials: L
authors.lastname: Collins
authors.affiliation: Novartis Pharma S.A.S., Rueil-Malmaison, France.
authors.forename: T
authors.initials: T
authors.lastname: Brechenmacher
authors.affiliation: Novartis Oncology, East Hanover, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.affiliation: Novartis Oncology, East Hanover, USA.
authors.forename: L
authors.initials: L
authors.lastname: Morgan
authors.affiliation: Chinese Academy of Medical Science, Cancer Institute and Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011758:Pyrroles / Q000627:therapeutic use; D000077210:Sunitinib; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077210:Sunitinib
keywords: everolimus; metastatic renal cell carcinoma; prospective study; second-line; sequential targeted therapy