title: Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.
abstract: BACKGROUND
  In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results.
  
  
  METHODS
  Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392.
  
  
  RESULTS
  Median overall survival was 20.1 months (95% CI 16.7-23.4) with axitinib and 19.2 months (17.5-22.3) with sorafenib (hazard ratio [HR] 0.969, 95% CI 0.800-1.174; one-sided p=0.3744). Median investigator-assessed PFS was 8.3 months (95% CI 6.7-9.2) with axitinib and 5·7 months (4.7-6.5) with sorafenib (HR 0.656, 95% CI 0.552-0.779; one-sided p<0.0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20.7 months (95% CI 18.4-24.6) versus 12.9 months (10.1-20.4) in the axitinib group (p=0.0116), and 20.2 months (17.1-32.0) versus 14.8 months (12.0-17.7) in the sorafenib group (one-sided p=0.0020).
  
  
  CONCLUSIONS
  Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma.
  
  
  BACKGROUND
  Pfizer Inc.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: motzerr@mskcc.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Piotr
authors.initials: P
authors.lastname: Tomczak
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: M Dror
authors.initials: MD
authors.lastname: Michaelson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Negrier
authors.forename: Stephane
authors.initials: S
authors.lastname: Oudard
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gore
authors.forename: Jamal
authors.initials: J
authors.lastname: Tarazi
authors.forename: Subramanian
authors.initials: S
authors.lastname: Hariharan
authors.forename: Connie
authors.initials: C
authors.lastname: Chen
authors.forename: Brad
authors.initials: B
authors.lastname: Rosbrook
authors.forename: Sinil
authors.initials: S
authors.lastname: Kim
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D007191:Indazoles / Q000009:adverse effects / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D000077157:Sorafenib; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D000077784:Axitinib