title: Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial.
abstract: BACKGROUND
  Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted.
  
  
  METHODS
  Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4-2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumour measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least one dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897.
  
  
  RESULTS
  As of December, 2007, 4564 patients were enrolled in 52 countries. 4371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1418 (32%) aged 65 years or more. Patients received a median of five treatment cycles (range 1-25). Reasons for discontinuation included lack of efficacy (n=1168 [27%]) and adverse events (n=362 [8%]). The most common treatment-related adverse events were diarrhoea (n=1936 [44%]) and fatigue (n=1606 [37%]). The most common grade 3-4 adverse events were fatigue (n=344 [8%]) and thrombocytopenia (n=338 [8%]) with incidences of grade 3-4 adverse events similar across subgroups. In 3464 evaluable patients, the objective response rate (ORR) was 17% (n=603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]) and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10.9 months (95% CI 10.3-11.2) and overall survival was 18.4 months (17.4-19.2).
  
  
  CONCLUSIONS
  In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4-2 was manageable and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials.
  
  
  BACKGROUND
  Pfizer Inc.
authors.affiliation: Royal Marsden Hospital NHS Trust, London, UK. martin.gore@rmh.nhs.uk
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gore
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.forename: Sergio
authors.initials: S
authors.lastname: Bracarda
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.forename: Subramanian
authors.initials: S
authors.lastname: Hariharan
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Haanen
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.forename: Eduard
authors.initials: E
authors.lastname: Vrdoljak
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Paul
authors.initials: P
authors.lastname: Mainwaring
authors.forename: Alejandra
authors.initials: A
authors.lastname: Nieto
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yuan
authors.forename: Ronald
authors.initials: R
authors.lastname: Bukowski
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib