Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alpha (IFN-alpha) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC).

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2006

Presenter: Robert J. Motzer
Presenter's Affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY
Type of Session: Plenary


  • Clear cell renal cell carcinoma (RCC) is characterized by mutation or silencing of the VHL gene, which in turn leads to increased activity of hypoxia inducible factor (HIF). This in turn leads to over-expression of receptors and ligands involved in angiogenesis
  • Sorafenib, a multikinase inhibitor that targets Raf kinase and angiogenesis receptor tyrosine kinases, doubled progression free survival (PFS) when used as second-line treatment, which lead to FDA approval in 12/2005
  • Sunitinib (SU11248) is an anti-angiogenic small molecule, multikinase inhibitor that targets VEGFR-1, 2, and 3, PDGFR-alpha, beta, Ret, Flt3 and Kit
  • Two multicenter Phase II trials of sunitinib used as 2nd line monotherapy showed a 39-40% response rate
  • The FDA approved sunitinib for use as first line therapy in mRCC and second line therapy for GI stromal tumors in January 2006
  • This is a randomized trial that tested sunitinib vs. IFN-alpha in first line treatment of mRCC

Materials and Methods

  • Phase III study design:
    • International, multicenter, randomized
  • - 750 patients with mRCC accrued 8/2004-10/2005 were randomized 1:1 to:
    • IFN-alpha (n=350) vs. sunitinib (n=350)
  • IFN-alpha administration: 3 million units (MU) s.q. three times weekly x 1 wk, that was dose escalated to 6 MU x 1 wk, then 9 MU
  • Sunitinib administration: 50 mg daily for 4 wks, then 2 wks off. Cycles repeated.
  • Criteria: mRCC patients with measurable disease, no prior systemic treatment
  • Stratification: serum LDH, performance status, nephrectomy
  • Endpoints:
    • Primary: Progression-free survival (PFS) as assessed by 3rd party review of imaging
    • Secondary: Objective response rate, overall survival, and adverse events
  • Statistics:
    • Powered to detect a 35% increase in PFS (20 wks predicted for IFN-alpha, powered to detect increase to 27 wks) with 90% power with a planned sample size of 690
    • The results reported here are from a planned analysis on the primary endpoint, PFS


  • Baseline characteristics were well balanced between the groups
    • Nephrectomy: 91% sunitinib arm, 89% IFN-alpha arm
    • Median age: 62 years sunitinib arm, 59 years IFN-alpha arm
    • MSKCC risk factors, sites of disease involvement
  • Median PFS was 22 wks longer in sunitinib arm:
  • Sunitinib: 47.3 wks (95% CI 40.9-not reached)
  • IFN-alpha: 24.9 wks (95% CI 21.9-37.1)
  • This difference was highly significant: HR 0.394 (95% CI 0.297-0.521, p<0.000001)
  • The PFS benefit was observed in all subsets analyzed, including favorable, intermediate, and high risk by MSKCC criteria
  • Objective response rates:
    • By investigator were significantly better (p<0.000001) in sunitinib arm
  • Sunitinib: 35.7% (95% CI 30.9-40.8%)
    • One complete response
  • IFN-alpha: 8.8% (95% CI 6.1-12.1%)
  • By central review the results were similar (p<0.00001):
    • Sunitinib: 31% (all partial responses)
    • IFN-alpha: 6%
  • Study follow-up period continues:
  • 66% of patients still on sunitinib compared with 34% still on IFN-alpha
  • Median overall survival (OS) not reached
  • OS difference between arms is not currently significant
  • Sunitinib was well tolerated compared with IFN-alpha
    • Quality of life measures (FACT-G) were much higher in sunitinib arm throughout treatment
    • Grade 3/4 fatigue was higher in INF-alpha arm (11% vs. 7%)

Author's Conclusions

  • Sunitinib significantly prolonged PFS in mRCC compared to IFN-alpha when used as first line treatment
  • Safety of sunitinib is acceptable and patient reported outcomes were better.
  • Sunitinib is the new reference standard for mRCC first line therapy
  • The molecular mechanism underlying the rationale for use of anti-angiogenic agents in RCC is validated

Clinical/Scientific Implications

  • The last agents to show an improvement in survival advantage in mRCC was IFN-alpha, which had been used as the standard arm in this trial
    • High dose IL-2 has been shown to have a role in very selected patients, which is why the authors did not used this as the reference immunotherapy arm
  • The improvement in PFS and response rate with sunitinib was not only highly statistically significant, but it is a clinically important improvement with a near doubling of median PFS
  • This study was conducted well and the results are convincing:
  • Arms were well balanced.
  • The results replicate Phase II results for sunitinib response rates
  • The median PFS for the standard arm was close to historical experience and did not “under-perform”
  • The ultimate impact on OS awaits longer follow-up.
    • The availability of good salvage treatments in the IFN-alpha arm (e.g. cross over to sunitinib or sorafenib) may mask a benefit
    • Crossover results from the sorafenib trial support the notion that anti-angiogenesis therapy in advanced RCC can be delayed several months and still have a benefit
  • Results from a Phase III trial with first-line temsirolimus presented at the same plenary session (ASCO 2006 #LBA4) showed a survival benefit compared to IFN-alpha in high-risk mRCC
    • The choice of first line agent in mRCC should consider the population characteristics of the study groups
  • Resistance to sunitinib did develop; therefore, mechanisms of resistance need to be studied, especially in respect to cross-resistance to agents in the same class