A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC)

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

Presenter: Gary Hudes
Presenter's Affiliation: Fox Chase Cancer Center, Philadelphia, PA
Type of Session: Plenary


  • Several recent advances in the treatment of advanced RCC using targeted therapy have been made
    • 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 provided a PFS benefit as first-line therapy in metastatic RCC presented in this same plenary session
  • mTOR is a kinase downstream of PI3K/Akt signaling that regulates cell growth and angiogenesis
  • Temsirolimus (TEMSR) inhibits mTOR by binding to FKBP-12 which forms an inhibitory complex
  • In a single-agent, phase II study, TEMSR in heavily pre-treated patients with adv RCC showed promising 15-month median overall survival (OS)
    • Subset analysis showed a particularly impressive benefit in the poor-risk group as classified by MSKCC risk factors
  • In a phase I study evaluating TEMSR + IFN combination therapy, the maximally tolerated doses were TEMSR 15 mg i.v. weekly + IFN 6 million units (MU) s. q. three times weekly
  • This is a randomized trial that tested IFN vs. TEMSR vs. TEMSR + IFN in first line treatment of poor-risk adv RCC (Global ARCC Trial)

Materials and Methods

  • Phase III study design:
    • International, multicenter, open-label, randomized
    • 626 patients with adv RCC accrued 7/2003-4/2005 were randomized 1:1:1 to:
      • IFN alone (n=207) vs. TEMSR alone (n=209) vs. TEMSR + IFN (n=210)
  • Doses on 3 Arms:
    • IFN alone: up to 18 MU s.q. three times weekly
    • TEMSR alone: 25 mg i.v. weekly
    • TEMSR + IFN: 15 mg i.v. weekly + 6 MU s.q. three times weekly
  • Criteria: 
    • adv RCC patients with measurable disease, no prior systemic treatment, KPS>=60
    • Poor-risk criteria >=3 of 6 of the following:
      •     five MSKCC (Motzer) criteria
      •     >1 metastatic site
  • Endpoints:
    • Primary: Overall survival (OS)
    • Secondary: Progression free survival
  • Statistics:
    • Powered to detect 40% differences comparing the TEMSR-containing study arms to the standard IFN arm
    • Two planned interim analyses. The results reported here are from the second planned analysis.


  • Baseline characteristics were well balanced between the groups
    • age, gender, KPS, nephrectomy
    • 69-75% poor risk by Motzer criteria
  • Median OS was longer in TEMSR alone arm, but the combination arm did not have improved OS compared to IFN alone:
    • IFN: 7.3 mos (95% CI 6.1-8.9)
    • TEMSR: 10.9 mos (95% CI 8.6-12.7)
    • TEMSR + IFN: 8.4 mos (95% CI 6.6-10.2)
    • The difference between IFN alone and TEMSR alone was significant: HR 0.73 (95% CI 0.57-0.92, p=0.0069)
  • There was a PFS benefit in both TEMSR-containing arms compared with IFN alone
    • IFN: 1.9 mos
    • TEMSR: 3.7 mos (p<0.0001)
    • TEMSR + IFN: 3.7 mos (p=0.0019)
  • Objective response rates:
    • IFN: 7%
    • TEMSR: 9%
    • TEMSR + IFN: 11%
  • Single agent TEMSR was better tolerated than other arms
    • Grade 3 asthenia (IFN 27%, TEMSR 12%, TEMSR+IFN 30%)
    • Grade 3 anemia (IFN 24%, TEMSR 21%, TEMSR+IFN 39%)
    • Grade 3 dyspnea (IFN 8%, TEMSR 9%, TEMSR+IFN 11%)

Author's Conclusions

  • TEMSR alone significantly increases the OS of first-line, poor-risk adv RCC patients compared with IFN with an acceptable safety profile.
  • TEMSR is a new reference standard for poor-risk adv RCC first-line therapy
  • Although this trial focused on poor-risk patients, TEMSR may be useful in a broader population of RCC patients

Clinical/Scientific Implications

  • TEMSR represents the first agent since IFN to demonstrate an overall survival advantage in adv RCC
  • TEMSR alone had a survival advantage not seen in the combination arm
    • In the combination arm, a lower dose of TEMSR was used which may account for this difference
    • This lower dose may be enough to provide a PFS benefit, but more follow-up is needed
    • These results show that combination therapy may not be better than single-agent therapy, especially if dose-reduction of the active agent is required
  • Results from a Phase III trial with first-line sunitinib presented at the same plenary session (ASCO 2006 #LBA3) showed a progression free survival benefit compared to IFN-alpha in all-risk groups of mRCC
    • The choice of first line agent in mRCC should consider the population characteristics of the study groups
    • Formal head-to-head trials will be needed to determine the optimal first-line agent
  • Resistance to TEMSR did develop; therefore, mechanisms of resistance need to be studied, especially in respect to cross-resistance to purer anti-angiogenesis agents