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

Background

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.

Results

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