1. What’s Next? Unanswered Questions in Renal Cell Carcinoma
May 19, 2006
Atlanta, Georgia
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2. What’s Next? Unanswered Questions in Renal Cell Carcinoma
Brian I. Rini, MD Staff Physician Department of Solid Tumor Oncology and Urology Cleveland Clinic Taussig Cancer Center Associate Professor of Medicine CCF/CWRU Lerner College of Medicine Cleveland, Ohio
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3. Adjuvant Therapy
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4. Adjuvant Therapy: Rationale
Patients with recurrent disease following nephrectomy have micrometastatic disease at the time of surgery
There is a 35%-65% recurrence rate* with locally aggressive tumors
Use of effective therapy may reduce the risk of relapse
*Depending on pathologic stage.
Lam JS, et al. BJU Int. 2005;96:
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5. Adjuvant Therapy
To date, all adjuvant therapy trials have failed to demonstrate DFS or OS advantage
High-dose (HD) IL-2
Interferon
Autologous tumor cells + BCG vaccine
Vitespen (HSPPC-96) vaccine
Given the risk/benefit profile, no adjuvant treatment is appropriate outside clinical trial
VHL mutation (and thus VEGF production) is an early oncogenic event in RCC
Radiation therapy
Megestrol acetate
BCG, Bacillus Calmette-Guérin; VEGF, vascular endothelial growth factor.
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6. ASSURE Trial (Intergroup Sponsored by ECOG)
1 year
Stratification by UISS stage (II-V) and histologic subtype (clear cell or nonclear cell)
Sunitinib 50 mg daily for 4 of 6 wks
Patients with nonmetastatic kidney cancer
Disease stage II-IV
(N = 1332)
Sorafenib 800 mg daily continuously
Nephrectomy
UISS, UCLA integrated staging system.
Placebo daily continuously
Eligibility: nonmetastatic kidney cancer
Disease  T1b N any (resectable) M0 by radiologic criteria
Primary endpoint: DFS
Available through
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7. SORCE (MRC Adjuvant trial)
1 year
3 years
Sorafenib
Patients with high- and intermediate-risk resected RCC
(Planned N = 1420)
Sorafenib
Placebo
Placebo
Eligibility
No evidence of residual disease after RCC resection
Leibovich prognostic score 3-8 (high or intermediate risk of metastatic RCC or death) postsurgery
≥ 4 weeks and ≤ 4 months since surgery
Endpoints
Primary: metastasis-free survival
Secondary: DFS, toxicity, genomics
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8. ARISER Study 24 weeks cG250 (WX-G250) IV over 15 minutes once weekly
Patients with clear-cell nonmetastatic RCC
(N = 600+)
Nephrectomy
Placebo IV over 15 minutes once weekly
Eligibility
Clear-cell RCC, no metastasis, ECOG status 0
RCC patients at high-risk of recurrence*
Primary endpoints: DFS, OS
* T3b/T3c/T4 N0/XM0; All T stages N+M0; T1b/T2 N0/XM0 with G ≥ 3 and MVI or T3a N0/XM0 with G ≥ 3
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9. Neoadjuvant Trials Phase II
Neoadjuvant sunitinib: Cleveland Clinic Foundation
For patients with “unresectable” primary renal tumors (with or without metastases)
Neoadjuvant RAD-001 (mTOR inhibitor): UCLA
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10. Metastatic RCC: Frontline/Monotherapy
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11. CALGB 90206: Interferon alfa-2b ± Bevacizumab in Advanced RCC
Stratified for nephrectomy status and MSKCC risk group
Interferon alfa-2b 9 MU SC 3 times weekly
(n = 350)
Patients with untreated, metastatic or unresectable clear-cell RCC
(N = 700)
Interferon alfa-2b 9 MU SC 3 times weekly + Bevacizumab 10 mg/kg IV Days 1 and 15, every 28 days
(n = 350)
Endpoints
Primary: OS
Secondary: TTP, ORR, toxicity
Follow-up
Every 3 months for 2 years
Annual thereafter (up to 10 years from study entry)
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12. European Phase III Trial of IFN/Bevacizumab in RCC (BO17705)
Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks +
Placebo every 2 weeks until disease progression
Patients with metastatic clear cell RCC, status post nephrectomy
(N = 638)
Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks + Bevacizumab 10 mg/kg every 2 weeks until disease progression
Primary endpoint
OS (improvement from months)
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13. Phase III Trial of Sunitinib vs Interferon alfa in Metastatic RCC
Sunitinib orally administered daily (4 of every 6 weeks)
(n = 345)
Patients with metastatic clear cell RCC
(N = 690)
Interferon alfa administered 3 times weekly
(n = 345)
Randomized, open-label, multicenter trial
100 Sites (US, Canada, Europe, Australia, Brazil)
Endpoints
Primary: PFS
Secondary: TTP, OS, RR, QoL, safety, cost-effectiveness
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14. CCI-779: mTOR inhibitor Phase II trial 111 patients RR: 7%
TTP: 5.8 months
OS: 15 months
Toxicity: rash, fatigue, mucositis, nausea
Growth/survival factors
Plasma membrane
ATP
Cytoplasm 02
Amino acids
TOR
Phosphatidic acid
Mitochondria
Protein stability
ASK1
S6K1
4E-BP1
Transcription-factor translocation
Translation ribosomal proteins
eIF4E
Nucleus
Nutritional-stress response
Apoptosis
Ribosome biogenesis
Cap-dependent translation
Schematic from Bjornsti and Houghton Nat Rev Cancer 4L (2004) Atkins J, et al. J Clin Oncol. 2004;22:
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15. Temsirolimus (CCI-779) + Interferon alfa in Advanced RCC
Interferon alfa SC
up to 18 MU TIW as tolerated
Patients with previously untreated advanced RCC
Poor risk criteria[1]
(Planned N = 600)
CCI-779 IV
25 mg weekly
CCI mg IV weekly +
Interferon alfa 6 MU SC TIW
International phase III randomized trial
Endpoints
Primary: OS
Secondary: Safety, PFS, RR, health outcomes
1. Motzer RJ, et al. J Clin Oncol. 2002;20:
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16. CA IX and Response to Interleukin-2 (IL-2) Therapy in RCC
Outcome
UCLA, % (N = 83)
Boston, % (N = 66)
No of metastatic pts with > 85% CA IX 77 62
Response in high CA IX
27* 51
Response in low CA IX 14 24
Responders with high CA IX 91 78
Nonresponders with high CA IX 80
*Including all CRs.
Bui MH, et al. Clin Cancer Res. 2003;9: Atkins M, et al. Clin Cancer Res. 2005;11:
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17. HD IL-2 “Select” Trial: Study Design
rIL ,000 IU/kg q8h by 15-min infusion
Rest
rIL ,000 or q8h by 15-min infusion
5 days
9 days
5 days
Eligibility
Measurable metastatic RCC; all histologic subtypes
Consented to provide tumor blocks
No prior systemic therapy
Candidate for HD IL-2
ECOG PS 0-1 and good organ function
Maximum 3 courses per patient. Responses independently audited.
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18. Metastatic RCC: Determining Clinical Cross-Resistance to VEGF-Targeted Agents
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19. Approach to Tyrosine Kinase Inhibitor (TKI)–Resistant Disease
mTOR inhibitor (temsirolimus, CCI-779)
HIF O2
VEGF
Bevacizumab
KDR
Sorafenib, sunitinib, AG13736
Hypothesis
Resistance to 1 TKI will be mediated by pathways sensitive to inhibition by another TKI
Varying response rates and toxicity profiles suggest some differences between TKIs
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20. A  B Trials Sunitinib in bevacizumab-refractory RCC
VEGF-R (and other targets like PDGF) after VEGF ligand inhibition
ASCO 2006: definite activity, data to be presented
Sorafenib in sunitinib or bevacizumab-refractory RCC
Multitargeted agent, plus Raf kinase inhibition
AG in sorafenib-refractory RCC
More potent VEGFR inhibition
All 3 are standard clinical trials
No insights into mechanisms of resistance, etc, are possible
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21. 6-Arm Randomized Phase II Trial (E9805): Sunitinib Failures
Arm A
Sunitinib daily
Arm B
Patients failing sunitinib
Sunitinib + Bevacizumab
Arm C
Change to Sorafenib
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22. 6-Arm Randomized Phase II Trial (E9805): Sorafenib Failures
Arm D
Arm D
Arm D
Increase Sorafenib dose
Arm E
Arm E
Patients failing sorafenib
Sorafenib + Bevacizumab
Arm F
Change to Sunitinib
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23. Metastatic RCC: Combinations
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24. Phase I and II Combination Studies
Sorafenib + bevacizumab
Sunitinib + bevacizumab
CCI bevacizumab
CCI sorafenib
AMG386 (anti-Ang2/Tie2) + bevacizumab, TKI
HD IL-2 + bevacizumab (Phase II CWG study)
CWG, Cytokine Working Group
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25. ECOG “BEST” Trial Patients with advanced RCC (N = 360*)
Stratified by prior therapy (prior cytokine/vaccine or no prior cytokine) and Motzer risk category (low, intermediate, or high)
Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15)
Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) and Temsirolimus 25 mg IV weekly (Days 1, 8, 15 and 22)
Patients with advanced RCC
(N = 360*)
Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15)
Sorafenib 400 mg PO twice daily
DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging.
Sorafenib PO twice daily and Temsirolimus IV weekly (Days 1, 8, 15 and 22)†
Randomized phase II study
Endpoints
Primary: PFS
Secondary: ORR, OS, correlates (DCE-MRI, biomarkers)
*Accrual goal. †Arm to be added when phase II doses are available from ongoing phase I trials.
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26. Phase III Renal EFFECT Trial
1 year
Sunitinib, 50 mg/d orally, 4 weeks on 2 weeks off (n = 149)
Patients with clear cell RCC
(N = 499)*
Sunitinib, daily, 4 weeks on 2 weeks off, plus Interferon alfa-2b every 3 weeks (n = 149)
Sunitinib 35 mg/d orally for 6 weeks (n = 149)
KPS, Karnofsky Performance Status
Primary endpoint: improvement in TTP from 8-12 months; 85% power (hazard ratio = 0.67); 222 events required.
1 year of follow-up after end of treatment
*Initial, nonrandomized dose-finding study for sunitinib and interferon-alfa2b in first 25 patients at 4 sites
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27. Conclusions VEGF and other targeted therapies
Robust activity in metastatic RCC
Cornerstone of future therapy
Currently under investigation
Value in earlier stages of disease
Clinical cross-resistance
Optimal sequencing/combination
Clinical trials
Participation mandatory for benefit of all
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