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Reviewer: Dr. Daniel Heng Date posted: March 2009

Everolimus (RAD001) After TKI Progression in Metastatic Renal Cell Carcinoma AUTHORS: A. Kay, R. Motzer, R. Figlin, B. Escudier, S. Oudard, C. Porta, T. Hutson, S. Bracarda, N. Hollaender, G. Urbanowitz, A. Ravaud GU ASCO 2009. Reviewer: Dr. Daniel Heng Date posted: March 2009.

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Reviewer: Dr. Daniel Heng Date posted: March 2009

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  1. Everolimus (RAD001) After TKI Progression in Metastatic Renal Cell CarcinomaAUTHORS: A. Kay, R. Motzer, R. Figlin, B. Escudier, S. Oudard, C. Porta, T. Hutson, S. Bracarda, N. Hollaender, G. Urbanowitz, A. Ravaud GU ASCO 2009 Reviewer: Dr. Daniel Heng Date posted: March 2009

  2. RAD001 (Everolimus) 10 mg PO OD N=277 R Placebo + Best Supportive Care Cross over to RAD001 on progression N=139 410 patients Previous Tx: Sunitinib 45% Sorafenib 29% Both 26% Nephrectomy: 96% MSKCC Risk*: Favorable: 29% Intermediate: 56% Poor: 15% *MSKCC Previously Treated Criteria (Ca, Hb, KPS) Motzer et al JCO 2004

  3. RESULTS *81% of pts who progressed on BSC crossed over to Everolimus

  4. Progression Free Survival by Independent Review

  5. Cross-over patients PFS of crossover patients is 5.09 months which is similar to the 4.9 months for patients in the original RAD001 arm. Is it okay to wait?

  6. STUDY COMMENTARY • Most common side effects included stomatitis, anemia and asthenia. • 14% of patients in the RAD001 arm had pneumonitis including 2 patient deaths. • 81% of pts who progressed on placebo crossed over to Everolimus so it is unlikely that the overall survival secondary endpoint will be positive. • PFS of placebocrossover RAD001 group is similar to that of patients initially treated with RAD001 suggesting that patients do not need to begin treatment immediately if they can receive it later. However, this cohort is biased/selected because all patients that crossed over to RAD001 were healthy enough to receive another therapy.

  7. BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS • This is the first randomized trial demonstrating PFS benefit of an agent after first-line targeted therapy • Best supportive care is no longer the standard of care for second-line treatment and can no longer be used as a comparator arm in future clinical trials • Clinical trials are ongoing to determine whether mTOR inhibitors vs. another VEGF inhibitor is the most beneficial after initial targeted therapy • In clinical practice, second-line targeted therapy after initial VEGF therapy can include an mTOR inhibitor (RAD001 on expanded access program, temsirolimus) or another VEGF inhibitor (sunitinib, sorafenib) • It is unknown if this benefit is unique to Everolimus or if it is an mTOR inhibitor class effect • Everolimus is not yet Health Canada approved (and was FDA approved March 31, 2009)

  8. Treatment of mRCC:Current Status *Bevacizumab and Everolimus are not yet Health Canada Approved for RCC Adapted with permission from Dr. Brian Rini

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