ASCO 2009 BEVACIZUMAB IN METASTATIC RENAL CELL CARCINOMA: An Update of the CALGB and AVOREN Trials Reviewed by: Dr. Daniel Heng and Dr. Lori Wood Abstract: LBA5019 and 5020 Date posted: June 9, 2009

BACKGROUND Previously: Phase II trials of bevacizumab monotherapy have been performed and showed activity with single agent Bevacizumab Thus, two phase III trials were designed. Their updated and final overall survival results were presented: Rini BI et al: Bevacizumab plus interferon-alpha versus interferon- alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for CALGB Escudier B et al: Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon- alpha (IFN) in metastatic renal cell carcinoma (mRCC)

R Interferon alpha 9MIU SC 3x/wk Bevacizumab 10mg/kg IV q2wks Interferon alpha 9MIU SC 3x/wk No placebo 732 pts metastatic RCC, Previously untreated Any clear cell component, No brain metastases No nephrectomy needed STUDY DESIGN 1 o Endpoint: Overall Survival 2 o Endpoint: PFS, ORR CALGB AVOREN R Interferon alpha 9MIU SC 3x/wk Bevacizumab 10mg/kg IV q2wks Interferon alpha 9MIU SC 3x/wk Placebo IV q2wks 649 pts metastatic RCC, Previously untreated Any clear cell component, No brain metastases Prior nephrectomy needed 1 o Endpoint: Overall Survival 2 o Endpoint: PFS, ORR

PATIENT CHARACTERISTICS Bevacizumab +IFN IFN alone Bevacizumab +IFN IFN alone Median Age (yrs) MSKCC Prognosis Profile Favorable Intermediate Poor 26% 64% 10% 26% 64% 10% 27% 56% 9% 29% 56% 8% Nephrectomy85% 100% CALGB 90206AVOREN

RESULTS Bevacizuma b +IFN IFN alone p- value Bevacizuma b +IFN IFN alone p- value Response Rate (CR+PR) (%) 25.5%13.1%< %12%<.0001 PFS (median, mos) < <.0001 OS (median, mos) CALGB 90206AVOREN

STUDY COMMENTARY These Phase III trials demonstrate PFS benefit but predictably no OS benefit due to the use of subsequent 2 nd and 3 rd -line targeted therapy. For example, in the CALGB trial, 62% of IFN patients went on to receive further therapy The major difference between the 2 trials is that the CALGB trial included 15% of patients without nephrectomy and the AVOREN trial included a placebo Additionally, very few patients (10%) with MSKCC poor prognostic profiles were included in this study. Thus, the true effect of bevacizumab/IFN in this population is unknown The efficacy of bevacizumab alone is unknown and many wonder what the results would have been if the 2 arms were IFN versus Bevacizumab alone. The AVOREN trial did not show a difference in OS for those who required a dose reduction of IFN

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS Bevacizumab has not yet been approved by the FDA or Health Canada for the treatment of mRCC Use of this combination first-line is less desirable than the standard oral anti-VEGF inhibitors such as sunitinib because: IFN is not well tolerated This combination is not orally administered The cost of bevacizumab at 10mg/kg plus interferon is higher than sunitinib, sorafenib or temsirolimus There are no head-to-head trials comparing bevacizumab to sunitinib This drug has potential application in third- or forth-line settings however this has yet to be studied

Treatment of mRCC: Current Status SettingPatientsTherapy (level 1 evidence) Other Options (>level 1 evidence) UntreatedGood or intermediate risk Sunitinib Bevacizumab* + IFN HD IL-2 Sorafenib Clinical Trial Observation Poor riskTemsirolimusSunitinib Clinical Trial Second-lineCytokine refractorySorafenibSunitinib, Bevacizumab* + IFN Prior VEGF (or mTOR) Everolimus* Clinical Trial Targeted therapy not previously used *Bevacizumab and Everolimus are not yet Health Canada Approved for mRCC Adapted with permission from Dr. Brian Rini