1. www.OncologyEducation.ca Cabozantinib (XL184) in metastatic castration- resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial. Authors: Hussain M. et al, ASCO 2011 Abstract: 4516 Reviewed by: Dr. Lori Wood Date posted: June 2011

2. www.OncologyEducation.ca Thank you for downloading this update. Please feel free to use it for educational purposes. Please acknowledge OncologyEducation.ca and Dr. Lori Wood when using these slides.

3. www.OncologyEducation.ca STUDY RATIONALE New agents for metastatic CRPCa are needed Cabozantinib (XL184) –An oral TKI of MET and VEGFR –MET drives tumor cell invasion and metastases –MET and VEGFR synergize to promote angiogenesis In prostate cancer –Pre-clinically – ADT  MET expression –MET  with progression and metastases

4. www.OncologyEducation.ca R PR/CR STUDY DESIGN - Metastatic CRPCa patients: - 0-1 prior chemotherapy - all received Cabozantinib 100 mg p.o. qd x 12 weeks - Primary objectives: - lead-in stage – RECIST RR - randomized stage - PFS - Planned n=200; accrual discontinued after n=171 due to better than expected results Phase III Randomized Discontinuation Trial SD PD Continue Continue (n=14) Placebo (n=17) Stop

5. www.OncologyEducation.ca RESULTS PR/CR Open Label Extension n=79 (46%) SD Randomized n=31 (18%) Off Study n=61 (36%) PD = 16% AE = 15% Death = 1% Other = 4% At 12 Weeks

6. www.OncologyEducation.ca RESULTS Lead-in stage –68% overall objective disease control at week 12 –74% measurable soft tissue disease regression –76% complete or partial bone scan resolution –67% improvement in pain –PSA changes did not correlate with radiological response Randomization stage –PFS = 21 weeks vs. 6 weeks

7. www.OncologyEducation.ca RESULTS CR = 19% PR = 56% SD = 21% PD = 3% Best Overall Effect on Bone Scan (n = 108)

8. www.OncologyEducation.ca TOXICITY Grade  3 adverse events in lead-in stage –Fatigue = 16% –Thrombosis = 7% –Hypertension = 6% –Hand/Foot = 6% –Anorexia = 5% –GI Perforation = 2% 51% of patients had  dose reduction 1 death potentially 2  treatment (unexplained death)

9. www.OncologyEducation.ca STUDY COMMENTARY Cabozantinib is a first in class TKI to act on both MET and VEGFR. This phase II randomized discontinuation study with Cabozantinib showed very impressive results, especially bone scan and pain improvement. Will the endpoints looked at (bone scan and pain improvement) translate into an improvement in overall survival? This drug is in many other clinical trials right now with prostate cancer patients and no doubt we will hear a lot more about it.

10. www.OncologyEducation.ca BOTTOM-LINE FOR CANADIAN MEDICAL ONCOLOGISTS Very exciting drug Would be great to participate in clinical trials with this drug