1. Systemic treatment for non-clear cell histology Alessandra Mosca Medical Oncology «Maggiore della Carità» University Hospital University of East Piedmont “A. Avogadro” Novara

2. De Vita VT el al, 2005 Sporadic/hereditary (Sporadic)/hereditary (hereditary leiomyomatosis) (+)(-) HIF, VEGF

3. Linehan et al, Annu Rev Med 2010

4. clear cell Histology clear cell 124 pts (20%) non-clear cell clear cell Axitinib vs Sorafenib 723 2nd line PFS 6.7 vs 4.7 mo (p<0.0001) clear cell 8 Rini BI et al, Lancet 2011

5. REGIMENNR of PTSEFFICACY (MEDIAN)/ ACTIVITY Temsirolimus vs IFN vs Tem+IFN (phase III) Hudes, NEJM 2007 Dutcher JP, Med Oncol 2009 124 non-clear 55 papillaryPFS 7.0 vs 1.8 mo (Tems vs IFN) OS 11.6 vs 4.3 mo (Tems vs IFN) Sunitinib or Sorafenib (retrospective) Choueiri TK, JCO 2008 41 papillaryPFS 11.9 (Sunitinib) vs 5.1 mo (Sorafenib) Sunitinib (phase II) Ravaud A, JCO 2009, abstr 5146 5 papillary type I 23 papillary type II No response 1 PR PFS/OS ongoing Sunitinib (EAP) Gore ME, Lancet Oncol 2009 588 non-clearOS 9.4 (non-clear) vs 13.4 (clear) mo Erlotinib [EGFR inhibitor] (phase II) Gordon MS, JCO 2009 45 papillary64% SD+PR OS 27 mo Sunitinib (phase II) Plimack ER, JCO 2010, abstr 4604 23 papillaryPFS 1.6 mo, OS 10.6 mo Sorafenib (EAP) Stadler WM, Cancer 2010 202 non-clear: 107 papillary 20 chromophobe 84% SD+PR; 16% PD 90% SD+PR; 10% PD PFS 11.5 mo; OS 12.5 mo Gemcitabine + Cisplatin or Carboplatin (phase II) Oudard S, J Urol 2007 23 mets collecting duct RCC26% PR (5) + CR (1) PFS 7.1 mo, OS 10.5 mo CLINICAL TRIALS CONSIDERING NON-CLEAR CELL RCC

7. REGIMENNR of PTSEFFICACY (MEDIAN)/ ACTIVITY Bortezomib (phase II) NCI, Los Angeles http://clinicaltrials.gov/NCT00276614 3 mets non-clear-Start Date: April 2006 -Estimated Study Completion: July 2009 Everolimus (RAPTOR-phase II) http://clinicaltrials.gov/NCT00688753 60 advanced papillary-study start:July 2009 -estimated primary completion: July 2011 Temsirolimus vs Sunitinib (phase II) Central European Society http://clinicaltrials.gov/NCT00979966 108 advanced or mets non- clear -Start Date: July 2009 -Estimated Study Completion: July 2011 Sunitinib (phase II) IC Humanitas (MI) http://clinicaltrials.gov/NCT01034878 55 mets non-clear-Start Date: Dec 2009 -Estimated Study Completion: Nov 2011 Sunitinib (phase II) Asan Medical Center http://clinicaltrials.gov/NCT01219751 35 advanced non-clear-Start Date: June 2008 -Estimated Study Completion: September 2011 NEW CLINICAL TRIALS FOR NON-CLEAR CELL RCC: COMPLETED -I-

8. REGIMENNR of PTSEFFICACY (MEDIAN)/ ACTIVITY Gemcitabine + Irinotecan (phase II) NCI, Cleveland http://clinicaltrials.gov/NCT00401128 30 mRCC (clear and non-clear)-2ary endpoint: % response of clear vs non-clear -Start Date: May 2004 Pemetrexed + Gemcitabine (phase II) MDACC (Houston) http://clinicaltrials.gov/NCT00491075 16 advanced non-clear-Start Date: Dec 2005 -Estimated Study Completion: Sep 2011 Capecitabine (phase II) Kidney Cancer Research Bureau http://clinicaltrials.gov/NCT01182142 51 mets non-clear-Start Date: Sept 2007 -Estimated Study Completion: August 2010 NEW CLINICAL TRIALS FOR NON-CLEAR CELL RCC: COMPLETED -II-

9. REGIMENEstimated NR of PTSEFFICACY (MEDIAN)/ ACTIVITY Everolimus (phase II) Seoul National University Hospital http://clinicaltrials.gov/NCT00830895 48 mets non-clear-study start:January 2009 -estimated primary completion: March 2012 Sunitinib (phase II) MDACC (Houston) http://clinicaltrials.gov/NCT00465179 60 advanced non-clear-Start Date: March 2010 -Estimated Study Completion: March 2013 Everolimus vs Sunitinib (phase II) MDACC (Houston) http://clinicaltrials.gov/NCT01185366 108 advanced non-clear-Start Date: August 2010 -Estimated Study Completion: August 2013 Everolimus vs Sunitinib (phase II) Duke University http://clinicaltrials.gov/NCT01108445 108 mets non-clear-Start Date: September 2010 -Estimated Study Completion: September 2014 Everolimus + Bevacizumab (phase II) MSKCC http://clinicaltrials.gov/NCT01399918 34 advanced non-clear-Study start: July 2011 -Estimated study completion: July 2013 Erlotinib + Bevacizumab (phase II) http://clinicaltrials.gov/NCT01130519 40 papillary (sporadic/hereditary) -Study start: May 2010 -Estimated study completion: March 2017 Tivozanib (phase II) AVEO Pharmaceuticals http://clinicaltrials.gov/NCT01297244 100 advanced RCC (clear and non-clear) -Start Date: January 2011 -Estimated Study Completion: June 2012 NEW CLINICAL TRIALS FOR NON-CLEAR CELL RCC: ONGOING

10. UP DATE FROM

11. 894/2076 (43%) pts ineligible for clinical trials

12. Adapted from Heng D et al, ASCO GU 2012

16. Non-clear cell histology remains a significant and independent risk factor for cancer specific death for mRCC pts treated by TT 25 non-clear cell 132 clear cell treated with TT: median survival 15.4 mo (non-clear) vs 35 mo (clear) p=0.007

17. 37 pts -> intermittent schedule 37 pts -> daily schedule Adverse events: -Hypertension 50% -Pulmonary embolism 11% -Fatigue 6.8% -Diarrhea 6.8%

18. Adapted from Choueiri TK et al, ASCO GU 2012

19. 67/74 pts evaluable for both MET mutation and response to Foretinib: 5/10 (50%) pts with germline MET mutation: PR 5/10 (50%) pts with germline MET mutation: SD 5/57 (9%) pts without germline MET mutation: PR 1/5 (20%) pts with somatic MET mutation: PR

20. Sporadic papillary RCC is different from hereditary papillary RCC?

21. Adapted from Cho D, ASCO GU 2012 CONCLUSIONS -I-

22. Adapted from Cho D, ASCO GU 2012 CONCLUSIONS -II-

23. CONCLUSIONS -III- Multidisciplinary approach to RCC patients (Pathologist, Urologist, Oncologist, Radiologist, Statistician, Nurse, …)