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

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

Linehan et al, Annu Rev Med 2010

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

REGIMENNR of PTSEFFICACY (MEDIAN)/ ACTIVITY Temsirolimus vs IFN vs Tem+IFN (phase III) Hudes, NEJM 2007 Dutcher JP, Med Oncol 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 papillaryPFS 11.9 (Sunitinib) vs 5.1 mo (Sorafenib) Sunitinib (phase II) Ravaud A, JCO 2009, abstr papillary type I 23 papillary type II No response 1 PR PFS/OS ongoing Sunitinib (EAP) Gore ME, Lancet Oncol non-clearOS 9.4 (non-clear) vs 13.4 (clear) mo Erlotinib [EGFR inhibitor] (phase II) Gordon MS, JCO papillary64% SD+PR OS 27 mo Sunitinib (phase II) Plimack ER, JCO 2010, abstr papillaryPFS 1.6 mo, OS 10.6 mo Sorafenib (EAP) Stadler WM, Cancer 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 mets collecting duct RCC26% PR (5) + CR (1) PFS 7.1 mo, OS 10.5 mo CLINICAL TRIALS CONSIDERING NON-CLEAR CELL RCC

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

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

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

UP DATE FROM

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

Adapted from Heng D et al, ASCO GU 2012

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

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

Adapted from Choueiri TK et al, ASCO GU 2012

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

Sporadic papillary RCC is different from hereditary papillary RCC?

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

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

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