HOW TO SELECT AMONG AVAILABLE OPTIONS FOR THE TREATMENT OF ADVANCED RCC:

1. HOW TO SELECT AMONG AVAILABLE OPTIONS FOR THE TREATMENT OF ADVANCED RCC: • FAVORABLE AND INTERMEDIATE RISK PATIENTS Dr.CamilloPorta S.C. di OncologiaMedica, I.R.C.C.S. FondazionePoliclinico San Matteo, Pavia

2. Riskstratification: Motzer or Heng? (I) 1999 MSKCC (or Motzer’s) prognosticstratification system1 low KPS (<80%), high LDH levels (>1.5 x ULN), lowHblevels, high corrected Ca++ (>10 mg/dL) and the absence of previousnephrectomy 2000 MSKCC (or Motzer’s) prognosticstratification system2 low KPS (<80%), high LDH levels (>1.5 x ULN), lowHblevels, high corrected Ca++ (>10 mg/dL) and time from diagnosis to treatment < 1 year 1Motzer RJ, et al. JClinOncol 1999; 2Motzer RJ, et al. JClinOncol 2000

3. Riskstratification: Motzer or Heng? (II) 2009 Heng’sprognosticstratification system1 low KPS (<80%), lowHblevels, time from diagnosis to treatment < 1 year high Ca++levels high plateletcount high neutrophilcount 0 riskfactors – favorablerisk 1-2 riskfactors – intermediate risk 3-6 riskfactors – poorrisk 1Heng DY, et al. JClinOncol 2009

4. My choiceis … Keepitsimple, folks!!!

5. 2012 ESMO Guidelines Escudier B, et al. AnnOncol 2012

6. Standard 1st-line treatment options Motzer RJ, et al. NEnglJMed 2007; Escudier B, et al. Lancet 2007; Sternberg CN, et al. JClinOncol 2010

7. Whydifferences in the levels of evidence? Sunitinib – right comparator, goodstudy design, primary end-pointmet Bevacizumab + Interferon-a– idealcomparator (+ placebo), reasonablestudy design, primary end-point NOT met Pazopanib– criticizablestudy design (placebo-controlled, mix of Tx-naïve and pre-treatedpts), primary end-pointmet Escudier B, et al. AnnOncol 2012

8. Anyother option? High-dose i.v. IL_2 And, do not forget another (even though difficult) option, i.e., wait and see … Rosenberg SA, et al. Ann Surg 1998 Escudier B, et al. AnnOncol 2012

9. Sorafenibregistrative study1wasperformed in a 2nd-line setting (mainly in patientsrefractory to cytokines), butitslabel, atleast in the EU, allows the treatment also of patientsunsuitable for cytokines, leaving open the opportunity of usingit 1st-line And, whataboutSorafenib? Despite this drawback, this study lead to the erroneous conclusion that Sorafenib is a weaker TKI Despitethis, a randomizedphase II study of Sorafenib or Interferon in 1st- line failed to demonstrateany PFS benefit for Sorafenib over Interferon2 1Escudier B, et al.N Engl J Med 2007; 2Escudier B, et al. J ClinOncol 2009

10. ASCO GU 2013Results from phase III AGILE 1051 report that PFS was not statistically different with AxitinibvsSorafenibas 1st-line therapy Even though … Furthermore, … Adapted from the slide presented by Professor Tim Eisen at ASCO 2012 to show only first-line data; to show data according to time of first presentation, rather than final publication (hence variation between publication year and year on graph); and to indicate how many patients were included in the sorafenib arm/analysis (using bubble size) Motzer RJ, et al. ASCO 2012; Rini B, et al. Cancer 2012; Stadler WM, et al. Cancer 2010; Bellmunt J, et al. Clin Transl Oncol 2010; Jonasch E, et al. Cancer 2010; Procopio G, et al. Br J Cancer 2011; Beck J, et al. ECCO 2007; Escudier B, et al. J Clin Oncol 2009.

11. Now, let’s try to address an embarassing question …

12. The ‘PISCES’ trial1 showed that: • Pazopanibis preferred by patients over Sunitinib • Pazopanibis better tolerated and induces less AEs Shouldwemove from Sunitinib to Pazopanib? If so, why not shifting all our patients from Sunitinib to Pazopanib? • The ‘COMPARZ’ trial2 showed that: • Pazopanib is not inferior as compared to Sunitinib in terms of efficacy • Pazopanib is able to induce higher objective response rates as compared to Sunitinib 1. Escudier B, et al. J ClinOncol2012; 2. Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)

13. Let’s go for bugs in the ‘PISCES’ trial …

14. ‘PISCES’: patients’ preference trial of Pazopanib vs Sunitinib Period 2 Period 1 Pazopanib800 mg OD Sunitinib50 mg 4/2a Patient preferenceof further treatment R 1:1 n = 169 Pazopanib800 mg OD Sunitinib50 mg 4/2a 2-week washout 10 weeks 10 weeks End of study Double-blind phase 12 0 10 22 Time (weeks) • Stratification factors: • ECOG PS (0 vs 1) • metastatic sites (1 vs ≥ 2) a4 weeks on treatment → 2 weeks matching placebo → 4 weeks on treatment Escudier B, et al. J ClinOncol2012;30(suppl.):abs. CRA4502

15. ‘PISCES’: patients’ preference trial of Pazopanib vs Sunitinib Period 2 Period 1 Pazopanib800 mg OD Sunitinib50 mg 4/2a Patient preferenceof further treatment R 1:1 n = 169 Pazopanib800 mg OD Sunitinib50 mg 4/2a 2-week washout 10 weeks 10 weeks End of study Double-blind phase 12 0 10 22 Time (weeks) • Stratification factors: • ECOG PS (0 vs 1) • metastatic sites (1 vs ≥ 2) a4 weeks on treatment → 2 weeks matching placebo → 4 weeks on treatment Escudier B, et al. J ClinOncol2012;30(suppl.):abs. CRA4502

16. 1. The lenght of the observationperiod Motzer RJ, et al. J ClinOncol2012

17. HFSR Diarrhoea Fatigue Hypertension Furthermore, weknowthat … (1) 35 Sorafenib 30 25 20 New occurrence of AE (%)* 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Cycle *Percentage of new events occurring in a particular cycle Hutson TE, et al. Eur J Cancer 2010

18. Furthermore, weknowthat … (2) Sunitinib (EAP) *Includes protocol violation, lost to follow-up, laboratory abnormality(ies), sponsor decision, not meeting entrance criteria, and missing patients Porta C, et al. ASCO 2008

19. Furthermore, weknowthat … (2) Sunitinib (EAP) MOTION REJECTED Even though long term safety has not been considered, all TKIs act almost the same way *Includes protocol violation, lost to follow-up, laboratory abnormality(ies), sponsor decision, not meeting entrance criteria, and missing patients Porta C, et al. ASCO 2008

20. 2. The timing of QoLassessment (I) • Timing of assessment of patients’ preference clearly unfavouredSunitinib [in both the ‘PISCES’1 and COMPARZ’2 trial] • Indeed, end of week 22 = Day 28 (i.e., the worst possible in terms of toxicity) in a typical Sunitinibcycle3 1Schmidinger M, ESMO 2012 GU Posters Discussion; 2Eisen T, ESMO 2012 Presidential Symposium II Discussion; 3Cella D, et al. Ann Oncol2012

21. 2. The timing of QoLassessment (II) • Two recent analyses1,2 examined the impact of Sunitinib dosing schedule on measurement of patient-reported fatigue and HRQoL Fatigue • Compared with baseline, patients reported worse fatigue during the first cycle of Sunitinib treatment; however, less fatigue was reported in all consecutive treatment cycles1 • Sunitinib Schedule 4/2 was associated with an “on–off” effect, with patients reporting more fatigue on Day 29 of each cycle following 4 weeks on treatment and less fatigue on Day 1 of each cycle following the 2-week off-treatment period1 HRQoL • Variability in patient experience of HRQoL on Day 1 compared with Day 28 for Sunitinib on Schedule 4/2 is statistically significant, and should be accounted for when collecting HRQoL data2 MOTION ACCEPTED This discrepancy could have greatly affected safety evaluations 1Cella D, et al. J Clin Oncol2012; 2Bushmakin A, et al. Ann Oncol 2012

22. 3. Patients’ perception and theirlevel of information • Were the patients informed that side-effects [at least, some of them, e.g., hypertension and HFSR] are regarded as predicitve of efficacy? How would preference then look like?1 MOTION REJECTED Relationship between toxicities – other than hypertension – and outcome is weak 1Schmidinger M, ESMO 2012 GU Posters Discussion

23. Let’s go for bugs in the ‘COMPARZ’ trial …

24. RANDOMISATION Pazopanib800 mg OD Pazopanib vs Sunitinib: the ‘COMPARZ’ trial • Locally advanced or metastatic RCC, with clear cell component histology • No prior systemic therapy Sunitinib50 mg 4/2a n = 876 • Primary endpoint: • PFS (non-inferiority) • Secondary endpoints: • OS • ORR (objective response rate) • duration of response • safety • QoL (quality of life) ‘COMPARZ’ trial (NCT00720941) Start date: August 2008 Recruitment: complete a4 weeks on treatment → 2 weeks off treatment = 1 treatment cycle

25. PFS non-inferiority demonstrated if upper bound of 95% CI for HR<1.25 Cox proportional hazard analysis adjusted for stratification factors By independent review 631 PFS events needed for 80% power Planned enrollment of 1100 patients* * original sample of 876 increased during study conduct to 1100 to obtain the 631 prespecified number of PFS events ‘COMPARZ’ trial: statistical design Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)

26. In non-inferiority studies, the non-inferiority bounds of 95% CI for HR is usually comprised between 1.15 and 1.20; for example: S9346 Study1 (ASCO 2012) – the upper bound of 95% CI for HR was 1.20 For an HR for OS = 1.09 (0.95-1.24), the study was declared as negative PHARE Study2 (ESMO 2012) – the upper bound of 95% CI for HR was 1.15 For an HR for DFS = 1.28 (1.04-1.56), the study was declared as negative Methodology of non-inferioritystudies (1) 1Intermittant Androgen Deprivation vs Continuous Androgen Deprivation (prostate); 2Six months vs twelve months adjuvant Trastuzumab (breast)

27. BOUND Non-inferiority NOT demonstrated Methodology of non-inferioritystudies (2) Non-inferiority NOT demonstrated Non-inferiority NOT demonstrated Non-inferiority demonstrated 1 1.25 Favor experimental arm (Pazopanib) Favors control arm (Sunitinib)

28. BOUND Non-inferiorityCIs in the ‘COMPARZ’ trial MOTION REJECTED nobody could have predicted the CI bounds of the ‘COMPARZ’ study Non-inferiority demonstrated 1.22 0.898 1.15 1.20 1 1.25 Favor experimental arm (Pazopanib) Favors control arm (Sunitinib)

29. PFS non-inferiority demonstrated if upper bound of 95% CI for HR<1.25 Cox proportional hazard analysis adjusted for stratification factors By independent review 631 PFS events needed for 80% power Planned enrollment of 1100 patients* * original sample of 876 increased during study conduct to 1100 to obtain the 631 prespecified number of PFS events ‘COMPARZ’ trial: statistical design Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)

30. ‘COMPARZ’ trial: the issue of a mixedpopulation ACCEPTED by EMA, but methodologically acceptable?

31. Asian patients and Sunitinib MOTION ACCEPTED This is indeed a potentially huge bias In Asian patients, Sunitinib is less tolerated, leading to higher toxicity rates and the widespread use of reduced doses1,2; since a clear-cut relationship exists between exposure and efficacy3, an inferior activity in these patients could be expected. And indeed, Tx duration in Asia is definitely lower than in the rest of the world1,2,4 1Yoo C, et al. Jpn J ClinOncol2010;2Kim HS, et al. Eur J Cancer 2012; 3Houk BE, et al. CancerChemotherPharmacol 2010; 4Choueiri TK, et al. Manuscript in preparation.

32. ‘PISCES’ and ‘COMPARZ’ clearly support the use of Pazopa-nib as a reasonable Tx option in 1st line Pazopanib safety profile is superior as compared to Suni-tinib; however, Sunitinib – despite the non-inferiority results of the ‘COMPARZ’ trial – remains slightly more efficacious As Medical Oncologists and Urologist, we should be happy for the availability of different Tx options (and do not forget other drugs!) to really tailor Tx on the basis of each given patient’s needs So what?

33. Considering all the above Is there a reasonable Tx standard for mRCC today?

34. Try to makesimplewhatiscomplex “… EventhoughPhysicstellsusthatchaos can be, and oftenis, a property of verysimplesystems, meaningthatsimplequestionsusuallyhavecomplicatedanswers , ouronly way out could be foundturningupside-down thisconcept: in a complexsystem (e.g., kidneycancer) weshould look for an easy – and credible – answer to ourdoubts. And such an answerprobablyis Chris Ryan’s ‘simplifiedalgorythm’ statement: “chooseany agent Youwant. Use itwell” … A shortcut, for sure, but a smartone, and also a glowingglance of simplicity to move out from the fogs of chaos”. Porta C. EurUrol2011

35. ThankYou for Your kindattention!!! T c.porta@smatteo.pv.it