1. Dr. Camillo Porta S.C. di Oncologia Medica, I.R.C.C.S. Fondazione Policlinico San Matteo, Pavia

2. Risk stratification: Motzer or Heng? (I) 1999 MSKCC (or Motzer’s) prognostic stratification system 1 low KPS (<80%), high LDH levels (>1.5 x ULN), low Hb levels, high corrected Ca ++ (>10 mg/dL) and the absence of previous nephrectomy 1999 MSKCC (or Motzer’s) prognostic stratification system 1 low KPS (<80%), high LDH levels (>1.5 x ULN), low Hb levels, high corrected Ca ++ (>10 mg/dL) and the absence of previous nephrectomy 2000 MSKCC (or Motzer’s) prognostic stratification system 2 low KPS (<80%), high LDH levels (>1.5 x ULN), low Hb levels, high corrected Ca ++ (>10 mg/dL) and time from diagnosis to treatment < 1 year 2000 MSKCC (or Motzer’s) prognostic stratification system 2 low KPS (<80%), high LDH levels (>1.5 x ULN), low Hb levels, high corrected Ca ++ (>10 mg/dL) and time from diagnosis to treatment < 1 year 1 Motzer RJ, et al. J Clin Oncol 1999; 2 Motzer RJ, et al. J Clin Oncol 2000

3. Risk stratification: Motzer or Heng? (II) 2009 Heng’s prognostic stratification system 1 low KPS (<80%), low Hb levels, time from diagnosis to treatment < 1 year high Ca ++ levels high platelet count high neutrophil count 2009 Heng’s prognostic stratification system 1 low KPS (<80%), low Hb levels, time from diagnosis to treatment < 1 year high Ca ++ levels high platelet count high neutrophil count 0 risk factors – favorable risk 1-2 risk factors – intermediate risk 3-6 risk factors – poor risk 0 risk factors – favorable risk 1-2 risk factors – intermediate risk 3-6 risk factors – poor risk 1 Heng DY, et al. J Clin Oncol 2009

4. My choice is … Keep it simple, folks!!!

5. 2012 ESMO Guidelines Escudier B, et al. Ann Oncol 2012

6. Standard 1 st -line treatment options Motzer RJ, et al. N Engl J Med 2007; Escudier B, et al. Lancet 2007; Sternberg CN, et al. J Clin Oncol 2010

7. Why differences in the levels of evidence? Escudier B, et al. Ann Oncol 2012 Sunitinib – right comparator, good study design, primary end-point met Bevacizumab + Interferon-  – ideal comparator (+ placebo), reasonable study design, primary end-point NOT met Pazopanib – criticizable study design (placebo-controlled, mix of Tx-naïve and pre- treated pts), primary end-point met Sunitinib – right comparator, good study design, primary end-point met Bevacizumab + Interferon-  – ideal comparator (+ placebo), reasonable study design, primary end-point NOT met Pazopanib – criticizable study design (placebo-controlled, mix of Tx-naïve and pre- treated pts), primary end-point met

8. Any other option? Rosenberg SA, et al. Ann Surg 1998 High-dose i.v. IL_2 Escudier B, et al. Ann Oncol 2012

9. Sorafenib registrative study 1 was performed in a 2 nd -line setting (mainly in patients refractory to cytokines), but its label, at least in the EU, allows the treatment also of patients unsuitable for cytokines, leaving open the opportunity of using it 1 st -line Despite this, a randomized phase II study of Sorafenib or Interferon in 1 st - line failed to demonstrate any PFS benefit for Sorafenib over Interferon 2 1 Escudier B, et al. N Engl J Med 2007; 2 Escudier B, et al. J Clin Oncol 2009 And, what about Sorafenib?

10. 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. Should we move from Sunitinib to Pazopanib? The ‘PISCES’ trial 1 showed that: – Pazopanib is preferred by patients over Sunitinib – Pazopanib is better tolerated and induces less AEs The ‘COMPARZ’ trial 2 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 Clin Oncol 2012; 2. Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)

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

14. a 4 weeks on treatment → 2 weeks matching placebo → 4 weeks on treatment Stratification factors: ECOG PS (0 vs 1) metastatic sites (1 vs ≥ 2) 2-week washout Period 2 Period 1 End of study n = 169 Sunitinib 50 mg 4/2 a Pazopanib 800 mg OD Sunitinib 50 mg 4/2 a R Time (weeks) 0 12 2210 Double-blind phase Patient preference of further treatment 10 weeks 1:1 Escudier B, et al. J Clin Oncol 2012;30(suppl.):abs. CRA4502 ‘PISCES’: patients’ preference trial of Pazopanib vs Sunitinib

15. a 4 weeks on treatment → 2 weeks matching placebo → 4 weeks on treatment Stratification factors: ECOG PS (0 vs 1) metastatic sites (1 vs ≥ 2) 2-week washout Period 2 Period 1 End of study n = 169 Sunitinib 50 mg 4/2 a Pazopanib 800 mg OD Sunitinib 50 mg 4/2 a R Time (weeks) 0 12 2210 Double-blind phase Patient preference of further treatment 10 weeks 1:1 Escudier B, et al. J Clin Oncol 2012;30(suppl.):abs. CRA4502 ‘PISCES’: patients’ preference trial of Pazopanib vs Sunitinib

16. 1. The lenght of the observation period Motzer RJ, et al. J Clin Oncol 2012 nMedian PFS, months (95% CI) HRP Tivozanib18112.7 (9.1–15.0)0.7560.037 Sorafenib1819.1 (7.3–10.8)

17. Furthermore, we know that … (1) Hutson TE, et al. Eur J Cancer 2010 35 30 25 20 15 10 5 0 123456789 12131415161718 New occurrence of AE (%)* Cycle Diarrhoea Fatigue Hypertension 0 *Percentage of new events occurring in a particular cycle 11 HFSR Sorafenib

18. Furthermore, we know that … (2) Reason for discontinuation, n (%) <6 months of sunitinib treatment (n=1,696) ≥6 months of sunitinib treatment (n=1,264) Adverse event217 (13)77 (6) Consent withdrawn115 (7)114 (9) Lack of efficacy570 (34)540 (43) Death487 (29)188 (15) Other*307 (18)345 (27) *Includes protocol violation, lost to follow-up, laboratory abnormality(ies), sponsor decision, not meeting entrance criteria, and missing patients Sunitinib (EAP) Porta C, et al. ASCO 2008

19. Furthermore, we know that … (2) Reason for discontinuation, n (%) <6 months of sunitinib treatment (n=1,696) ≥6 months of sunitinib treatment (n=1,264) Adverse event217 (13)77 (6) Consent withdrawn115 (7)114 (9) Lack of efficacy570 (34)540 (43) Death487 (29)188 (15) Other*307 (18)345 (27) *Includes protocol violation, lost to follow-up, laboratory abnormality(ies), sponsor decision, not meeting entrance criteria, and missing patients Sunitinib (EAP) Porta C, et al. ASCO 2008

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

21. 2. The timing of QoL assessment (II) Two recent analyses 1,2 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 cycles 1 – 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 period 1 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 data 2 1 Cella D, et al. J Clin Oncol 2012; 2 Bushmakin A, et al. Ann Oncol 2012

22. 3. Patients’ perception and their level 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 1 Schmidinger M, ESMO 2012 GU Posters Discussion

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

24. Pazopanib vs Sunitinib: the ‘COMPARZ’ trial 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 n = 876 Sunitinib 50 mg 4/2 a Pazopanib 800 mg OD RANDOMISATIONRANDOMISATION Locally advanced or metastatic RCC, with clear cell component histology No prior systemic therapy a 4 weeks on treatment → 2 weeks off treatment = 1 treatment cycle

25. ‘COMPARZ’ trial: statistical design 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 Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)

26. Methodology of non-inferiority studies (1) 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 Study 1 (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 Study 2 (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 1 Intermittant Androgen Deprivation vs Continuous Androgen Deprivation (prostate); 2 Six months vs twelve months adjuvant Trastuzumab (breast)

27. Methodology of non-inferiority studies (2) 11.25 Non-inferiority demonstrated Non-inferiority NOT demonstrated BOUND Favor experimental arm (Pazopanib) Favors control arm (Sunitinib) Non-inferiority NOT demonstrated

28. Non-inferiority CIs in the ‘COMPARZ’ trial 11.25 BOUND 1.22 0.898 1.20 1.15 Non-inferiority demonstrated Favor experimental arm (Pazopanib) Favors control arm (Sunitinib)

29. ‘COMPARZ’ trial: statistical design 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 Motzer RJ, et al. ESMO 2012 (Presidential Symposium II)

30. ‘COMPARZ’ trial: the issue of a mixed population

31. Asian patients and Sunitinib In Asian patients, Sunitinib is less tolerated, leading to higher toxicity rates and the widespread use of reduced doses 1,2 ; since a clear-cut relationship exists between exposure and efficacy 3, an inferior activity in these patients could be expected. And indeed, Tx duration in Asia is definitely lower than in the rest of the world 1,2,4 1 Yoo C, et al. Jpn J Clin Oncol 2010; 2 Kim HS, et al. Eur J Cancer 2012; 3 Houk BE, et al. Cancer Chemother Pharmacol 2010; 4 Choueiri TK, et al. Manuscript in preparation.

32. So what? ‘PISCES’ and ‘COMPARZ’ clearly support the use of Pazopa- nib as a reasonable Tx option in 1 st 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

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

34. Try to make simple what is complex “… Even though Physics tells us that chaos can be, and often is, a property of very simple systems, meaning that simple questions usually have complicated answers, our only way out could be found turning upside-down this concept: in a complex system (e.g., kidney cancer) we should look for an easy – and credible – answer to our doubts. And such an answer probably is Chris Ryan’s ‘simplified algorythm’ statement: “choose any agent You want. Use it well” … A shortcut, for sure, but a smart one, and also a glowing glance of simplicity to move out from the fogs of chaos”. Porta C. Eur Urol 2011

35. Thank You for Your kind attention!!! T T c.porta@smatteo.pv.it