1. Roberto Sabbatini Azienda Ospedaliero Universitaria di Modena Policlicnico di Modena HOT TOPICS Controversie Oncologiche Prima linea di Trattamento Scuola di UrOncologia Tumore del rene Roma 23-24 maggio 2014

2. My disclosures

3. RCC accounts for: – 80–85% of renal cancers 1 – 2–3% of all adult malignancies 2 – 63,000 new cases/year in Europe – 26,000 mortalities annually RCC is: – More common in men than women 3,4 – Most frequently occurs in 60–70 year olds 4 – More common in people from Northern European and North American countries 3,4 1. Motzer RJ et al. N Engl J Med 1996;335:865–75; 2. Levine E et al. Adult malignant renal parenchymal neoplasms. In Clinical urography, 2nd edition. 2000, Saunders: Philiadelphia, USA. p. 1440–559; 3. GLOBOCAN 2002; Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006 http://www-dep.iarc.fr/; 4. Cancer Research UK, UK kidney cancer statistics. 2008 http://info.cancerresearchuk.org/cancerstats/types/kidney/?a=5441. Incidence Mortality Renal Cell Carcinoma The epidemiology Renal Cell Carcinoma The epidemiology

4. Renal Cell Carcinoma: an unrelenting, progressive disease Renal Cell Carcinoma: an unrelenting, progressive disease Presentation at diagnosis 1 : 45% with localized disease 25% with locally advanced disease 20–30% metastatic disease 33% of patients treated for localized disease will develop metastatic disease 2 Common sites of metastasis include lung (75%), liver (18%), bone (20%), brain (8%) 3 Median survival for patients with metastatic RCC in the era of cytokine was 6–12 months 4–7 1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009; 2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90. 3. Sachdeva K et al. Renal cell carcinoma., in eMedicine. 2008; 4. Gay PC et al. J Neurooncol 1987;5:51–6; 5. Decker DA et al. J Clin Oncol 1984;2:169–73; 6. Culine S et al. Cancer 1998;83:2548–53; 7. Doh LS et al. Oncology 2006;20:603–13.

5. Disease specific survival by Time Period of non-Clear Cell RCC pts Disease specific survival by Time Period of Clear Cell RCC pts Disease-Specific Survival in de novo mRCC in the Cytokine and Targeted Therapy Era Pal SK, PLoS ONE 2013

6. Axitinib Cytokine/Suniti nib failure 2005 2006 2007 2008 2009 Explosion of Targeted Therapy for mRCC (phase III trial) SorafenibCytokine-resistant Sunitinib I line therapy Temsirolimus Poor prognosis Bevacizumab + IFNα I line therapy 2006 2007 2008 2009 20102014 EverolimusVEGFi-failurePazopanib I line and cytokine-failure

7. Key drivers in first-line treatment selection: Efficacy and Experience Clinical efficacy = primary driver to guide treatment decisions Targeted agents: Standard of care for mRCC Schmidinger M, Kidney Cancer Symposium, Vienna 2012

8. Temsirolimus (Hudes 2007) Sorafenib (Escudier, 2007) Bev + INF-α (Rini, 2008) Bev + INF-α (Escudier 2007) Sunitinib (Motzer 2007) Pazopanib (Sternberg 2010) Target CALGB 90206 AVOREN A6181034 VEG105192 3.7/5.5 5.7* 8.5* 10.2* 11.0* 11.1* 1.9 3 (Placebo) 5.4 (IFN) 5.2 (IFN) 5.1 (IFN) 2.8 (Placebo) 1110850 Sperimental Arm Control Arm *p<.05 4 8mos Ist-line phase III trials in mRCC Progression Free Survival

9. 7–9 Kane 2006 7.3 IFN 10.9*Temsirolimus 15.2 Placebo 17.8Sorafenib 17.4 IFN Rini ASCO 2009 18.3 BEV/IFN 18.5 Gore ASCO 2008 18.7 19.8 IFN NR 22.9 Bevacizumab + IFN 20.5 Sternberg EJC 2010 21.8 Placebo Placebo 26.4 IFN 2007 to present Phase III trials in mRCC Overall Survival *p<.05 Motzer JCO 2009 Sunitinib Motzer 2013 29.3 28.4

10. SettingTherapy Level 1 Level 2 First-line Therapy Low+Intermed Risk Sunitinib Beva/IFN Pazopanib HD Il-2 Sorafenib Poor Risk TemsirolimusSunitinib Clinical trial Second- line Therapy Prior Cytokine Sorafenib Pazopanib Axitinib Sunitinib Clinical trial Prior TKiEverolimus Axitinib Sequential TKi Algorithm for Clear Cell RCC 2012

11. 2nd-generation trials: Head to Head studies 1st-line phase III trial in mRCC AgentsN. pts Line of treatment Median PFS (mos) Median OS (mos) Tivozanib vs Sorafenib 1 500 First or CK treated 11.9 vs 9.1*NA Everolimus–Sunitinib vs Sunitinib-Everolimus 2 471First7.8 vs 10.7*NA Axitinib vs Sorafenib 288First10.1 vs 6.5*NA Pazopanib vs Sunitinib 4 1110First8.4 vs 9.528.4 vs 29.3 Axitinib “dose tritation” 5 213First 16.6 (not eligible) vs 14.5 (eligible) NA * p<.05 1. Motzer R, ASCO 2012; 2. Motzer R. ASCO 2013; 3. Hudson TE, ASCO-GU 2013 4. Motzer R, NEJM 2013; 5. Rini B, ASCO-GU 2013

12. Case study: TIVO-1 Treatment allocation imbalance? Motzer RJ, et al. J Clin Oncol 2013 Sorafenib 400 mg BID (n=257) Recurrent or mRCC with a clear cell component Measurable disease Treatment-naïve or 1 prior treatment: cytokines, investigational agent, hormonal therapy, chemotherapy Prior nephrectomy ECOG PS 0 or 1 n=517 1:1 Tivozanib 1.5 mg/day (3 weeks on-treatment; 1 week off-treatment) (n=260) RANDOMISATIONRANDOMISATION Cross-over with Tivozanib 1.5 mg/day permitted upon disease progression; extension protocol (NCT01076010) Phase III randomized, open label multicenter trial: Primary endpoint: PFS by independent review (assessment of response every 8 wks) Secondary endpoints: overall survival, ORR, quality of life

13. Primary endpoint: Tivozanib significantly prolonged PFS versus sunitinib Overall population n Median PFS (95% CI) HR P value Tivozan ib 260 11.9 mos (9.3– 14.7) 0.79 7 0.042 Sorafen ib 257 9.1 mos (7.3– 9.5) PFS probability Time, months 05101520 1.0 0.8 0.6 0.4 0.2 0.0 Motzer RJ, et al. J Clin Oncol 2013

14. BUT - No significant difference in OS (secondary endpoint) 024 6 8101214161820222426283032 0 20 40 60 80 100 Time (months) % survival Motzer RJ, et al. J Clin Oncol 2013 FDA. Tivozanib, June 2013. n Median OS (95% CI) HR P value Tivozani b 260 28.8 mos (22.5– NR) 1.250.105 Sorafeni b 257 29.3 mos (29.3– NR) Overall population

15. Why no OS benefit? 1.Garnick MB. J Clin Oncol 2013 2.FDA. Tivozanib, June 2013. http://www.fda.gov A sequential trial of two agents, sorafenib followed by tivozanib, compared with one agent, tivozanib “The sanctity of OS was compromised” 1 Sorafenib 400 mg BID (n=257) Tivozanib 1.5 mg/day (3 weeks on-treatment; 1 week off-treatment) (n=260) RANDOMISATIONRANDOMISATION *Due to lack of available TKIs in Eastern Europe Balanced? Infrequent second line treatment at time of disease progression* Cross over to tivozanib at time of disease progression FDA conclusion: “Inconsistent PFS and OS results and imbalance in post-study treatments make the trial results inconclusive when making a risk-benefit assessment necessary for approval.” 2 At the time of the final OS analysis, 156 patients (61%) randomly assigned to sorafenib had crossed over to tivozanib

16. Sunitinib 50 mg qd 4 wk on/2 wk off Sunitinib 50 mg qd 4 wk on/2 wk off Pazopanib 800 mg qd Continuous dosing Pazopanib 800 mg qd Continuous dosing COMPARZ: a non-inferiority trial Stratification factors: Karnofksy Performance Status (KPS; 70/80 vs. 90/100) Prior nephrectomy (yes vs. no) Baseline lactate dehydrogenase (LDH; >1.5 vs. ≤1.5 x ULN) Key Eligibility Criteria Advanced/metastatic RCC Clear-cell histology No prior systemic therapy Measurable disease (RECIST 1.0) KPS ≥ 70 Adequate organ function Randomized 1:1 (N = 1110) NCT01147822, n = 183 NCT00720941, n = 927 Motzer R, NEJM 2013

17. Primary Endpoint: PFS (Independent Review) 17 Median PFS (95% CI) Pazopanib8.4 mo (8.3, 10.9) Sunitinib9.5 mo (8.3, 11.1) HR (95% CI ) = 1.047 (0.898,1.220) Motzer R, NEJM 2013

18. 18 Chemistry labs Pazopanib (n = 554) %Sunitinib (n = 548) % All GradesGrade 3/4All GradesGrade 3/4 AST6111/1603/0 ALT6015/2434/<1 Hyperglycemia545/0574/<1 Total bilirubin363/<1272/<1 Hypophosphatemia364/0528/<1 Hyponatremia357/<1327/<1 Hypoalbuminemia33<1/0422/0 Creatinine32<1/046<1/<1 Hematology labs Leukopenia431/0786/0 Neutropenia374/<16819/1 Thrombocytopenia413/<17818/4 Lymphopenia385/05514/<1 Anemia311/<1606/1 a Reported in (≥30%) of patients in either arm. Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib. Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib. Laboratory Abnormalities a Motzer R, NEJM 2013

19. 19 Adverse Event a Pazopanib (n = 554) %Sunitinib (n = 548) % All GradesGrade 3/4All GradesGrade 3/4 Any event b >9959/15>9957/17 Diarrhea63 9/0 57 7/<1 Fatigue55 10/<1 63 17/<1 Hypertension46 15/<1 41 15/<1 Nausea45 2/0 46 2/0 Decreased appetite37 1/0 37 3/0 Hair color changes30 0/0 10 <1/0 Hand-foot syndrome29 6/0 50 11/<1 Common Treatment-Emergent Adverse Events a a Adverse events ≥30% in either arm b 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events. Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib. Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib. Motzer R, NEJM 2013

20. ……. The median duration of treatment was similar in the two groups: 8.0 months (range, 0 to 40) in the pazopanib group and 7.6 months (range, 0 to 38) in the sunitinib group. Similar percentages of patients in the pazopanib and sunitinib groups had a dose interruption of 7 days or more (44% and 49%, respectively) or a reduction in the dose (44% and 51%, respectively). The proportion of patients who discontinued the study drug because of adverse events was 24% in the pazopanib group and 20% in the sunitinib group (Table S5 in the Supplementary Appendix); the higher discontinuation rate observed for pazopanib, as compared with sunitinib, was primarily due to abnormalities in liver-function tests (6% vs. 1%). COMPARZ trial: Adverse Events Motzer R, NEJM 2013 ….. There were no between-group differences in the rates of cardiovascular adverse events. The percentages of patients meeting cardiac-dysfunction criteria15 were similar: 13% in the pazopanib group and 11% in the sunitinib group (Table S7 in the Supplementary Appendix). The incidence of myocardial infarction or ischemia was similar in the pazopanib and sunitinib groups (2% and 4%, respectively).

21. Everolimus 10 mg/day Sunitinib 50 mg/day*** 2 nd Line *NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off. Primary PFS-1 st line Secondary Combined PFS ORR-1 st line OS Safety Study endpoints Cross-over upon progression 1 : 1 RANDOMIZ E** E** Everolimus 10 mg/day SCREENSCREENSCREENSCREEN Sunitinib 50 mg/day*** 1 st Line RECORD-3: Phase II randomized trial comparing sequential 1st-line everolimus and 2nd-line sunitinib vs 1st-line sunitinib and 2nd-line everolimus Motzer R, ECC 2013 Primary Endpoint: 1st-line PFS for non-inferiority of everolimus vs sunitinib Bayesian method: non-inferiority declared if observed HR ≤1.1 (1-month difference in the median first-line PFS) 318 first-line events needed (total 460 patients)

22. Primary End Point: First-line PFS 100 90 80 70 60 50 40 30 20 10 0 03691215182124273033 Time (months) 238 233 164 181 118 145 88 108 68 84 44 55 31 42 23 28 12 15 5959 0303 0000 Number of patients still at risk Everolimus Sunitinib Everolimus (events/N = 182/238) Sunitinib (events/N = 158/233) Cumulative event-free probability (%) K-M Median PFS (mo) EverolimusSunitinib 7.8510.71 Hazard Ratio = 1.43 Two-sided 95% CI [1.15, 1.77] Motzer R, ECC 2013

23. RECORD-3: combined PFS* 100 90 80 70 60 50 40 30 20 10 0 03691215182124273033 EVE→SUN SUN→EVE 238 Number of patients still at risk 233 186 196 145 171 112 135 88 105 65 74 48 52 37 35 19 6 12 0 4 0 0 Cumulative event-free probability (%) Time (months) EVE→SUN (events/N = 88/238) SUN→EVE (events/N = 80/233) * Time from randomization to progression following second-line treatment or death (any time). K-M Median PFS (mo) EVE→SUNSUN→EVE 21.1325.79 Hazard Ratio = 1.28 Two-sided 95% CI [0.94, 1.73] Log-rank p-value = 0.116 Motzer R, ECC 2013

24. RECOR-3: Overall Survival 100 90 80 70 60 50 40 30 20 10 0 0369121518212427303336 Cumulative event-free probability (%) Time (months) EVE→SUN (events/N = 108/238) SUN→EVE (events/N = 96/233) 238 Number of patients still at risk 233 208 220 189 198 165 185 151 164 137 152 103 115 66 71 43 38 15 22 2 6 0 1 0 0 K-M Median OS (mo) EVE→SUNSUN→EVE 22.4132.03 Hazard Ratio = 1.24 Two-sided 95% CI [0.94, 1.64] EVE→SUN SUN→EVE

25. Drugs blinded by over-encapsulation Patients on sunitinib received matchingplacebo during 2-week ‘off-period’ 2-week washoutPeriod 2Period 1Off study 1:1 Randomisation Patient choice of treatment to progression n=169 Sunitinib 50 mg 4/2, 10 weeks Pazopanib 800 mg once daily, 10 weeks Sunitinib 50 mg 4/2, 10 weeks Time (weeks) 0122210 Double-blind PISCES Timing assessments Escudier B, et al. JCO 2014 Cross-over design:

26. Primary endpoint: Significantly more pts preferred PAZO over SUNI Patients, % p<0.001 70% (n=80) 22% (n=25) 8% (n=9) Patients were still blinded when they stated their preference Escudier B, et al. JCO 2014

27. Temsirolimus (Hudes 2007) Sorafenib (Escudier, 2007) Bev + INF-α (Rini, 2008) Bev + INF-α (Escudier 2007) Sunitinib (Motzer 2007) Pazopanib (Sternberg 2010) Target CALGB 90206 AVOREN A6181034 VEG105192 3.7/5.5 5.7* 8.5* 10.2* 11.0* 11.1* 1.9 3 (Placebo) 5.4 (IFN) 5.2 (IFN) 5.1 (IFN) 2.8 (Placebo) 1110850 Sperimental Arm Control Arm Tivozanib (Motzer 2013) VEG105192 11.9* 9.1 (Sorafenib) COMPARZ 8.4 9.5 (Sunitinib) Pazopanib (Motzer 2013) *p<.05 4 8mos Ist-line phase III trials in mRCC Progression Free Survival RECORD-3 Everolimus (Motzer 2014) 7.8 10.7 (Sunitinib)

28. SettingTherapy Level 1 Level 2 First-line Therapy Low+Intermed Risk Sunitinib Beva/IFN Pazopanib HD Il-2 Sorafenib Poor Risk TemsirolimusSunitinib Clinical trial Second- line Therapy Prior Cytokine Sorafenib Pazopanib Axitinib Sunitinib Clinical trial Prior TKiEverolimus Axitinib Sequential TKi Algorithm for Clear Cell RCC 2014

29. Key drivers in first-line treatment selection: Efficacy and Experience Clinical efficacy = primary driver to guide treatment decisions Safety and Clinical experience should also be considered when making treatment decisions Targeted agents: Standard of care for mRCC Schmidinger M, Kidney Cancer Symposium, Vienna 2012

30. EB Guideline Efficacy Safety Multiple factors that should be considered when selecting a targeted therapy for mRCC pts Patient Proflie Safety

31. Major drugs suspected of potential drug interaction with targeted agents

32. EB Guideline Efficacy Safety Multiple factors that should be considered when selecting a targeted therapy for mRCC pts Patient Proflie Patient Profile Safety

33. Tolerability Profiles Can Help to Guide Selection of Treatment: Patient-related Factors and Comorbidities Patient with reduced EF Patients with impaired mobility Patient with nutrition disorders Consider the patient's profession Consider comedications (drug interactions) 3 Chronic obstructive pulmonary disease Thromboembolic disease Diabetes Mellitus

34. clinical trial populations may not represent real-life populations of patients, because trial inclusion and exclusion criteria often eliminate numerous patients from study Targeted Therapies Real World

35. EB Guideline Efficacy Safety Multiple factors that should be considered when selecting a targeted therapy for mRCC pts Patient Proflie Patient Profile Clinician Familiarity Safety

36. Ist-line Targeted Therapy: rates of treatment interruptions, reductions and discontinuations % of pts SUNI 1 n. 375 BEVA 2 plus IFN n. 337 PAZO 3 n. 290 TIVO 5 n. 259 TEM 4 n. 208 SORA 6 n. 451 Dose reduction 324024 12 2313 Treatment interruption 38NA 18 NA21 *Treatment discontinuation 828144710 * No lack of efficacy SUNI 7 EAP n. 1381 43 NA 14 SORA 8 ARCCSn.2504 35 50 10 1. Motzer, et al. JCO 2009; 2. Escudier, et al. Lancet 2007; 3. Sternberg, et al JCO 2010 4. Hudes, et al. NEJM 2007; 5. Motzer, et al. ASCO 2012; 6. Escudier et al. NEJM 2007 4. Hudes, et al. NEJM 2007; 5. Motzer, et al. ASCO 2012; 6. Escudier et al. NEJM 2007 7. Gore et al. Lancet 2009; 8. Stadler et al, Cancer 2010

37. Targeted Agent Management AEs Healthcare Resources and Increased Costs

38. EB Guideline Efficacy Safety Multiple factors that should be considered when selecting a targeted therapy for mRCC pts selecting a targeted therapy for mRCC pts Patient Proflie Patient- Reported Outcomes Patient Profile Clinician Familiarity Safety

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40. Which targeted agent do you use in 1st-line mRCC: some answers more questions mRCC treatment: to personalize or not to personalize? Patients Preferences: going forward by going backward? Patient-reported Outcomes: what can we do? Hot Question in mRCC