Evidencia disponible en subgrupos de pacientes Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense University Associate Professor of Medicine

Targeted agents currently approved for mRCC in Europe Sorafenib (oral) Advanced RCC after IFN ‑ α/IL-2 or if unsuitable for IFN-α/IL-2 2 Bevacizumab (+IFN-α) (IV) First-line mRCC 3 Everolimus (oral) Advanced RCC after VEGF ‑ targeted therapy 5 Axitinib (oral) Advanced RCC after sunitinib or a cytokine 7 Temsirolimus (IV) Advanced RCC with 3–6 prognostic risk factors 4 Pazopanib (oral) Advanced RCC 6 Sunitinib (oral) Advanced/mRCC 1 1. Sunitinib SmPC, Jan 2014; 2. Sorafenib SmPC, Feb 2013; 3. Bevacizumab SmPC, Feb 2014; 4. Temsirolimus SmPC, Oct 2013; 5. Everolimus SmPC, Nov 2013; 6. Pazopanib SmPC, Dec 2013; 7. Axitinib SmPC, Oct IFN-α, interferon-alpha; IL-2, interleukin-2; IV, intravenous

Evolution in the first-line treatment of mRCC Median survival (months) PFSOS 3–6 6–15* 13–22 18–32* After Before Median survival before and after the introduction of targeted agents (TKIs) 1–11 1. Coppin et al. Cochrane Database Syst Rev 2005; 2. Gore et al. Lancet 2010; 3. Motzer et al. N Engl J Med 2007; 4. Escudier et al. Lancet 2007; 5. Rini et al. J Clin Oncol 2008; 6. Motzer et al. N Engl J Med 2013; 7. Motzer et al. J Clin Oncol 2009; 8. Escudier et al. J Clin Oncol 2010; 9. Rini et al. J Clin Oncol 2010; 10. Michel et al. ASCO GU 2014; 11. Motzer et al. ASCO *With targeted agents as first-line mRCC therapy primarily in favourable/intermediate risk patients

Have we improved OS since 2006? 2007/2013 1,2 2010/2013 2, Motzer et al. J Clin Oncol 2009; 2. Motzer et al. N Engl J Med 2013; 3. Sternberg et al. Eur J Cancer 2013; 4. Motzer et al. J Clin Oncol 2013; 5. Michel et al. ASCO GU 2014; 6. Motzer et al. ASCO Median OS, months Please refer to local prescribing information for each treatment option Median OS for VEGF-targeted therapies in mRCC in clinical studies Eve. Everolimus; Seq., sequence; Sor, sorafenib; Sun, sunitinib

First-line Second-line 1. Escudier et al. Ann Oncol 2012; 2. Corrigendum Ann Oncol 2013; 3. Temsirolimus SmPC, Oct Second-line targeted treatment options: VEGFR-TKI or mTOR inhibitor? mRCC 1,2 Temsirolimus* Poor prognosisGood/intermediate prognosis VEGFR-TKI or mAb-VEGF-A+IFNα mTOR inhibitor VEGFR-TKI *Temsirolimus is indicated for the first-line treatment of advanced RCC with 3-6 prognostic risk factors 3 ; mAb, monoclonal antibody

Introduction With the arrival of targeted therapies, the treatment paradigm for mRCC has become increasingly complex Maximising the long-term benefit of these agents requires informed decision-making based on both… Clinical trial dataReal-world experience

In this symposium we will explore… assess the current treatment paradigm for mRCC assess the importance of maximising treatment lines Clinical evidence, to… Evidence from the real world, clinical practice, and real-life case studies, to… assess how best to optimise the treatment options available help make informed treatment decisions for each individual patient

Special subgroups of patients -ELDERLY PATIENTS -PERFORMANCE STATUS 2 -BRAIN METASTASES -COMORBILITIES (CARDIAC DISORDES, RENAL FAILURE, …) -NON CLEAR CELL CARCINOMA

Percent of New Cases by Age Group: Kidney and Renal Pelvis Cancer Median age at diagnostic: 64 SEER , All Races, Both Sexes 48,3% ≥ 65 23,1% ≥ 75 Percent of new cases by age group

Median age in pivotal studies DrugNº patientsBenefit (months) Median age%>70 years Sunitinib [ ] NR Sorafenib9032,7 59 [ ] 16% Beva-IFN649 y 732 4,8 y 3,3 61 [ ] 61 [56-70] NR Temsirolimus6262,4 58 [ ] NR Everolimus4102,1 61 [ ] NR Pazopanib [ ] 35% (>65 a)

Efficacy is mantained regardless of age

Efficacy and safety of sunitinib in elderly patients with mRCC Hutson TE, et al. Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma. Br J Cancer Mar 4;110(5): N= 1059 (19% ≥70 a)

Efficacy and safety of sunitinib in elderly patients with mRCC Hutson TE, et al. Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma. Br J Cancer Mar 4;110(5):

More common (P<0.05) in patients aged ≥70 years: Fatigue Cough Anemia Peripheral edema Thrombocytopenia Decreased weight Decreased appetite Dizziness Hypothyroidism Dehydration Urinary tract infection Efficacy and safety of sunitinib in elderly patients with mRCC

Expanded Access Program: experience in elderly patients DrugNº patients %≥70 yearsMedian ageEfficacy Sunitinib (Gore) (32%) (Nota:≥65 a) 59 [ ] SLP global: 10,9 m SG global: 18,4 m SLP ≥65 a: 11,3 m SG ≥65 a: 18,2 m Sorafenib Europeo (Beck) (23%) 62 [ ] SLP global: 6,6 m TP: 7,9 m SLP ≥70 vs <70 a: 8,0 vs 6,4 m (ns) Sorafenib Norteamericano (Stadler) (29%) 63 [ ] SLP global: 36 sem SG global: 50 sem SLP ≥70 vs <70 a: 46 sem vs 50 (ns) Everolimus (Grünwald) (43.3%) (Nota:≥65 a) 63 [ ] Median treatment global: 14 sem Gore et al. Lancet Oncol 2009; Beck et al Ann Oncol 2011; Stadler, et al. Cancer 2010; Bukowski, et al. Oncology 2010

Dosing decisions Treatment duration decisions Toxicity management decisions Personalising treatment to maximise outcomes with targeted therapy: experience from the real world How can we select the best treatment for these patients?

Standard vs adapted sunitinib regimen in elderly patients with mRCC De Giorgi et al. Clin Genitorinary Cancer 2013; 12(3): 182-9

11 meses25.5 meses De Giorgi et al. Clin Genitorinary Cancer 2013; 12(3): Standard vs adapted sunitinib regimen in elderly patients with mRCC

Why dose titrate? Dose titration allows treatment to be personalised with maintenance of therapeutic drug levels, which are associated with better outcomes Efficacy is the main driver in RCC treatment

RAINBOW study: modified sunitinib scheduling in patients with mRCC Retrospective observational study of mRCC patients administered sunitinib on a 2/1 schedule* Group A (n=208) Sunitinib 50 mg/day* Switched from schedule 4/2 to 2/1 due to TEAE Group B (n=41) Sunitinib 50 mg/day* Schedule 2/1 ab initio due to poor clinical condition Objective  Evaluate efficacy and safety of 2/1 vs 4/2 schedule Eligibility criteria  Patients with advanced RCC N=276 BASELINEBASELINE Group C (n=27) Sunitinib 50 mg/day* Schedule 4/2 (control) Safety endpoint: Incidence of adverse events Efficacy endpoint: PFS and treatment duration *Dose reductions were possible TEAE, treatment-emergent adverse events Bracarda et al. ASCO GU 2014

RAINBOW study: AE rate in patients switched from 4/2 to 2/1 schedule Rate (%) † ‡ §¶ *p<0.001; † p=0.008; ‡ p=0.063; § p=0.003; ¶ p=0.007 HFS, hand-foot syndrome Bracarda et al. ASCO GU 2014

Toxicity evaluation after 2 weeks on first course Modify dose/schedule DL-1: Pts than cannot take 50 mg for 28 d - 50 mg individualized # of days / 7 days off DL-2: Pts than cannot take 50 mg for at least 7 d mg individualized # of days / 7 days off DL-3: Pts than cannot take 37.5 mg for at least mg individualized # of days / 7 days off Modify dose/schedule DL-1: Pts than cannot take 50 mg for 28 d - 50 mg individualized # of days / 7 days off DL-2: Pts than cannot take 50 mg for at least 7 d mg individualized # of days / 7 days off DL-3: Pts than cannot take 37.5 mg for at least mg individualized # of days / 7 days off ≤ Grade-1 toxicity: Continue Rx ≤ Grade-1 toxicity: Continue Rx ≥ Grade-2 toxicity before 4 weeks: Stop Rx for 7 d** ≥ Grade-2 toxicity before 4 weeks: Stop Rx for 7 d** ≤ Grade-1 toxicity At 4 weeks: Stop Rx for 7 d** ≤ Grade-1 toxicity At 4 weeks: Stop Rx for 7 d** Grade-2 toxicity At 4 weeks: Stop Rx for 7 d** Grade-2 toxicity At 4 weeks: Stop Rx for 7 d** Reduce off-Rx time to 7d** DL+: 50mg 28/7d Reduce off-Rx time to 7d** DL+: 50mg 28/7d Escalate dose/modify schedule DL+1: 62.5 mg 14/7 DL+2: 75.0 mg 14/7 Escalate dose/modify schedule DL+1: 62.5 mg 14/7 DL+2: 75.0 mg 14/7 Toxicity evaluation after 4 weeks on first course ≥ Grade-2 toxicity: Stop Rx for 7 d** ≥ Grade-2 toxicity: Stop Rx for 7 d** Sunitinib Titration Study (Bjarnason et al. ESMO 2014) ** Or until toxicity has resolved Individually maximize days on Rx during continued therapy based on toxicity Subsequent Cycles First cycle

Current dose schedule distribution for 91 pts: Sunitinib dose (mg) Schedule (d on/off) # patients currently or when came off study 59.3% of patient with improved dose intensity vs. standard dose criteria 7514/74 18 pts (19.8%) dose escalated 7510/ / / / /719Many recently entered on study 5028/ /71 36 pts (39.5%) 50 mg dose maintained but for fewer days on Would have been dose reduced by standard criteria 5020/ / / /72 507/ /7 and 90/72 11 pts (12%) reduced to 37.5 mg ( % in rand trials) / / /71 4 pts (4.4%) reduced to 25 mg (27- 43% in rand trials) /71 257/72 4 pts (4.4%) d/c early due to toxicity ( % in rand trials) Motzer RJ, Hutson TE, Olsen MR et al. J Clin Oncol 2012; 30: Motzer RJ, Hutson TE, Tomczak P et al. J Clin Oncol 2009; 27: Barrios C, Hernandez-Barajas D, Brown M et al. ESMO conference 2009; Abstract Escudier B, Roigas J, Gillessen S et al. J Clin Oncol2009; 27:

Response data for 65 evaluable pts Individ Sunitinib dosing EFFECT 50 mg dose Sunit data vs. INF Phase-III Pazo data vs. Sut Phase-III Axitinib data vs. Sorafenib Phase-III N CR %4.6 (n=3)00<10 PR %50.8 (n=33) CR+PR %55.4* (n=36) SD %33.8 (n=22) CR+PR+SD89.2 (n=58) PD %10.8 (n=7) PFS (mo)n/a *Similar to RR for Axitinib dose titration arm (n=56)

Motzer RJ, et al. Interferon-Alfa as a Comparative Treatment for Clinical Trials of New Therapies Against Advanced Renal Cell Carcinoma. J Clin Oncol Jan 1;20(1):

Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009; 27:

Outcome of patients with mRCC that do not meet eligibility criteria for clinical trials 8,6 vs 5,0 meses 28.4 vs 12.5 meses Heng DY, et al. Annals of Oncology 25: 149–154, 2014.

Gore M, et al. ESMO 2011

Annals of Oncology 23: 973–980, 2012 Retrospectivo: pacientes Brain Metastases: Epidemiology

903 TARGET  139 Annals of Oncology 21: 1027–1031, 2010

Cancer Feb 1;117(3):501-9 Safety and efficacy of sunitinib for mRCC with brain metastases

Non-clear Cell Renal Cell Carcinoma Description and Prevalence nccRCC represents a diverse group of tumors with varying genetic and histologic characteristics 1,2 –Approximately 25% of RCC cases are nccRCC 1 Many nccRCC subtypes have only recently been described as discrete entities; some are considered new and emerging, and others remain unclassified Cohen HT et al. N Engl J Med. 2005;353: Srigley JR et al. Mod Pathol. 2009; 22 (suppl 2): S2-S23.

Temsirolimus ARCC Trial: OS and PFS 1,2 33 ARCC, advanced renal cell carcinoma. 1.Hudes G et al. N Engl J Med. 2007;356: Dutcher JP et al. Med Oncol. 2009;26: Overall Survival INF-αTemsirolimusTemsirolimus vs INF-α Median (mo, 95% CI) HR (95% CI) ccRCC8.2 (6.6 – 10.4)10.7 (8.5 – 13.0)0.82 (0.64 – 1.06) nccRCC4.3 (3.2 – 7.3)11.6 (8.9 – 14.5)0.49 (0.29 – 0.85) Progression-free Survival INF-αTemsirolimusTemsirolimus vs INF-α Median (mo, 95% CI) HR (95% CI) ccRCC3.7 (2.5 – 4.6)5.5 (3.8, 7.1)0.76 (0.60 – 0.97) nccRCC1.8 (1.6 – 2.1)7.0 (3.9 – 8.9)0.38 (0.23 – 0.62)

Tumor response (per RECIST), n (%) Number of evaluable patientsAll (n = 3464)Non-clear cell histology (n = 437) OR603 (17)48 (11) CR34 (1)2 (<1) PR569 (16)46 (11) SD ≥ 3 months2029 (59)250 (57) PR or SD < 3 months832 (24)139 (32) Clinical benefit*2632 (76)298 (68) Summary of Median PFS and OS Number of evaluable patientsAll (n = 4349)Non-clear cell histology (n = 588) PFS, months (median; 95% CI)10.9 (10.3 – 11.2)7.8 (6.3 – 8.3) OS, months (median; 95% CI)18.4 (17.4 – 19.2)13.4 (10.7 – 14.9) 34 OR, objective response. *Clinical benefit = OR + SD for ≥ 3 months. Gore ME et al. Lancet Oncol. 2009;10: Safety and efficacy of sunitinib for non clear cell carcinoma (EAP)

SUPAP: Phase 2 Trial of First- Line Sunitinib in Papillary mRCC 35 Primary end point: objective tumor response Secondary end points: safety, OS, PFS, time to response, duration of response Eligibility Criteria Age ≥18 years Locally advanced or metastatic, histologically confirmed type1 or 2 papillary RCC Measurable disease by RECIST ECOG PS ≤1 No prior systemic therapy for mRCC (including sunitinib) Sunitinib 50 mg/d; 4 weeks on/2 weeks off N = 61 Type 1: n = 15 Non-type 1: n = 46 Disease progression or unacceptable toxicity Open-label, single-arm phase 2 study 61 patients were enrolled (15 with type 1; 46 with non- type 1) Two-stage study design based on SIMON 2-step method: 21 patients are included to achieve a 20% ORR. If ≥2 patients achieve this goal, 20 additional patients are added A separate, identical study in patients with type 1 or non-type 1 tumors was conducted Ravaud A et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria.

SUPAP Interim Analysis: Patient Characteristics (1) 36 All, n (%) N = 61 Type 1, n (%) n = 15 Non-type 1, n (%) n = 46 Age, y (Median, min-max)64 (32–81)69 (53–8-0)61 (32–81) Female (%)10 (16)1 (7)9 (20) Nephrectomy Yes53 (87)115 (100)38 (83) No8 (13)—8 (17) Metastatic site >1 site 55 (90)13 (87)42 (91) Lung 38 (62)13 (87)25 (54) Retroperitoneal lymph nodes 33 (54)7 (47)26 (57) Mediastinum 29 (48)6 (40)23 (50) Bone 17 (28)6 (40)11 (24) Liver 11 (18)—11 (24) Other 27 (44)8 (53)19 (41) MSKCC Group 0 Favorable12 (22)4 (29)8 (20) 1-2 Intermediate33 (61)7 (50)26 (65) ≥3 Poor9 (17)3 (21)6 (15) Undetermined7 (–)1 (–)6 (–) Ravaud A et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria.

SUPAP Interim Analysis: Best Response 37 Best Response, n (%) All, n (%) N = 61 Type 1, n (%) n = 15 Non-type 1, n (%) n = 46 Assessable patients60 a (100)15 b (100)45 c (100) Partial response (PR)7 (12)2 (13)5 (11) Stable disease (SD)35 (58)10 (67)25 (56) SD ≥12 weeks15 (25)5 (33)10 (22) Progression18 (30)3 (20)15 (33) Objective response rate (95% CI)12% (3%–20%)13% (0%–31%)11% (2%–20%) Nonprogression rate (95% CI)70% (58%–82%)80% (60%–100%)67% (53%–80%) a One patient died before first tumor evaluation from a cause other than disease progression. b One patient has been reviewed as type 2 (with a PR). c Two patients have been reviewed as type 1 (both with SD), 1 as a nonpapillary type (with a PR) and 1 as doubtful (with a SD). Ravaud A et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria.

SUPAP Interim Analysis : PFS 38 *Product limit survival estimate with number of patients at risk. PFS, progression-free survival. Ravaud A et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria.

SUPAP Interim Analysis: OS 39 Survival Probability *Product limit survival estimate with number of patients at risk. Ravaud A et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria.

Nonrandomized, single-group assignment Phase 2 Trial of Everolimus in Patients With mRCC and Non-Clear Cell Histology Study Design 1-3  A total of 49 patients were enrolled from 5 centers; 23 patients had been treated with VEGF-TKI prior to the study enrollment  Median age was 57 years (range 24 ‒ 75 years) and male to female ratio was 37:12  Histology of the patients included papillary (n = 29), chromophobe (n = 8), collecting duct (n = 2), sarcomatoid (n = 4), and unclassifiable carcinoma (n = 6) 40 Everolimus 10 mg/day orally Disease progression or unacceptable toxicity Study start Study end Primary end point: PFS Secondary end points: Objective response rate Clinical benefit rate Disease control rate Safety Key eligibility criteria: ≥ 18 years old with mRCC of non clear-cell histology, with or without previous VEGF-TKI therapy ECOG PS 0 or 1 Key exclusion criteria: Previous use of an mTOR inhibitor Clinically uncontrolled CNS metastasis Interstitial pulmonary disease ECOG PS, Eastern Cooperative Oncology Group Performance Status. 1.Koh Y et al. J Clin Oncol. 2012;30(suppl):abstract Koh Y et al. Poster presented at the ASCO annual meeting, June 1-5, 2012, Chicago, Illinois. 3.ClinicalTrials.gov Identifier: NCT

Phase 2 Trial of Everolimus in Patients With mRCC and Non-Clear Cell Histology: Efficacy and Safety 1,2  Toxicity profiles were commensurate with previous reports of everolimus in patients with mRCC 41 Outcomes Everolimus (10 mg/d) N = 49 Best overall response, (n) % Partial response5 † (10.2) Stable disease25 (51.0) Progressive disease16 (32.7) Not eligible for assessment3 (6.1) Median PFS, months5.2 ORR, %10.2 CBR, %57.1 DCR, %61.2 ORR, objective response rate; CBR, clinical benefit rate; DCR, disease control rate. 1.Koh Y et al. J Clin Oncol. 2012;30(suppl.): abstract Koh Y et al. Poster presented at the ASCO annual meeting, June 1-5, 2012, Chicago, Illinois. Efficacy of Everolimus According to Histology

RAPTOR Phase 2 Trial of First-Line Everolimus in Papillary mRCC 1,2 42 Primary end point: Proportion of patients progression free at 6 months Secondary end points: DCR, ORR, duration of response, median PFS, safety Eligibility Criteria Age ≥18 years Metastatic papillary RCC Measurable disease ECOG PS ≤1 No prior mTOR inhibitor No prior systemic therapy for mRCC (including VEGF or mTOR inhibitors International, multicenter, open-label study 1.ClinicalTrials.gov identifier: NCT Escudier B et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria. Trial Sites: Belgium, France, Germany, Italy, Poland, Spain Everolimus 10 mg/d N = 92 Disease progression or unacceptable toxicity

RAPTOR Interim Analysis: Patient Characteristics 43 Escudier B et al. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28–October 2, 2012; Vienna, Austria. Sex, n (%) Female20 (21.7) Male72 (78.3) Age, y n92 Mean (SD)59.9 (14.9) Median62.0 Range23–84 Patients with PS, n (%) 056 (60.9) 136 (39.1) MSKCC, n (%) Favorable48 (52.2) Intermediate38 (41.3) Poor1 (1.1) Missing5 (5.4) Nephrectomized patients, n (%) No16 (17.4) Yes76 (82.6) Organs with lesions, n (%) 1 organ13 (14.1%) 2 organs23 (25.0%) >2 lesions48 (52.2%) Missing8 (8.7%) Time from diagnosis to treatment n88 Mean (SD) ( ) Median Range14.0– Type Type 123 (25.0) Type 239 (42.4) Missing30 (32.6)

RAPTOR Final Analysis: PFS, OS (ASCO GU 2014) 44 *Kaplan-Meier estimate for the proportion of patients without PFS event (progression or death due to any cause).. Escudier B et al. Presented at the ASCO GU 2014

ESPN TRIAL Everolimus versus Sunitinib prospective evaluation in metastatic non-clear cell carcinoma Tannir E, ASCO 2014 (Abstract 4505)

ESPN TRIAL: PFS in First Line (Primary Endpoint) 46 1.Tannir E, ASCO 2014 (Abstract 4505)

ESPN TRIAL: Overall Survival 47 1.Tannir E, ASCO 2014 (Abstract 4505)

Conclusions: What have we learnt?  What the current treatment paradigm is in mRCC  The importance of maximising therapy lines in mRCC  That efficacy is the main driver in RCC treatment Real-world data Real-life case studies  Strategies to personalise targeted therapy to maximise outcomes  Dosing, treatment duration and toxicity management decisions Clinical evidence  The value of maximising mRCC therapy in daily clinical practice

THANK YOU Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense University Associate Professor of Medicine