Cáncer Renal avanzado. Nuevas estrategias para el tratamiento individualizado.

Transcription

1 Cáncer Renal avanzado. Nuevas estrategias para el tratamiento individualizado. Daniel Castellano Oncología Médica.Unidad de Tumores GenitoUrinarios Hospital Universitario 12 de Octubre. I + 12 Research Institute

2 Treatment options for metastatic RCC have been revolutionised in a short period of time Sunitinib (Jan 2006) 2 Pazopanib (Oct 2009) 6 High dose interleukin-2 IFN-α Sorafenib (Dec 2005) 1 Temsirolimus (May 2007) 3 Bevacizumab + IFN-α (Jul 2009) 5 Everolimus (Mar 2009) 4 Axitinib (Jan 2012) US FDA. Sorafenib, US FDA. Sunitinib malate, US FDA. Temsirolimus, US FDA. Everolimus, US FDA. Bevacizumab, US FDA. Pazopanib, US FDA. Axitinib, Tivozanib (2012??)

3 RCC: efficacy proven across histological subtypes Tumour type Clear cell Papillary (type I + II) Chromophobic Histology 1 Incidence (% of all RCCs) Note: patients may have more than one histological subtype 1. Linehan WM, et al. J Urol 2003; 2. Motzer RJ, et al. N Engl J Med Escudier B, et al. N Engl J Med 2007; 4. Beck J, et al. ECCO Knox JJ, et al. EMUC 2007; 6. Chouieri TK, et al. J Clin Oncol Golshayan AR, et al. ASCO-GU 2008; 8. Motzer RJ, et al. J Clin Oncol 2002

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7 Overview of targeted agents in mrcc1 5 Bevacizumab Anti-angiogenesis VEGF-A VEGF-B VEGF-C VEGF-D VEGF-E VEGFR-2 VEGFR-1 PDGFR-α VEGFR-3 PDGFR-ß c-kit Flt-3 References are in slide notes Pazopanib Raf Sorafenib Sunitinib Preclinical in vitro data need to be validated in a clinical setting 5

8 Patient-focused treatment strategy Need to define the optimal setting for each treatment the best treatment for each given patient For any given patient, treatment decisions require consideration of multiple factors disease characteristics patient characteristics treatment aim and previous treatment history

9 Which parameters potentially influence treatment choices? Disease characteristics sites and number of metastases tumour histology MSKCC risk Patient characteristics age cardiac risk renal impairment general comorbidities/overall health of patient Treatment aim and previous treatment history objective of treatment suitability for cytokine therapy failure of prior therapy

10 Proposed schema: factors to consider prior to prescribing treatment for RCC DISEASE MSKCC Good Intermediate Poor No. met sites >4 Site of mets Lymph nodes Liver Lung Bone Brain Histology Clear cell Non-clear cell PATIENT Age P.S. Comorbidity Haematological Wound healing <65 years 65 years Controlled HT Cardiac disease grade 2* > grade 2* Diabetes Fatigue Thyroid Cirrhosis Renal Naive TREATMENT History Suitable for CK Unsuitable for CK Prior CK Prior targeted therapy Aim Prolong survival Tumour shrinkage Disease stabilisation Maintain QoL * Including controlled arrhythmias CK = cytokine; HT = hypertension; mets = metastases; PS = performance status; QoL = quality of life

11 Aim of treatment for RCC Naive TREATMENT History Suitable for CK Unsuitable for CK Prior CK Prior targeted therapy Aim Prolong survival Tumour shrinkage Disease stabilisation Maintain QoL

12 Selecting first-line treatment: A clinician s perspective Efficacy is key when selecting first-line treatment, but there are also other considerations Robust evidence and guidelines Experience Patient characteristics Patient preference

13 Algoritmo CCRm Setting Patients Therapy Options First-line Favourable- or Sunitinib HD IL-2 intermediate-risk Pazopanib Tivozanib? Cytokines Sorafenib Beva - IFN-α Poor-risk Temsirolimus Sunitinib Second-line Prior cytokine Axitinib Pazopanib Sorafenib Sunitinib Prior VEGF TKI Axitinib Sorafenib? Prior VEGF TKI Everolimus Clinical trial Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2009, NCCN guidelines 2010 SOGUG 2010

14 Recommended targeted agents for first-line treatment: Results from pivotal trials Agent n Median PFS (months) Median OS (months) ORR (%) Sunitinib vs IFN-α vs 5 p<0.001 Bevacizumab + IFN-α vs IFN-α 2, vs 5.4 p< Bevacizumab + IFN-α vs IFN-α 4, vs 5.2 p< Pazopanib vs placebo 6, vs 2.8 p< Poor-risk patients Temsirolimus vs IFN-α vs 3.1 p<0.001 *Includes cytokine refractory and treatment-naïve patients; Poor-risk patients (modified MSKCC criteria) NS, not studied 26.4 vs 21.8 p= vs 21.3 p= vs 17.4 p= vs 20.5* p= vs 7.3 p= vs 12 p< vs 13 p= vs 13 p< vs 3* p< vs 4.8 NS 1. Motzer RJ, et al. J Clin Oncol 2009;27: ; 2. Escudier B, et al. Lancet 2007;370: ; 3. Escudier B, et al. J Clin Oncol 2010;28: ; 4. Rini BI, et al. J Clin Oncol 2008;26:5422 8; 5. Rini BI, et al. J Clin Oncol 2010;28: ; 6. Sternberg C, et al. J Clin Oncol 2010;28:1061 8; 7. Sternberg C, et al. Eur J Cancer 2013;49: ; 8. Hudes G, et al. New Engl J Med 2007;356:

15 Probabilidad de SLP Probability of survival Sunitinib : Estudio fase III como tratamiento de primera línea en el CCR avanzado Criterios de elegibilidad 18 años de edad CCRm Histología de células claras Sin tratamiento sistémico previo Enfermedad medible por RECIST ECOG PS 0 o 1 Función orgánica adecuada Mediana de la SLP (revisión central independiente) Sunitinib Mediana: 11.0 meses (95% IC: ) IFN-α Mediana: 5.1 meses (95% IC: ) N=750 A L E A T O R I Z A C I Ó N Sunitinib 50 mg diario (Esquema 4/2) N=375 IFN-α 3 MU SC, TIW primera semana, 6 MU SC, TIW segunda semana, 9 MU SC, TIW a partir de entonces N=375 Mediana de SG Sunitinib (n=375) Mediana: 26.4 meses (95% IC: ) IFN-α (n=375) Mediana: 21.8 meses (95% IC: ) HR=0.538 (95% IC ) P< Tiempo (meses) No. en riesgo Sunitinib: IFN-α: HR=0.821 (95% IC: ) P=0.051 (log-rank) Total deaths Sunitinib 190 IFN-α Tiempo (meses) nmuertes/nriesgo Sunitinib /326 38/283 48/229 42/180 14/61 4/2 IFN-α /295 46/242 52/187 25/149 15/53 1/1 RECIST = Response Evaluation Criteria in Solid Tumors; ECOG = Eastern Cooperative Oncology Group; SLP = supervivencia libre de progresión; SG = supervivencia global Motzer RJ, et al. N Engl J Med 2007 Motzer RJ, et al. ASCO 2007; Motzer RJ, et al. J Clin Oncol 2009

16 Probabilidad Probabilidad Programa de acceso expandido de Sunitinib: Escenario Real Programa internacional que incluyó 4,564 pacientes con CCRm (vírgenes al tratamiento o refractarios a citokinas) SLP Mediana: 10.9 meses (95% lc: ) SG Mediana: 18.4 meses (95% lc: ) Tiempo (meses) No. en riesgo 4,349 1, Tiempo (meses) 4,349 2, Gore ME, et al. Lancet Oncol 2009

17 Proportion progression-free Progression-free survival in the treatment-naïve subpopulation 1.0 Median PFS (months) 0.8 Placebo Pazopanib Hazard ratio (95% CI) p value (1-sided) (0.27, 0.60) < Pazopanib 11.1 mo Pazopanib Placebo Number at risk, n Pazopanib Placebo Time (month) In the treatment-naïve subpopulation, PFS was significantly greater in pazopanib- versus placebotreated patients (p<0.0001) Sternberg et al. J Clin Oncol 2010;28:

18 COMPARZ study design: Phase III, open-label, non-inferiority trial Enrolment criteria: Locally advanced or mrcc Clear-cell histology No prior systemic therapy Measurable disease (RECIST 1.0) KPS 70 Adequate organ function N=927 N=1,110 Randomised 1:1 Pazopanib 800 mg QD Continuous daily dosing Sunitinib 50 mg QD Schedule 4/2 Study start: August 2008 VEG Phase III n=927 VEG Phase II (Asia) n=183 COMPARZ: 1,110 patients KPS, Karnofsky Performance Scale; RECIST, Response Evaluation Criteria in Solid Tumors; Schedule 4/2, 4 weeks on treatment, 2 weeks off (NCT ; NCT )

19 Proportion progression-free COMPARZ primary endpoint: PFS (IRC-assessed) 1.0 N Median PFS (95% CI) 0.8 Pazopanib mo (8.3, 10.9) Sunitinib mo (8.3, 11.1) HR (95% CI ) = (0.898,1.220) Months Number at risk Pazopinib Sunitinib Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8

20 COMPARZ: PFS (IRC-assessed) 1,2 Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ) PFS (ITT population) Pazopanib (n=557) Sunitinib (n=553) Median PFS, months (95% CI) 8.4 (8.3, 10.9) 9.5 (8.3, 11.1) HR (95% CI) (0.8982, ) PFS (PP population) Pazopanib (n=501) Sunitinib (n=494) Median PFS, months (95% CI) 8.4 (8.3, 10.9) 10.2 (8.3, 11.1) HR (95% CI) (0.910, 1.255) PP, per-protocol 1. GSK. Clinical Study Register. Study Available at: (last accessed February 2013); 2. Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8; 3. Available at (last accessed April 2013)

21 Laboratory Abnormalities Chemistry labs ( 35%) ALT AST Hypoalbuminemia Bilirubin Creatinine Hyperglycemia Hyponatremia Hypophosphatemia Hematology labs Leukopenia Neutropenia Thrombocytopenia Lymphopenia Anemia Pazopanib (n = 554), % All Grades Sunitinib (n = 548),% All Grades Yellow highlight: Risk greater for pazopanib and 95% CI for relative risk does not cross 1

22 Laboratory Abnormalities Chemistry labs ( 35%) ALT AST Hypoalbuminemia Bilirubin Creatinine Hyperglycemia Hyponatremia Hypophosphatemia Hematology labs Leukopenia Neutropenia Thrombocytopenia Lymphopenia Anemia Pazopanib (n = 554), % All Grades Sunitinib (n = 548),% All Grades Blue highlight: Risk greater for sunitinib and 95% CI for relative risk does not cross 1

23 COMPARZ: Common AEs (treatment-emergent) AE* Pazopanib (n=554), % Sunitinib (n=548), % Risk ratio All grades Grade 3/4 All grades Grade 3/4 All grades 95% CI Any event >99 59/15 >99 57/17 NA NA Diarrhoea 63 9/0 57 7/< , 1.20 Fatigue 55 10/< /< , 0.96 Hypertension 46 15/< /< , 1.31 Nausea 45 2/0 46 2/ , 1.11 Decreased appetite 37 1/0 37 3/0 NA NA ALT increased 31 10/2 18 2/< , 2.17 Hair colour changes 30 0/0 10 <1/0 NA NA HFS 29 6/ /< , 0.68 Taste alteration 26 <1/0 36 0/0 NA NA Thrombocytopenia 10 2/< / , 0.40 *AE 30% in either arm; 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 AEs ALT, alanine transaminase; AST, aspartate transaminase; HFS, hand foot syndrome; NA, not applicable

24 TIVO-1 Trial: Phase III Head-to-Head Trial of Tivozanib Vs. Sorafenib Eligibility Requirements Advanced clear cell RCC Prior nephrectomy No prior VEGF treatment ECOG PS: 0 1 First head-to-head RCC registration trial vs. an active comparator Primary end point: PFS Secondary end points: OS, ORR, QOL Treatment schedule (1 cycle = 4 wks) Tivozanib: 1.5 mg/day for 3 wks, followed by 1-wk break Sorafenib: 800 mg/day for 4 wks R A N D O M I Z E 1:1 Tivozanib (n = 250) Sorafenib (n = 250) PD Tivozanib Extension Protocol Continue tivozanib until PD Continue sorafenib until PD QOL = quality of life. US NIH, 2011a, 2011b.

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26 Study design* Previously untreated metastatic RCC R A N D O M I Z E 2:1 Axitinib 5 mg BID (n=192) Sorafenib 400 mg BID (n=96) Randomization stratified by ECOG PS (0 vs 1). * ClinicalTrials.gov: NCT Titrated stepwise to 7 mg BID and then 10 mg BID in patients without grade 3 or 4 (CTCAE v3.0) axitinib-related AEs for a consecutive 2-week period, unless BP >150/90 mmhg. Hutson TE et al. Abstract No. 348, ASCO-GU

27 PFS (probability) Progression-free survival (IRC Assessment) = censored for axitinib = censored for sorafenib Axitinib Sorafenib Time (months) No. events (%) 111 (58) 60 (63) Stratified HR, 0.77* (95% CI ) 1-sided P= mpfs, mo (95%CI) 10.1 ( ) 6.5 ( ) *Stratified by ECOG PS; assuming proportional hazards, HR <1 indicates a reduction in favor of axitinib and HR >1 indicates a reduction in favor of sorafenib. IRC = independent radiology committee; mpfs = median progression-free survival Patients at risk, n Axitinib Sorafenib

28 Conclusions Study did not achieve its primary endpoint statistically Statistical design: HR=0.56 (high bar) Actual: HR=0.77 (95% CI );1-sided P=0.038 PFS difference observed in subgroups vs sorafenib Patients with nephrectomy: 10.3 vs 6.4 mo* (P=0.009) PS 0: 13.7 vs 6.6 mo (P=0.022) ~90% patients from outside the US (variability in PS 0 vs 1) First-line therapy with axitinib demonstrated Numerically longer PFS (3.6-mo improvement) Significantly higher ORR Acceptable safety profile OS data not yet mature * Unstratified HR, 0.67 (95% CI ) Unstratified HR, 0.64 (95% CI ) Hutson TE et al. Abstract No. 348, ASCO-GU

29 Selecting first-line treatment: A clinician s perspective Efficacy is key when selecting first-line treatment, but there are also other considerations Robust evidence and guidelines Experience Patient characteristics Patient preference

30 Modelos Integrados de Predicción Pronóstica en CCR avanzado

31 Comorbidities Are Common In Patients With RCC 54% of patients with kidney cancer have at least one comorbidity. 1 72% of patients 75 years of age with kidney cancer have at least one comorbidity. 1 The most common comorbidities are heart disease, hypertension, and diabetes Coebergh JWW, et al. J Clin Epidemiol. 1999;52:

32 P e r c e n t S u r v i v i n g Extent of Comorbidities Correlates with OS in RCC Patients Undergoing Nephrectomy Retrospective study of patients with RCC who underwent radical or partial nephrectomy (N = 697) Cormorbidities were scored based on the Adult Comorbidity Evaluation-27 (ACE-27) validated tool 75% of patients had at least 1 comorbidity Median follow-up was 36.5 months Overall survival for all patients at 1, 3, and 5 years was 92.0%, 75.3%, and 52.7%, respectively N o n e M i l d M o d e r a t e S e v e r e Severe vs. None Adjusted HR: % CI: P < D u r a t i o n ( Y e a r s ) Berger DA, et al. Urology. 2008;72(2):

33 Multivariate models of associations between AEs and survival in patients with mrcc on sunitinib Schedule 4/2 Results of a retrospective analysis of pooled data from 770 patients AE at any time point AE by the 12-week landmark AE Endpoint HR 95% CI p value* HR 95% CI p value* Hypertension PFS OS , , 0.43 < < , 0.84 NS Hand foot syndrome PFS OS , , , 0.98 NS Asthenia/fatigue *Wald chi-square test PFS 0.49 OS 0.72 Donskov F, et al. Presented at ESMO 2012; Abstract 785O 0.38, , 0.96 < NS NS

34 Selecting first-line treatment: A clinician s perspective Efficacy is key when selecting first-line treatment, but there are also other considerations Robust evidence and guidelines Experience Patient characteristics Patient preference

35 PISCES Study Pazopanib versus sunitinib patient preference study in treatment naïve advanced or metastatic renal cell carcinoma (A randomised, double-blind, cross-over patient preference study of pazopanib versus sunitinib in treatment-naïve locally advanced or metastatic renal cell carcinoma) ONCE/PAZ/0049/12 Date of preparation:may 2012

36 Study design1 Randomisation n=169 Pazopanib 800 mg once daily, 10 weeks Sunitinib 50 mg 4/2, 10 weeks Period 1 Sunitinib 50 mg 4/2, 10 weeks Pazopanib 800 mg once daily, 10 weeks 2-week washout Period 2 Double-blind Patient choice of treatment to progression Off study :1 randomisation Time (weeks) Both drugs were over-encapsulated Patients on sunitinib received placebo during 2-week off-period 1. ClinicalTrials.gov. NCT

37 Patients (%) Primary endpoint: Patient preference for study treatments (Primary analysis population) % CI (for difference): ; p< % (n=80) 22% (n=25) 8% (n=9) Preferred pazopanib Preferred sunitinib No preference 1. Escudier B, et al. ASCO 2012 oral presentation;abstract 4502.

38 Temsirolimus: Estudio Fase III de 1º línea en MSKCC-mal pronóstico 3/6 Poor Risk Features LDH >1.5 x ULN Randomize IFN 3 MU-18 MU (n=207) CR + PR 7% CR + PR + SD 29% Med. OS 7.3 months Hgb < LLN Ca ++ (cor) >10 KPS <70% DFI <1 year TEM 25 mg QW (n=209) CR + PR 9% CR + PR + SD 46% Med. OS 10.9 months 1.0 Multiple sites of metastases Metastatic RCC (N=626) IFN 6 MU + TEM 15 mg QW (n=210) CR + PR 11% CR + PR + SD 41% Med. OS 8.4 months Survival distribution function Arm 1: IFN Arm 3: IFN + Temsirolimus Arm 2: Temsirolimus Parameter IFN Arm 1 (n=207) TEMSR Arm 2 (n=209) TEMSR + IFN Arm 3 (n=210) Median survival (mos) Comparisons Arm 2:Arm 1 Arm 3:Arm 1 Stratified log-rank p Time to death *Modified MSKCC poor risk; Stratification by country and nephrectomy status SD 16 weeks; p= Hudes G et al. N Engl J Med. 2007;356:

39 Median PFS: 1st Line Treatement in mrcc from Pivotal Studies Progression Free Survival BCS 2 3 Kane 2006 INF-α alone Multiple studies Present INF-α+ IL-2+5-FU Temsirolimus Sorafenib Bevacizumab + INF-α Gore ASCO 2008 Torisel PI Nexavar PI EscudierASCO Sunitinib Figlin ASCO Pazopanib StembergASCO Tivozanib Motzer Kane et al. Clin Cancer Res. 2006;12:7271, Gore et al. ASCO 2008, Nexavar PI, Figlin et al. ASCO 2008, Escudier ASCO Time (months)

40 Beyond the first Line: Understanding resistance mechanisms can allow identification of optimal treatment strategies Potential approaches to overcoming resistance include Adjust dose or scheduling of TKI 1,2 Switch from one TKI to another 3 Switch from a TKI to an mtor inhibitor 4 Use of novel agents Combination of traditional agents with new agents? 1 Escudier B, et al. J Clin Oncol 2009; 2 Escudier B, et al. J Clin Oncol Rini BI, et al. J Clin Oncol 2009; 4 Motzer RJ, et al. Lancet Hainsworth JD, et al. J Clin Oncol 2010; 6 Rini BI, et al ASCO GU 2010

41 AXIS1032: Axitinib pivotal trial in second-line setting First Phase III, head-to-head study vs a targeted agent in second-line mrcc Eligibility: mrcc clear-cell histology Failure of one first-line regimen containing: Sunitinib Bevacizumab + IFN-α Temsirolimus, or Cytokines Stratification by prior regimen and ECOG PS n=723 R A N D O M I S E 1:1 Axitinib 5 mg BID* Sorafenib 400 mg BID Primary endpoint: PFS ECOG PS, Eastern Cooperative Oncology Group performance status; *Starting dose 5 mg BID with option for dose titration to 10 mg BID Rini BI, et al. Lancet 2011;378:1931 9

42 PFS (probability) Axitinib* showed greater efficacy in extending mpfs vs sorafenib PFS in overall ITT population Axitinib Sorafenib mpfs, mo p< (log-rank) Stratified HR % CI 6.4, , 6.3 (95% CI, 0.56, 0.81) Time (months) 90% power to show improvement in PFS using a one-sided log-rank test at a significance of * Axitinib is indicated for advanced RCC after failure of prior treatment with sunitinib or a cytokine; ITT, intention-to-treat; mpfs, median progression-free survival Axitinib European SmPC

43 OS: Overall population 43

44 Probability (%) Probability (%) Switch from a tyrosine kinase inhibitor to an mtor inhibitor: RECORD-1 PFS* OS HR=0.33 (95% CI: ) Median PFS Everolimus: 4.90 months Placebo: 1.87 months HR=0.87 (95% CI: ) Median OS Everolimus: months Placebo: months Log-rank P value <0.001 Log-rank P value = Everolimus (n=277) Placebo (n=139) Everolimus (n=277) Placebo (n=139) Months *Central radiology review OS = overall survival; PFS = progression-free survival Months Motzer R, et al. Cancer 2010

45 Probability (%) Probability (%) RECORD-1: Phase III evidence for the sequence of sunitinib or sorafenib followed by everolimus PFS in patients with prior sunitinib treatment PFS in patients with prior sorafenib treatment HR = 0.34 (95% CI: ) Median PFS Everolimus: 3.88 months Placebo: 1.84 months Log-rank P value = <0.001 Everolimus (n=124) Placebo (n=60) HR = 0.25 (95% CI: ) Median PFS Everolimus: 5.88 months Placebo: 2.83 months Log-rank P value = <0.001 Everolimus (n=81) Placebo (n=43) Months Patients at risk Everolimus Placebo Months Motzer R, et al. Cancer 2010; Escudier B, et al. ESMO 2008

46 RECORD-1: representative of second line? In RECORD-1 almost 80% of patients were treated with everolimus third-line or later 1,2 Firstline Secondline Thirdline Fourthline mtor fifthline n=82 Firstline Secondline Thirdline mtor fourthline n=104 79% Firstline Secondline mtor thirdline n=141 Firstline mtor secondline n=89 21% 1 Zustovich F, et al. Crit Rev Oncol Hematol 2011;83: ; 2 Motzer RJ, et al. Cancer 2010;18:

47 Beyond the second Line: Understanding resistance mechanisms can allow identification of optimal treatment strategies Potential approaches to overcoming resistance include New pathways Switch from one TKI to another 3 Switch from a TKI to an mtor inhibitor 4 Combination of traditional agents with new agents?

48 Enhancing Immune Responsiveness

49 Ipilimumab Ipilimumab is a human monoclonal antibody that blocks CTLA-4 CTLA-4 is an immune check point molecule that downregulates pathways of T-cell activation T-cell activation T-cell inactivation A B C T-cell activation T cell T cell T cell CTLA4 TCR CD28 CTLA4 TCR CTLA4 MHC B7 CD28 B7 MHC Anti-CTLA4 mab APC APC APC Fong L and Small E, J Clin Oncol 2008

50 Ipilimumab in mrcc Phase II study of ipilimumab in patients with mrcc Patients received either 3 mg/kg followed by 1 mg/kg or all doses at 3 mg/kg every 3 weeks Lower dose schedule 1/21 patients had a partial response Higher dose schedule 5/40 patients had a partial response Responses observed in patients who had not responded to IL-2 therapy previously Toxicity Grade 3/4 immune-mediated toxicity observed in 33% of patients Significant association between auto-immune events and tumour regression was observed Yang J et al. J Immunother 2007

51 Enhancing Immune Responsiveness

52 Programmed Death (PD)-1 pathway PD-1 downregulates T-cell function upon binding to its ligand (PD-L1) APC/ tumour cell PD-L1 PD-1 T-cell T-cell inactivation PD-L1 has been shown to be overexpressed in RCC In patients with mrcc, overexpression of PD-L1 has been shown to be associated with Adverse pathology Aggressive tumour behaviour Poor survival Thompson RH, et al. Clin Cancer Res 2007

53 Thompson et al, Increased B7H1 Expression in RCC Diminishes Survival

54 Resolving RCC Lytic Bone Metastasis in Patient Treated With Anti-PD-1 (10 mg/kg) 3/25/08 4/14/09 Responses may be correlated with PD- L1 expression 3/4 PRs in PDL-1+ tumors, 0/5 PDL-1 negative Control Ig B7H1 Brahmer et al, 2010.

55 3º Line Treatment Phase III TKI258 (dovitinib) Study Design: International, Prospective, Randomized, Openlabel, Multicenter Patients with advanced RCC, PD to prior VEGF and m- TOR targeted therapy -Primary end point: PFS -Prior Cytokines allowed R A N D O M I Z A T I O N 1:1 Dovitinib n=275 Sorafenib n=275

56 3º Line Treatment Phase III Anti-PD-1 study Study Design: International, Prospective, Randomized, Openlabel, Multicenter Patients with advanced RCC, PD to prior 2 VEGF targeted therapy -Primary end point: PFS/OS -Prior Cytokines allowed R A N D O M I Z A T I O N 1:1 Anti-PD-1 N=350 Everolimus n=350

57 Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012, NCCN guidelines 2013 SOGUG 2010 Algoritmo CCRm 2014? Setting Patients Therapy Options First-line Favourable- or intermediate-risk Sunitinib Pazopanib Tivozanib? Beva - IFN-α HD IL-2 Cytokines Sorafenib Poor-risk Temsirolimus Sunitinib Second-line Prior cytokine Axitinib Pazopanib Sorafenib Sunitinib Prior VEGF TKI Axitinib Sorafenib? Prior VEGF TKI Everolimus Clinical trial Third-line Prior TKI TKI Everolimus Anti-PD1?? Clinical Trial Prior TKI mtor Sorafenib/Dovitinib Clinical trial

58 Future Treatment options for metastatic RCC Anti-PD1 Dovitinib Sunitinib (Adjuvant Treatment)

59 Possible areas of unmet medical need Currently approved treatments are not curative, and Patients develop progressive disease Evolving need for effective therapeutics with unique mechanisms of action for patients who progress Non clear cell histologies Few studies are available to determine efficacy Biomarkers, new pathways, gene profile, mechanisms of resistance!!! 18

60 Manejo Integral Multidisciplinar del Carcinoma Renal Avanzado Manejo Efectos Adversos Medicina Basada Evidencia (Est.Clínicos) Tipo Tratamiento: - Secuencial - Individualización Tratamiento Integral Beneficio Clínico Uso Racional de Recursos Control Complicaciones Tumorales

61 Muchas Gracias

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