¿Qué ha cambiado en los últimos 10 años en el tratamiento de primera línea de cáncer renal? Hospital Universitario Central Asturias Servicio de Oncología Médica Emilio Esteban González

2006-2012: Cambio de Paradigma en el tratamiento del CRA Agentes con aprobación en CRA Sorafenib (US 2005, EU 2006)3,4 Sunitinib (US & EU 2006)3,4 Temsirolimus and Bevacizumab plus IFN (US & EU 2007)3,4 High-dose IL-2 approved in the US (1995). High treatment-related toxicity; small number of durable responses2 Axitinib (US & EU 2009) Tivozanib, Dovitinib Early 1940s: experiments with cytotoxic chemotherapy1 Everolimus (US & EU 2009)3,4 Early 1980s: IFN-α and high-dose IL-2 used for RCC treatment Pazopanib (US 2009, EU 2010)3,4 1. Abeloff MD, et al. Clinical Oncology 4th ed. Philadelphia, PA. 2. Coppin C, et al. Cochrane Database Syst Rev 2005;1:CD001425 3. U.S. Food and Drug Administration (www.accessdata.fda.gov). 4. European Medicines Agency (http://www.ema.europa.eu/) 2 2

Grupos Pronóstico CRA Criterios MSKCC Tratamiento con CK (1) Mediana SG (meses) Factores Pronóstico KPS < 80 Diagnostico al tratamiento < 1año Anemia Hipercalcemia Elevación LDH Grupo Favorable Ningún factor 20 Grupo Intermedio 1-2 factores 10 Grupo Malo > 2 Factores 4 1. Motzer RJ, Mazumdar M, Bacik J et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17: 2530-2540. 2. 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(34): 5794-5799.

Grupos Pronóstico CRA Criterios MSKCC Tratamiento con CK (1) Mediana SG (meses) Criterios de Heng (2) Tratamiento con Antiangiogénicos Factores Pronóstico KPS < 80 Diagnostico al tratamiento < 1año Anemia Hipercalcemia Elevación LDH Neutrofilia Trombocitosis Grupo Favorable Ningún factor 20 Ningún factor 38 Grupo Intermedio 1-2 factores 10 27 Grupo Malo > 2 Factores 4 3-6 factores 8,8 1. Motzer RJ, Mazumdar M, Bacik J et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17: 2530-2540. 2. 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(34): 5794-5799.

Tratamiento antiangiogénico Resultados 1ª Línea CRA Histología y grupo pronóstico Nº Pts ORR (%) Mediana SLP (meses) Mediana SG Guías y Recomendaciones Célula clara y favorable-intermedio pronóstico SEOM (1) Categoría y Evidencia ESMO (2) Nivel y grado Evidencia Sunitinib vs IFN- (3) 750 47 vs 12 11 vs 5 26,4 vs 21,8 1A Sunitinib I,A Bevacizumab+ IFN- vs IFN- (4) 649 31 vs 12 10 vs 5.5 23., vs 21,3 Bevacizumab + IFN Bevacizumab+ IFN Bevacizumab+ IFN- vs IFN-(5) 732 25.5 vs 13 8,4 vs 4,5 18. vs 17 Pazopanib vs Placebo (6) 233 32 vs 4 11 vs 2,8 22,9 vs 20,5 1B Pazopanib Pazopanib vs Sunitinib (7) 1110 33 vs 29 8,4 vs 9,5 28,4 vs 29,3 Predominante célula no clara y Mal pronóstico Temsirolimus vs IFN- (8) 626 8,6 vs 4,8 5,5 vs 3,1 10,9 vs 7,3 Temsirolimus II,A Temsirolimus (1)J. Bellmunt et al.. SEOM. Clin Transl Oncol DOI 10.1007/s12094-014-1219-1. (2) Escudier et al, ESMO. Ann Oncol 2014; 25 (suppl 3): 49-56. (3). Motzer et al . N Engl J Med 2007; 356 (2): 115–124.( 4). Escudier B et al , Lancet 2007; 370: 2103-2111. (6) Sternberg CN et al. J Clin Oncol. 2010; 28(6): 1061-1068. (7) Motzer RJ et al. N Engl J Med. 2013; 369(8): 722-731. (8) Hudes G et al. N Engl J Med 2007; 356 (22): 2271–2281.

Tratamiento antiangiogénico Resultados 1ª Línea CRA Histología y grupo pronóstico Nº Pts ORR (%) Mediana SLP (meses) Mediana SG Guías y Recomendaciones Célula clara y favorable-intermedio pronóstico SEOM (1) Categoría y Evidencia ESMO (2) Nivel y grado Evidencia Sunitinib vs IFN- (3) 750 47 vs 12 11 vs 5 26,4 vs 21,8 1A Sunitinib I,A Bevacizumab+ IFN- vs IFN- (4) 649 31 vs 12 10 vs 5.5 23., vs 21,3 Bevacizumab + IFN Bevacizumab+ IFN- vs IFN-(5) 732 25.5 vs 13 8,4 vs 4,5 18. vs 17 Pazopanib vs Placebo (6) 233 32 vs 4 11 vs 2,8 22,9 vs 20,5 1B Pazopanib Pazopanib vs Sunitinib (7) 1110 33 vs 29 8,4 vs 9,5 28,4 vs 29,3 Predominante célula no clara y Mal pronóstico Temsirolimus vs IFN- (8) 626 8,6 vs 4,8 5,5 vs 3,1 10,9 vs 7,3 Temsirolimus II,A Temsirolimus (1)J. Bellmunt et al.. SEOM. Clin Transl Oncol DOI 10.1007/s12094-014-1219-1. (2) Escudier et al, ESMO. Ann Oncol 2014; 25 (suppl 3): 49-56. (3). Motzer et al . N Engl J Med 2007; 356 (2): 115–124.( 4). Escudier B et al , Lancet 2007; 370: 2103-2111. (6) Sternberg CN et al. J Clin Oncol. 2010; 28(6): 1061-1068. (7) Motzer RJ et al. N Engl J Med. 2013; 369(8): 722-731. (8) Hudes G et al. N Engl J Med 2007; 356 (22): 2271–2281.

Uso Expandido (EAP) de SUNITINIB Características de los pacientes 4564 patients included from the real life clinical practice Patients not included in phase III clinical trials were recruited in the EAP n % Total 4,371pts** Age, median (range) 59 (19-89) Age >65yrs 1,418 32% Prior nephrectomy 3,873 89% Pts + brain mets 321 7% PS 2-4 582 13% Nonclear cell 588 1 metastatic site 833 19% >2 metastatic site 3,489 80% Prior cytokine 2,974 68% Prior antiangogenic 238 5% notes Contents are OK, but the slide needs to be simplified for a better look. Martin E. Gore et al. The Lancet Oncology 2009; 10; Nº1; 757-769. 7

Uso Expandido (EAP) de SUNITINIB Martin E. Gore et al Uso Expandido (EAP) de SUNITINIB Martin E. Gore et al. The Lancet Oncology 2009; 10; Nº1; 757-769.

Fases II/III en 1ª Línea CRA Study Treatment Median PFS (Months) A4061051 Axitinib vs Sorafenib 10,1 vs 6,5 TIVO -1 Tivozanib vs Sorafenib 11,9 vs 9,1 INTORACT Bevacizumab+INF vs Bevacizumab+Temsirolimus 9,3 9,1 RECORD-2 Bevacizumab+Everolimus 10 BEST Bevacizumab Vs Bevacizumab+Sorafenib Sorafenib+Temsirolimus 8,7 7,3 11,3 7,7

RECORD-3: Phase II study design Everolimus 10 mg/day Sunitinib 50 mg/day** Study endpoints Primary PFS 1st-line Secondary Combined PFS ORR 1st-line OS Safety Cross-over upon progression SCREEN RANDOM I Z E * 1:1 Sunitinib 50 mg/day** Everolimus 10 mg/day N=471 First-line Second-line Median follow-up 22.7 months *Stratified by MSKCC prognostic factors; **4 weeks on, 2 weeks off. Motzer RJ, et al. ASCO 2013; Abstract 4504.

RECORD-3: Phase II study design

SWITCH Phase III open-label study design Sorafenib 400 mg Twice daily Sunitinib 50 mg Once daily* Progression or intolerable toxicity Primary endpoint Total PFS** 365 patients mRCC unsuitable for cytokines and no prior systemic therapy Age >18 and ≤85 years ECOG PS 0/1 ≥1 measurable lesion Randomization 1:1 Sunitinib 50 mg Once daily* Sorafenib 400 mg Twice daily Patients enrolled in Germany, Austria, and The Netherlands Stratified by MSKCC prognostic group (favorable or intermediate) Primary endpoint: To evaluate whether total PFS is superior with So–Su vs. Su–So Total PFS defined as the time from randomization to confirmed progression or death during 2nd-line therapy 1st-line events were used for patients who did not switch to 2nd-line therapy Michel MS. Oral Presentation at ASCO GU 2014.

SWITCH Phase III open-label study design

Resultados en la Primera Línea de tratamiento en CRA

Selección de la Primera Línea de Tratamiento Consideraciones clave para el Médico La eficacia es la base para la selección de la primera línea pero también existen otros factores a tener en cuenta…. Robustez de la evidencia y Guías Características del paciente y el tumor Experiencia

Circulating/blood markers Clinical benefit/ surrogate endpoints Biomarcadores GROUP 1 GROUP 2 GROUP 3 Tumour tissue markers Circulating/blood markers Clinical benefit/ surrogate endpoints Fresh biopsy Fine needle aspiration Ascites Plasma Circulating-free DNA Imaging: DCE-MRI DCE-ultrasound CT Functional imaging Paraffin embedded Fresh Archived Serum Hypertension Circulating cells Circulating tumour cells Endothelial tumour cells Toxicities Hypothyroidism Skin changes

Cambio en el paradigma de clasificación y tratamiento de los tumores Paradigma clásico Toxic, non-selective chemotherapy Targeted therapy The wider therapeutic index, direct product of development of molecular biology of 1980s Paradigm of future Integration of molecular diagnostics with targeted therapy – personalised treatment Lugar del Tumor Histología Biología Molecular Perfiles Moleculares Slide 9: Discussion Points Over the past 50 years (and in particular the past 2 decades) there have been many fundamental changes in the field of oncology. One important change has been the increased focus on understanding tumours at the molecular level, which has major implications for both diagnostics and therapeutics. It has been known for quite some time that cancer is not a single disease; rather, it is a family of diseases, many of which can kill. As technology advances, so does our understanding of the true diversity of cancer. Years ago, cancer was diagnosed and treated primarily based on where the physician found it. This approach was not particularly successful. Like peeling an onion, our appreciation of the true diversity of cancer has, over time, extended to the microscopic level, to the molecular level, and, most recently, to the genetic level. Collectively, appreciation for the true diversity of cancer is producing a shift from the old paradigm of toxic, non-selective cytotoxic drugs selected primarily on the anatomic site of the tumor, to a new paradigm of truly integrated diagnostics and targeted therapeutics, where selection of particular therapies is based on the molecular and genetic characteristics of the tumour.

Factores pronósticos/predictivos Moleculares en CRA Manuscript: CL/2014/2595R. Britisn Journal of Cancer Title: IL8 Polymorphisms and Overall Survival in Pazopanib- or Sunitinib-Treated Patients with Renal Cell Carcinoma Chun-Fang Xu, Toby Johnson, Jesus Garcia-Donas et al. IL-8 relación con Sunitinib y Pazopanib VEGFR3 relación con Sunitinib

HIPERTENSIONARTERIAL Efectos adversos con valor predictivo independiente de actividad con SUNITINIB ASTENIA 0 5 10 15 20 25 30 35 40 45 50 Time (months) Probability of PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Present (n=583) Median, 10.9 months (95% CI: 0.6, 12.0) Absent (n=187) Median, 6.4 months (95% CI: 4.7, 8.0) HIPERTENSIONARTERIAL OS probability With HFS (n=179) Median: 38.2 months Without HFS (n=591) Median: 18.9 months p<0.001 SINDROME MANO-PIE Time (months) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 6 12 18 24 30 36 42 48 54 60 With hypertension (n=442) Median OS, 30.9 months (95% CI: 27.9 to 33.7) Without hypertension (n=92) Median OS, 7.2 months (95% CI: 5.6 to 10.7) 0 5 10 15 20 25 30 35 40 45 50 Time (months) p<0.0001 A. Rauvaud and M. Schmidinger. Clinical biomarkers of response in advanced renal cell carcinoma. Ann Oncol 2013; 24 (12): 2935-294.

HIPERTENSION ARTERIAL Efectos adversos con valor predictivo independiente de actividad con SUNITINIB HIPERTENSION ARTERIAL HIPOTIROIDISMO 0 5 10 15 20 25 30 35 40 45 50 Time (months) Probability of PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Present (n=583) Median, 10.9 months (95% CI: 0.6, 12.0) Absent (n=187) Median, 6.4 months (95% CI: 4.7, 8.0) With hypertension (n=442) Median OS, 30.9 months (95% CI: 27.9 to 33.7) Without hypertension (n=92) Median OS, 7.2 months (95% CI: 5.6 to 10.7) 0 5 10 15 20 25 30 35 40 45 50 Time (months) p<0.0001 ESTUDIO SULONG Javier Puente & SOGUG J Clin Oncol 32:5s, 2014 (suppl; abstr 4578)

Tres factores a tener en cuenta antes de iniciar un Tratamiento en CRA Elección del agente y Dosis Eficacia Óptima Manejo Efectos Secundarios Duración Tratamiento

RAINBOW study: Modificación de esquema terapéutico de sunitinib en CRA 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) 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 BASEL I NE Group C (n=27) Schedule 4/2 (control) En esa línea dos trabajos interesantes 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: Modificación de esquema terapéutico de sunitinib en CRA

Evidencia de respuestas completas con Sunitinib Sunitinib-treated patients: n=59; sorafenib-treated patients: n=5 Long lasting CRs can occur after TKI treatment alone or when combined with local treatment Relapsing patients responded well to further therapy Median time to CR was 12.6 months in patients receiving TKIs alone, highlighting the importance of maintaining therapy Albiges L, et al. J Clin Oncol. 2012;30:482–487.

Como resultado se ha mejorado la supervivencia de los pacientes Conclusiones… En los últimos diez años se ha conseguido identificar una nueva diana terapéutica antiangiogénica y sus grupos pronóstico Como resultado se ha mejorado la supervivencia de los pacientes La mejor estratégia terapéutica se basa en utilizar un agente único de forma óptima, no existen variables predictivas validadas Forma óptima se relaciona con la prevencion y manejo de efectos tóxicos así como mantener la dosis tolerable el maximo tiempo posible