Spanish Oncology GenitoUrinary Group 1st Ibero-American Forum on Metastatic Renal Cell Carcinoma: Establishing A Continuum of Care to Improve Patient Outcomes 14-15 March 2013. Buenos Aires,Argentina Daniel Castellano Oncología Médica.Unidad de Tumores GenitoUrinarios Hospital Universitario 12 de Octubre. I + 12 Research Institute. Chairman SOGUG

Bevacizumab + IFN-α (Jul 2009)5 High dose interleukin-2 Treatment options for metastatic RCC have been revolutionised in a short period of time… Sunitinib (Jan 2006)2 Pazopanib (Oct 2009)6 Sorafenib (Dec 2005)1 Bevacizumab + IFN-α (Jul 2009)5 Axitinib (Jan 2012)7 High dose interleukin-2 Temsirolimus (May 2007)3 Everolimus (Mar 2009)4 IFN-α 1992-2005 2005 2006 2007 2008 2009 2010 2011 2012 US FDA. Sorafenib, 2005. US FDA. Sunitinib malate, 2006. US FDA. Temsirolimus, 2007. US FDA. Everolimus, 2009. US FDA. Bevacizumab, 2009. US FDA. Pazopanib, 2009. US FDA. Axitinib, 2012. Tivozanib (2013 ??)

Algoritmo CCRm - 2013 Sunitinib Pazopanib Tivozanib ? Beva - IFN-α Setting Patients Therapy Options First-line Favourable- or intermediate-risk Sunitinib Pazopanib Tivozanib ? Beva - IFN-α HD IL-2 Cytokines Sorafenib Poor-risk Temsirolimus Second-line Prior cytokine Axitinib Sorafenib Prior VEGF–TKI Sorafenib ? Everolimus Clinical trial Third-line Prior TKI – TKI Everolimus Clinical Trial Prior TKI – mTOR Sorafenib/Dovitinib Clinical trial Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012, NCCN guidelines 2013 SOGUG 2010 3

New pathways and therapies in RCC More potent VEGFR2 TKIs Axitinib (confirmed) Tivozanib (confirmed) Novel antiangiogenics Angiopoietin inhibitor (not confirmed) VEGFR2 antibody (pending) DLL4 inhibitor (pending) FGF Inhibitors (pending) PI3K/Akt/mTOR inhibitors (early) Novel immunotherapy Ipilimumab (stopped) Anti-PD-1 (pending) Anti-PDL-1 (stopped) RCC = renal cell carcinoma; VEGFR = vascular endothelial growth factor receptor; TKIs = tyrosine kinase inhibitors; DLL4 = delta-like-4. Pal et al, 2010; Loges et al, 2010; Duignan et al, 2011.

Sunitinib (Adjuvant Treatment) Future Treatment options for metastatic RCC … Anti-PD1 Sunitinib (Adjuvant Treatment) Dovitinib 2013 2014 2015

Algoritmo CCRm – 2014? Sunitinib Pazopanib Tivozanib ? Beva - IFN-α Setting Patients Therapy Options First-line Favourable- or intermediate-risk Sunitinib Pazopanib Tivozanib ? Beva - IFN-α HD IL-2 Cytokines Sorafenib Poor-risk Temsirolimus Second-line Prior cytokine Axitinib Sorafenib Prior VEGF–TKI Sorafenib ? Everolimus Clinical trial Third-line Prior TKI – TKI Everolimus Anti-PD1?? Clinical Trial Prior TKI – mTOR Sorafenib/Dovitinib Clinical trial Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012, NCCN guidelines 2013 SOGUG 2010 6

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

Manejo Integral Multidisciplinar del Carcinoma Renal Avanzado Tipo Tratamiento: Secuencial Individualización Medicina Basada Evidencia (Est.Clínicos) Uso Racional de Recursos Tratamiento Integral Manejo Efectos Adversos Control Complicaciones Tumorales Beneficio Clínico 8

Spanish Oncology GenitoUrinary Group 2st Ibero-American Forum on Metastatic Renal Cell Carcinoma: Establishing A Continuum of Care to Improve Patient Outcomes March 2014 ??

Muchas Gracias