Redefiniendo el Tratamiento del Cáncer Renal Enrique Grande Head of Medical Oncology Director of Clinical Research

Disclosures Honoraria for ad boards and/or lectures: Pfizer, BMS, IPSEN, Roche, Eisai, Eusa Pharma, MSD, Sanofi-Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon, Celgene Research Grants: Pfizer, Astra Zeneca, MTEM/Threshold, Roche, IPSEN, Lexicon Leadership roles in medical societies: ENETS, GETNE and GETHI Stocks or ownership interest: None

Pathways and Current Drugs in Metastatic RCC Choueiri & Motzer. N Engl J Med 2017

Curti BD. N Engl J Med 2018

Survival, Durable Response, and Long-Term Safety in Patients With Advanced RCC Receiving Nivolumab Rini B, et al. 13th European International Kidney Cancer Symposium;April 27–28, 2018; Prague, Czech Republic

Spontaneous Regression in Renal Cancer Bloom & Wallace. Br Med J 1964

’Real World’ Immuno-Oncology Sequences Presented By Daniel Heng at 2019 Genitourinary Cancers Symposium

Broad range of systemic treatment options Adapted from NCCN v2.2019 Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

Broad range of systemic treatment options Active surveillance Adapted from NCCN v2.2019 Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

Active surveillance in mRCC: a prospective, phase 2 trial Median surveillance time 22.2 m Median surveillance time 8.4 m Active surveillance in patients with 0–1 IMDC risk factors and two or less organs involved with metastatic disease (favourable group) compared with all other patients (unfavourable group) Rini BI, et al. Lancet Oncol 2016

Broad range of systemic treatment options Active surveillance Metastasectomy Adapted from NCCN v2.2019 Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

Meta-analysis: Outcomes following complete metastasectomy Zaid HB, et al. J Urol 2016

Broad range of systemic treatment options Active surveillance Metastasectomy Cytoreductive Nephrectomy Adapted from NCCN v2.2019 Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

Role of Cytoreductive Nephrectomy in the Cytokines era Flanigan RC, et al. N Engl J Med. 2001 Mickish GHJ, et al. Lancet 2001

Role of Cytoreductive Nephrectomy in the Targeted Therapy era: Meta-anaalysis García-Perdomo HA, et al. Investig Clin Urol 2018

CARMENA: Overall Survival Méjean A, et al. N Engl J Med. 2018

Bex A, et al. Eur Urol 2018

Broad range of systemic treatment options Active surveillance Metastasectomy Cytoreductive Nephrectomy Systemic Treatment Adapted from NCCN v2.2019 Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

Broad range of systemic treatment options Nivolumab Everolimus Sunitinib Temsirolimus Pazopanib Active surveillance Tivozanib Metastasectomy Single agents Sorafenib Cytoreductive Nephrectomy Axitinib Cabozantinib Systemic Treatment Beva + INF Lenvatinib + Eve Nivo + Ipi Combos Atezo + Beva? Avelumab + Axi? Adapted from NCCN v2.2019 Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf Pembro + Axi?

RCC: a rapidly evolving field 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 2L

RCC: a rapidly evolving field INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 2L

PERCY Quattro trial: is there any better ’old’ immunotherapy for RCC? Negrier S, et al. Cancer 2005

RCC: a rapidly evolving field Sunitinib or Sorafenib INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 2L

First battle: Sunitinib vs Sorafenib Sunitinib vs INF Sorafenib vs INF Motzer RJ, et al. N Engl J Med 2007 Escudier B, et al. J Clin Oncol 2009

RCC: a rapidly evolving field Sunitinib or Sorafenib Sunitinib or Temsirolimus INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 2L

The Battle for Poor Risk and Non-Clear Cell Features: Temsirolimus – Global ARCC Trial IFN + TEM TEM IFN 7.3 10.9 8.4 Hudes G, et al. N Engl J Med 2007

The Battle for Poor Risk and Non-Clear Cell Features RECORD-3 Trial ASPEN Trial ESPN Trial Motzer RJ, et al. J Clin Oncol 2014 Armstrong AJ, et al. Lancet Oncol 2016 Tannir N, et al. Eur Urol 2016

The Battle for Poor Risk and Non-Clear Cell Features: Metaanalysis Ciccarese C, et al. Eur J Cancer 2017

RCC: a rapidly evolving field Sunitinib or Sorafenib Sunitinib or Temsirolimus INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 Everolimus or Sorafenib 2L

RECORD-1 trial: mTOR inhibition is active in refractory RCC Motzer RJ, et al. Lancet 2008

RCC: a rapidly evolving field Sunitinib or Sorafenib Sunitinib or Beva + INF Sunitinib or Temsirolimus INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 Everolimus or Sorafenib 2L

AVOREN and CALGB 90206 Trials: Pioneers in Doublets 8.5m 5.2m HR 0.63, 95% CI 0.52–0.75; p=0.0001 HR 0.71 (95% CI, 0.61 to 0.83; P .0001) Escudier B, et al. Lancet 2007 Rini B, et al. J Clin Oncol 2008

CALGB 90206 Trial Toxicity Profile (Grade 3 or 4 AEs) Adverse event Bevacizumab + IFN (n=366) IFN (n=352) Any grade 3/4 adverse event 79% 61% Fatigue/asthenia/malaise 37% 30% Anorexia 17% 8% Proteinuria 15% <1% Hypertension 11% 0% Hemorrhage 2% Venous thromboembolism 1% Gastrointestinal perforation Arterial ischemia Rini B, et al. J Clin Oncol 2008

RCC: a rapidly evolving field Sunitinib or Sorafenib Sunitinib or Beva + INF Sunitinib or Temsirolimus INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 Everolimus or Sorafenib 2L Axitinib or Everolimus

AXIS trial: Axitinib can overcome the resistance to sunitinib Rini BI, et al. Lancet 2011

RCC: a rapidly evolving field Sunitinib or Sorafenib Sunitinib or Beva + INF Sunitinib or Pazopanib Sunitinib or Temsirolimus INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 Everolimus or Sorafenib 2L Axitinib or Everolimus

COMPARZ Trial: Should we insist on Non-Inferiority Trials designs? Motzer RJ, et al. N Engl J Med 2013

RCC: a rapidly evolving field Sunitinib or Sorafenib Sunitinib or Beva + INF Sunitinib or Pazopanib Sunitinib or Temsirolimus INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 Everolimus or Sorafenib 2L Nivolumab or Cabozantinib Axitinib LENEVE Axitinib or Everolimus

Grande E, et al. World J Clin Oncol 2017

RCC: a rapidly evolving field Sunitinib or Nivo/IPI Cabozantinib Atezo/Bev Pembro/Axi Avelu/Axi Tivozanib 1L Sunitinib or Sorafenib Sunitinib or Beva + INF Sunitinib or Pazopanib Sunitinib or Temsirolimus INF vs IL-2 or combo 1992 … … 2005 … 2007 2008 2011 2009 2014 2011 2013 2016 2017 2018 2019 Everolimus or Sorafenib 2L Nivolumab or Cabozantinib Axitinib LENEVE Axitinib or Everolimus

Sunitinib vs Ipilimumab + Nivolumab CheckMate 214 1.096 Reported OS ITT HR 0.68 Int/poor risk Bevacizumab + Atezolizumab Immotion 151 915 PFS PDL1+ HR 0.74 Inv assess Axitinib + Avelumab Javelin Renal 830 PFS PDL1+ HR 0.61 IRC assess Axitinib + Pembrolizumab KEYNOTE 426 840 Press Release OS ITT HR 0.53 PFS ITT HR 0.69 Levatinib + Pembrolizumab CLEAR 1.050 Recruiting Est. Oct 2020 Lenvatinib + Everolimus Cabozantinib + Nivolumab CheckMate 9ER 1.014 Est. Feb 2021 Sunitinib vs The following references are available from www.clinicaltrials.gov: 1. NCT01099423; 2. NCT01235962; 3. NCT02231749; 4. NCT01582672; 5. NCT00492258; 6. NCT02627963; 7. NCT01599754; 8. NCT02420821; 9. NCT02853331; 10. NCT02811861; 11. NCT02684006; 12. NCT01120249.

Sunitinib vs Ipilimumab + Nivolumab CheckMate 214 1.096 Reported OS ITT HR 0.68 Int/poor risk Bevacizumab + Atezolizumab Immotion 151 915 PFS PDL1+ HR 0.74 Inv assess Axitinib + Avelumab Javelin Renal 830 PFS PDL1+ HR 0.61 IRC assess Axitinib + Pembrolizumab KEYNOTE 426 840 Press Release OS ITT HR 0.53 PFS ITT HR 0.69 Levatinib + Pembrolizumab CLEAR 1.050 Recruiting Est. Oct 2020 Lenvatinib + Everolimus Cabozantinib + Nivolumab CheckMate 9ER 1.014 Est. Feb 2021 Sunitinib vs The following references are available from www.clinicaltrials.gov: 1. NCT01099423; 2. NCT01235962; 3. NCT02231749; 4. NCT01582672; 5. NCT00492258; 6. NCT02627963; 7. NCT01599754; 8. NCT02420821; 9. NCT02853331; 10. NCT02811861; 11. NCT02684006; 12. NCT01120249.

ESMO 2019 Guidelines (IA recommedations) Good risk Intermediate risk Poor risk 1L Sunitinib Bevacizumab + IFN Pazopanib Tivozanib Nivolumab + ipilimumab Nivolumab + ipilimumab Post TKIs Post nivolumab + ipilimumab VEGF TKI VEGF MAb + IFN- 2L TKI + mTOR inhibitor Nivolumab Cabozantinib Any TKI Lenvatinib + everolimus PD-1 inhibitor (+ CTLA-4 inhibitor) Escudier B, et al. Ann Oncol 2019

egrande@mdanderson.es @drenriquegrande