Complete Remission is a Reachable Goal in mrcc L. Albiges Institut Gustave Roussy

Is complete remission an achievable goal in mrcc? Lessons from observation Lessons from immunotherapy Current status in VEGFR/mTOR targeting therapy Coming steps

Lessons from clinical case 73 year old lady 11/2000: Kidney tumor with pleural effusion and lung nodules Pleural biopsy showed pleural mets Nephrectomy performed: clear cell RCC, grade 2

11/2000 Control CT scan performed before systemic treatment 2/2001

11/2000 2/2001 2/2009

Is complete remission an achievable goal in mrcc? Lessons from observation Lessons from immunotherapy Current status in VEGFR/mTOR targeting therapy Coming steps

Immunotherapy ERA MRC Lancet 1999 Pyrhonen JCO 1999 Motzer JCO 2000 Fisher Can J Sci Am 2000 Atzpodien Cancer 2002 Study Treatment n Complete Remission (%) Coppin CochraneDatabase 2005 Négrier Cancer J Sci Am. 2000 Figlin Cancer J Sci Am. 1997 IFN vs MPA 335 2% IFN-vbl vs Vbl 160 8% (7/80) IFN-cRA vs IFN 284 5% (5/139) 1% (1/145) 4% IL2HD 255 7% (17/255) IL2- & IFN (+5FU or 13cRA) 443 8% (37/443) Meta analysis of randomized study with IFN 6117 4% 51 study/53 Median CR duration (months) 6 (3-65) 80 (7-131) 13 years 4 studies <8% Up to 5 years 6% (12/203) 36

Immunotherapy ERA Identification of predictive factors for CR? Factors of prolonged CR (predictive of CR duration) Number of metastatic site Cytoreductive Nephrectomy IL2 HD vs non HD Elias, Oncology 2001 Biological factors SELECT trial McDermott, ASCO JCO210

Is complete remission an achievable goal in mrcc? Lessons from observation Lessons from immunotherapy Current status in VEGFR targeting therapy Coming soon

VEGFR TKI era Achievable with medical treatment only? incidence among phase III? <1% across all Mecanism of action? VEGFR target, tumor cell effect Immuno-modulation Neo adjuvant data? No pcr!

VEGFR TKI era Retrospective cohort Case report n Description References 3 (3/74=4%) 2 2 TKI alone 1 TKI + surgery TKI sustained subsequently( RC>22mois) Potential predictive factor: Good Pstic & intermediate, lung mets, first line, early response 2 TKI + surgery Heng DY, Clin Genitourin Cancer. 2007 What kind of CR? medical/ multimodal What predictive factors of CR? Rini B Clin Genitourin Cancer. 2006 Case report 1 TKI+ surgery ( unifocal lung met) + TKI subsequent 1y Calvo OF, at 6 months, same site Anticancer drugs, Should pt stay under Jan 2010 treatment after CR? RC at TKI rechallenge and substequently sustained Case report 1 1 met site only TKI alone Treatment discontinued for toxicity García-Campelo R, Anticancer drugs, Jan 2010

Retrospective study 12 (12/266= 4%) Retrospective study 5 (5/194=2.5%) Retrospective study 36 (*12 + 24) n Caractéristiques Références 6 TKI alone 6 TKI + surgery Median FU 8.5 m; TTP: 6 mo 5/12 relapse (41%) 100% PR or SD at TKI re-introduction 5 ccrcc 2 TKI alone 3 TKI + surgery 4/5 case : TKI discontinuation, 1/5 TKI continuation Median FU 24 mo, no relapse 16 TKI alone 20 TKI+ local treatment 34/36 ccrcc Favorable pstic 39%, intermediate pstic: 61% 22 sunitinib; 11 sorafenib; 2 bevacizumab; 1 temsirolimus Median time to CR: 12mo : 24/36 ( 66,7%) TKI efficacy at re-introduction: PR or SD: 87% 12 Pt without relapse with 12mo median FU Median of drug off period: 7m Johanssen M, Eu Urol, Jun 2009 Staehler M, Urol Oncol, Mar 2010 Johannsen M, Ann Oncol 2011

Multicenter Retrospective analysis Patient developping CR With VEGFR-TKI alone With VEGFR-TKI plus local treatment Double radiological review Aim at: - Description CR incidence, profil - Description of management - Identify predictive marquers

CR with systemic therapy CR with VEGFR TKI alone (n=36) TKI discontinuation (n=16 ; 44%) TKI discontinuation after additional cycles (n=12; 33%) Median duration of TKI after CR obtention= 3.9 months (range 1.06 32.5) TKI continuation (n=8 ; 22%) (n=7/16 ; 44%) (n=4/12 ; 33%) (n=1/8 ; 13%) J Clin Onco 2012

CR with systemic therapy CR with VEGFR TKI alone (n=36) Median time to CR: 12.6 mo range [2-28] 12/36 relapsed (33%) TKI discontinuation (n=16 ; 44%) (n=7/16 ; 44%) TKI discontinuation after additional cycles (n=12; 33%) Media duration of TKI after CR obtention = 3.9 months (range 1.06 32.5) (n=4/12 ; 33%) TKI continuation (n=8 ; 22%) (n=1/8 ; 13%) Median time from CR to relapse: 7.9 months [3-32] 17/28 pts (61%) with treatment discontinuation had prolonged with median FUp 8.5mo J Clin Onco 2012

BL 08/01/08

BL 08/01/08 06/06/08

BL 08/01/08 BL 08/01/08 06/06/08 05/01/09

CR with multimodal approach CR with VEGFR TKI + local ttt (n=28) TKI discontinuation (n=19) TKI discontinuation after additional cycles (n=6) Median duration of TKI administration after CR obtention = 3.5 months (range 1.0 15.4) TKI continuation (n=3) (n=10/19 ; 52%) (n=3/6 ; 50%) (n=1/3 ; 33%) J Clin Onco 2012

CR with multimodal approach Site of local treatment n=28 % TKI discontinuation (n=19) CR with VEGFR TKI + local ttt (n=28) TKI discontinuation after additional cycles (n=6) TKI continuation (n=3) Lung LN Adrenal Pancreas Gastric/Colon Other (liver ) 13 4 5 2 2 3 46 14 18 7 7 11 Median duration of TKI administration after CR obtention = 3.5 months (range 1.0 15.4) Among the 22 surgical samples: NO pathological CR was observed (n=10/19 ; 52%) (n=3/6 ; 50%) (n=1/3 ; 33%) J Clin Onco 2012

CR with multimodal approach CR with VEGFR TKI + local ttt (n=28) Median time to CR: 18.5 mo range [5-45] 14/28 relapsed (50%) TKI discontinuation (n=19) TKI discontinuation after additional cycles (n=6) TKI continuation (n=3) Median time from CR to relapse: 8.2 months [3-25] Median duration of TKI administration after CR obtention = 3.5 months (n=10/19 ; 52%) (range 1.0 15.4) (n=3/6 ; 50%) (n=1/3 ; 33%) 12/25 pts (48%) with treatment discontinuation had prolonged with median FUp 10.7mo J Clin Onco 2012

CR with TKI : Conclusion (1/2) CR: Population Can be obtained in all prognosis group Can be obtained in various and multiple metastatic profil No predictive identified factors CR: feasibility of drug interruption Cons: Any proof of delaying recurrence? Potential rebound? Pros: Quality of life, prevention of drug resistance cost Efficacy of drug re-introduction at relapse 18 patient received subsequent VEGFR i (14 same TKI, 4 alternative TKI): 10 PR 4 SD 1 PD 3UKN J Clin Onco 2012

CR with TKI : Conclusion (2/2) CR: Proposed management TKI alone CR: sustained 3 months of TKIs after CR then drug arrest Multimodal CR: no «adjuvant» TKI after local treatment Follow up: CT- scan every 3 months during first year and then every 6 months J Clin Onco 2012

CR with TKI : Next step ANALYSE PROSPECTIVE DES REMISSIONS COMPLETES OBSERVEES SOUS SUNITINIB CHEZ DES PATIENTS ATTEINTS D UN CANCER DU REIN METASTATIQUE (mrcc) Prospective national study Case - control design study multicentric Central Radiological review Tissue collection Blood sampling at time of CR and relapse N = 120: 40 case, 80 control pts

PD1 inhibition Brahmer et al., JCO 2010 ASCO GU 2013,Dr Mc Dermott, Educational session CR : Coming soon Not obtained with combination of current VEFR/mTOR agents What about new agents alone or new combinations? No treatm Anti PD1 Sunitinib Sunitinib + Anti PD1

«It is ethical to believe in it!» Dr Besse