Imunoterapija u liječenju karcinoma bubrega. AUTOR: Milena Gnjidić

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1 Imunoterapija u liječenju karcinoma bubrega AUTOR: Milena Gnjidić

2 IMUNOTERAPIJA U 2013 LIJEČENJU KARCINOMA BUBREGA Milena Gnjidić KBC Zagreb Hrvatska SWOC

3 KARCINOM BUBREGA: SMJERNICE 2016 Nakon VEGF-I NIVOLUMAB CABOZANTINIB LENVATINIB + EVEROLIMUS EU USA

4 KARCINOM BUBREGA: ESMO 2016 Clear cell mrcc Non clear cell mrcc Good/intermediate risk Poor risk SUNITINIB (IIB) First line SUNITINIB (IA) PAZOPANIB (IA) BEVACIZUMAB+IFN (IA) High dose IL2 (IIIC) Sorafenib (IIB) TEMSIROLIMUS (IIA) Temsirolimus (IIIB) Sorafenib (IIIB) Pazopanib (IIIB) Everolimus (IIIB) Second line NIVOLUMAB (IA) CABOZANTINIB (IA) Axitinib ( IIB) Everolimus ( IIB) Sorafenib (IIIB) Third line Post 2TKIs Post TKI and mtor Post TKI/NIVO Post TKI/CABO NIVOLUMAB (IIA) CABOZANTINIB (IIA) Everolimus (IIB) SORAFENIB (IB) NIVOLUMAB (VA) CABOZANTINIB (VA) Other TKI (IVB) Rechallenge (IVB) CABOZANTINIB(VA) Axitinib (IVC) Everolimus (IVC) NIVOLUMAB (VA) Everolimus (VB) Axitinib (VB) HR

5 CHECKMATE 025: NIVOLUMAB VRS EVEROLIMUS OS Motzer RJ, Escudier B, et al. Nivolumab versus everolimus in advanced renal cell carcinoma. N Engl J Med 2015,373:

6 METEOR:CABOZANTINIB VRS EVEROLIMUS PFS OS Final results: 21.4 m 16.5 m HR Choueiri TK, Esudier B, Powles T et al. Cabozantinib versus everolimus in advanced RCC (METEOR): final results from randomised, openlabel, phase 3 trial. Lancet Oncol 2016; 17:

linija!? HR 0.69 ( 0.48-0.99) P-value = 0.

7 PRVA LINIJA MRCC: CABOSUN - FAZA II CABOZANTINIB SUNITINIB Hoće li CABO biti prva linija!? HR 0.69 ( ) P-value = 0.02 HR 0.80 ( ) Similar toxicity Čeka se faza III!!

STUDIJE FAZE 3 ZA ADJUVANTNO LIJEČENJE RCC Study Type of Drug Duration ASSURE S-TRAC ATLAS SORCE PROTECT EVEREST VEGF (Sunitinib, sorafenib) VEGF (Sunitinib) VEGF (Axitinib) VEGF (Sorafenib) VEGF

1 year DFS High & Int Risk f N=1500 1 year RFS High & Int Risk g N=1218 Negative 1 Status (www.ct.gov) Hoće li SUN ići adjuvantno?

8 STUDIJE FAZE 3 ZA ADJUVANTNO LIJEČENJE RCC Study Type of Drug Duration ASSURE S-TRAC ATLAS SORCE PROTECT EVEREST VEGF (Sunitinib, sorafenib) VEGF (Sunitinib) VEGF (Axitinib) VEGF (Sorafenib) VEGF (Pazopanib) mtor (Everolimus) Primary Endpoint Patient Population 1 year DFS High & Int Risk b N= year DFS High Risk c N=720 a 3 years DFS High Risk d N=700 3 years DFS High & Int Risk e N= year DFS High & Int Risk f N= year RFS High & Int Risk g N=1218 Negative 1 Status ( Hoće li SUN ići adjuvantno? Positive Presentation at: ESMO 2016 Trial ongoing Projected Readout Date: June 2017 Awaiting results Projected Readout Date: Completed per ct.gov (August 2012) Trial ongoing Projected Readout Date: April 2019 Trial ongoing Projected Readout Date: October 2021 a 615 patients in the main study b Per 2002 (American Joint Committee on Cancer [AJCC] 6 th edition) TNM staging c Per modified UISS criteria d Per 2010 AJCC TNM staging and ECOG PS e Leibovich score 3 to 11 f Per 2010 AJCC TNM staging and Fuhrman nuclear grading g Considered pathologically either intermediate high-risk or very high-risk disease Haas et al. Lancet 2016

Prilagodljivost 3. Memorija Chen DS, Mellman I.

9 IMUNOLOŠKI SUSTAV PROTIV TUMORA Jim Allison CTLA4 PD-1/PD-L1 Prednosti imunoterapije: 1. Specifičnost 2. Prilagodljivost 3. Memorija Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013

10 INHIBICIJA PD-1/PD-L1

11 IMUNOTERAPIJA U LIJEČENJU RAKA Više mutacija = bolji odgovor na imunoterapiju ccrcc = imunogenični tumor ( IL-2, INFa) UC = BCG

IMUNOLOŠKI EFEKTI VEGF INHIBICIJE Normalizira vaskulaturu tumora - omogućuje dolazak T limfocita VEGF potiče inhibitorne dendritične stanica / mijeloidne supresorske stanice VEGF inhibicija ima

12 IMUNOLOŠKI EFEKTI VEGF INHIBICIJE Normalizira vaskulaturu tumora - omogućuje dolazak T limfocita VEGF potiče inhibitorne dendritične stanica / mijeloidne supresorske stanice VEGF inhibicija ima antitumorski učinak imunogenična smrt stanice VEGF blokada povećava infiltraciju tumora T-limfocitima = potencira antitumorski imunološki odgovor!! Wallin JJ, et al. Atezolizumab in combination with bevacizumab enhances antigen specific T-cell migration in mrcc. Nat Commun. 2016

13 KOMBINACIJE IMUNOTERAPIJE I VEGF-I PRVA LINIJA - faza III Atezolizumab Više selektivni VEGF-I - BEV, AXI

14 PRVA LINIJA: PEMBROLIZUMAB+AXITINIB

15 LIJEČENJE KARCINOMA BUBREGA BIOMARKERI!! Stukalin I, et al. Contemporary treatment of mrcc. Oncol Rev. 2016

16 BIOMARKERI

17 BIOMARKERI

18 IMUNOTERAPIJA: BIOMARKERI PD-L1 ekspresija na tumorskim stanicama ili tumor infiltrirajućim imunim stanicama!? NE! Određena genska ekspresija tumorinfiltrirajućih imunih stanica ( TIIC) 1 Tumor-infiltrirajuće imune stanice: Th17 i CD8+T/Treg omjer = bolje preživljenje Th2 i Treg = lošije preživljenje 2 1. Rodriguez-Vida A, Strijbos M, Hutson T. Predictive and prognostic biomarkers of targeted agents and modern immunotherapy in RCC. ESMO Open Senbabaoglu Y, et al. Tumor immune microevironment characterization in ccrcc identifies prognostic and immunotherapeutically relevant mrna signatures. Genome Biol. 2016

19 IMUNOTERAPIJA: KOMBINACIJE

20 IMUNOTERAPIJA: KOMBINACIJE PD1/PDL1 inhibicija (NIVO, ATEZ, PEMB, AVE) Drugi Checkpoint inhibitor ( IPI) VEGF inhibitor ( BEV, AXI) T-cell agonist ( 41BB, Ox40) Personalizirane vakcine ( IMA-901, AGS-003) Adoptivna T-cell terapija (genetski modificirani T limfociti ili ekspanzija tumorinfiltrirajućih limfocita) Hammers H. Immunotherpy in kidney cancer: the past, present, and future. Curr Opin Urol. 2016

21 BUDUĆNOST: KOMBINACIJA ILI SEKVENCIJA??

22 HVALA NA PAŽNJI!

Sequencing of therapies in mrcc. Ari Hakimi MD Assistant Professor Urology Service, Department of Surgery MSKCC

Sequencing of therapies in mrcc Ari Hakimi MD Assistant Professor Urology Service, Department of Surgery MSKCC Old Paradigm Sequencing approved agents VEGF TKI Sunitinib Pazopanib Axitinib TKI TKI MTORi