Cezary Szczylik Klinika Onkologii Wojskowy Instytut Medyczny. Warszawa

Transkrypt

1 Cezary Szczylik Klinika Onkologii Wojskowy Instytut Medyczny. Warszawa

2 RNK* stanowi 3% nowotworów u dorosłych i 90 95% guzów nerki częstość : 3/ (w Polsce 5200 /rok/ mieszk) RCC x20 1 M/F ratio : 1.6/1 Średni wiek~ 60 rż * Rak nerkowokomórkowy

3 Baldewijns MM, van Vlodrop IJH, Schouten LJ, Soetekouw PM, de Bruïne AP, van Engeland M: Genetics and epigenetics of renal cell cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2008; 1785 (2);

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5 2008 Incidence of Renal Cancer CEE vs Big 5 Central & Eastern Europe 20 16,6 European Union Big ,2 5,8 9,1 11,0 7,5 13,2 11,9 5,1 7,8 4,4 8,4 5,4 11,0 9,0 7,6 7,4 10,8 7,4 5,8 7, Mortality of Renal Cancer CEE vs Big ,3 2,5 3,8 5,6 4,6 3,4 4,7 4,9 2,2 3,9 2,1 3,8 2,8 4,7 3,7 3,2 2,7 3,3 2,2 2,0 3,0 0 Vrdoljak E et al.. Expert Opin Pharmacother 2012;13:

6 Health Care Expenditure per Capita in 2008 Central & Eastern Europe European Union Big 5 $6 000 $5 000 $4 000 $3 000 $5 122 $4 628 $3 924 $3 533 $3 087 $2 000 $1 000 $406 $480 $1 419 $1 231 $924 $1 131 $971 $881 $181 $911 $2 117 $1 366 $441 $620 $499 $267 $0 Vrdoljak E et al.. Expert Opin Pharmacother 2012;13:

7 RNK to heterogenna grupa nowotworów Większość przypadków stanowi rak jasnokomórkowy Jasnokomórkowy Nie-jasnokomórkowy Guz - typ histologiczny Papillarny typ I,II +II II) Chromopho b Oncocytic Collecting duct Częstość (%) Mutacja genetyczna VHL c-met FH BHD BHD BHD = Birt Hogg Dubé; FH = fumarate hydratase; VHL = von Hippel Lindau

8 sporadyczny RNK ccrcc: Teoria 2 uderzeń 84-98% delecja jednego allelu (LOH) mutacje w 34-57% innych alleli Metylacja w 5-19% Cohen NEJM 2005 więcej 80% CCC: mutacje genu VHL Rini JCO 2005

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10 Acquisition of secondary KIT mutation Proliferation Erk 1/2 PLC-γ Survival Akt PI3K Mutated KIT Recruitment of proangiogenic BMDCs Bone marrow derived cells PDGFR CXCR4 Vascular permeability VEGFR NOS Migration Src Sunitinib sorafenib PlG F TKI-MEDIATED BLOCKAGE OF VEGF- AND PDGFMEDIATED ANGIOGENESIS PATHWAY AXIS PDGFR FAK P38 MAPK VEGFR PDGF Immunomodulatory effect VEGF SDF-1 Stromal cells PDGF Alternalive signalling in condition of RCC resistance to TKIs TIE2 TGFβ VEGF Cell survival CXCR2 FGFR PDGF SDF-1 PlG F PlG F VEGF VEGFR PDGF VEGF Alternalive signalling in condition of RCC resistance to TKIs Ang-2 Ang-2 IL-8 sunitinib FGF IL-8 FGF FGF IL-8 FGF Lysosomal sequestration VEGF VEGF PDGFR Β-catenin VEGF TYRO3 MITF PlG F PDGF Ras VEGF MAPK Ang-2 Ang-2 IL-8 IL-8 FGF HIF-1β FF FGF upregulation PRKX TTBK2 RSK Gene CPB/p300 expression HIF-1β HIF-1α switch HRE TARGET GENES HIF-1α MET Erk 1/2 Pericyte Ras Alk1 JAK/STAT downregulation E3 Ligase Complex Rbx1 TCEB2 TGFRβ2 CXCR4 eif-4e1 Mek 1/2 ESM1downregulation HOXA9 PECAM FGFR mtor EGFR PI3K Erk 1/2 PDGFR S6K Akt EGFR Increased pericyte expression and coverage Ang-2 SDF-1 SDF-1 PDGF PDGF VEGF VEGF? VEGFR Smad 2/3 Endothelial cell T cell B cell B cell T cell T cell B cellt cell B cell T cellb cell VEGFR PDGF PDGF RCC cytosol Tumour cell Increased migration and invasiveness/ EMT nucleus Cul2 HIF-1α TCEB1 VHL Ub Ub Ub Ub HIF-1α degradation Fig. by M. Buczek et al.

11 1566 pierwotnych guzów epitelialnych i 178 guzów przerzutowych

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14 Cytotoxic chemotherapy experiments performed 1 High-dose IL-2 FDA approved 2 IFN-α shows improved survival vs. hormonal therapy 3 Targeted therapy licensed for the treatment of mrcc Sorafenib: first targeted therapy l icensed in the US (2005) 5 Sunitinib approved in US (2006) 5 Both licensed in the EU (2006) 6 Temsirolimus and bevacizumab + IFN licensed 5,6 1940s 1980s / IFN-α and high-dose IL-2 used for treatment of RCC in early 1980s Gemcitabine plus capecitabine or doxorubicin shows some efficacy but high toxicity 3 TARGET 4 : first evidence of PFS benefit with targeted therapy Everolimus licensed in the US and EU 5,6 1. Abeloff MD, et al. Clinical Oncology 3rd ed. Philadelphia, PA. 2. Cochrane Database SystRev. 2005(1):CD Costa LT, et al. Oncologist.2007;12: Escudier B, et al. N Engl J Med 2007; 356: U.S. Food and Drug Administration ( 6. European Medicines Agency ( Pazopanib EU 2010 licensed in the US Axitinib, dovitinib, tivozanib

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16 Agent/ Class Sorafenib 1 Oral TKI Phase III data Comparator Line of treatment Benefit in PFS/OS Main exclusion criteria Placebo CK treated or CK unsuitable Yes Brain metastases, previous exposure to VEGF inhibitors Sunitinib2 Oral TKI IFN-α First line Yes Brain metastases, previous systemic therapy, uncontrolled hypertension, cardiovascular events Temsirolimus3 IV mtor inhibitor IFN-α First line poor risk only Yes Previous systemic therapy Bevacizumab + IFN-α4 IV anti-vegf Ab IFN-α First line Yes Previous systemic therapy, brain metastases, uncontrolled hypertension, cardiovascular disease, recent major surgery, anti-coagulant medication Everolimus5 Oral mtor inhibitor Placebo Second line Yes Brain metastases, previous exposure to mtor inhibitors, uncontrolled medical conditions Pazopanib6 Oral TKI Placebo First line or CK treated Yes Brain metastases, poorly controlled hypertension, cardiovascular or cerebrovascular events, prior exposure to targeted therapy CK = cytokine 1. Escudier B, et al. N Engl J Med 2007;356: Motzer RJ, et al. N Engl J Med 2007;356: Hudes G, et al. N Engl J Med 2007;356: Escudier B, et al. Lancet. 2007;370: Motzer RJ, et al. Cancer 2010;116: Sternberg CN, et al. J Clin Oncol 2010;28:

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18 First-line treatment Clear cell histology Non-clear cell histology Good/intermediate prognosis Poor prognosis Standard treatment options Sunitinib, Bevacizumab + interferonα Pazopanib, tivozanib, sorafenib? axitinib Temsirolimus Clinical trial Alternative treatment options Sorafenib Interleukin-2 Sunitinib Best supportive care Sorafenib Temsirolimus Sunitinib Escudier et al. Ann Oncol 2012;23(Suppl. 7):vii65-vii71 18

19 First-line treatment Clear cell histology Non-clear cell histology Good/intermediate prognosis Poor prognosis Standard treatment options Sunitinib Bevacizumab + interferonα Pazopanib, Tivozanib Temsirolimus Clinical trial Alternative treatment options Sorafenib Interleukin-2 Sunitinib Best supportive care Sorafenib Temsirolimus Sunitinib Escudier et al. Ann Oncol 2012;23(Suppl. 7):vii65-vii71 19

20 C -> A -> B -> D A -> B -> C -> D A -> C -> B B -> A -> C. A -> B -> D C -> D -> A -> B D -> A -> C -> B B -> A -> D..

21 Axitinib (1* following cytokine therapy and other TKIs) Sunitinib (1 following cytokine therapy, 2A following other TKI) Sorafenib (1 following cytokine therapy, 2A following other TKI) Pazopanib (1 following cytokine therapy, 3 following other TKI) Everolimus (1 following TKI therapy) Temsirolimus (2A following cytokine therapy, 2B following TKI) Bevacizumab (2A following cytokine therapy, 2B following TKI) IL-2 (2B) Best supportive care : See NCCN Palliative Care Guidelines Clinical trial mrcc = metastatic renal cell carcinoma; IL-2 = interleukin-2; NCCN = National Comprehensive Cancer Network. Kidney Cancer, NCCN v Clinical Practice Guidelines in Oncology. Available at:

22 Summarizing RCTs in 2 nd line RECORD-1 1 PFS OS N= 277 N= 139 Everolimus Placebo OS: p = not significant AXIS 2 N= 361 N= 362 Axitinib Sorafenib OS: p= not significan t INTORSECT 3 N= 259 N= 253 Temsirolimus Sorafenib OS: p=0.014 statistically significant (Months) 1. Motzer RJ, et al. Cancer 2010;116: ; 2. Rini BI, et al. Lancet 2011;378:1931 9; 3. Hutson TE, et al. ESMO 2012;abstract LBA22

23 RECORD-1: which line of Tx? 1 st Line 2 nd Line 3 rd Line mtor 4 th Line n = 82 5 th Line mtor 1 st Line 2 nd Line 3 rd Line 4 th Line n = % 1 st Line 2 nd Line mtor 3 rd Line n = st Line mtor 2 nd Line n = 89 21% 1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Motzer RJ, et al. Cancer 2010;116: ; 3. Calvo E, et al. Eur J Cancer 2012;48:333-9.

24 TKI/VEGF inhibitor TKI/VEGF inhibitor mtor inhibitor 7 badań retrospektywnych >400 pacjentów wspierają leczenie sekwencyjne z TKI 1-7 Skuteczność ewerolimusu jest porównywalna bez wgzlędu na liczbę stosowanych TKI 8 TKI/VEGF inhibitor mtor inhibitor? Jak dotąd brak danych dot. skuteczności innych leków po inhibitorach mtor 1. Tamaskar I, et al. J Urol 2008;179: Richter S, et al. Onkologie 2008;31:234, abst V Choueiri TK, et al. ESMO 2008; abstr Eichelberg C, et al. Eur Urol 2007; 54: Dudek AZ, et al. Cancer 2009; 115: Sablin MP, et al. ASCO 2007, abstr Porta EAU 2009; abstr? 8. Escudier B et al. presentation at ESMO 2008; abstr 720

25 Median PFS (months) % CI 11.5, 14.0 No. patients at risk CI, confidence interval; PFS, progression-free survival.

26 Median OS (months) % CI 25.4, 31.2 No. patients at risk CI, confidence interval; OS, overall survival.

27 FAVOURABLE Median OS (months) 38.2 ( ) INTERMEDIATE Median OS (months) 17.7 ( )

28 INTERMEDIATE FAVOURABLE

29 Lepsze zrozumienie biologii molekularnej dla losów przyszłych terapii Poszukiwanie komórek macierzystych RNK i analiza jej kontaktów z otaczającym środowiskiem Aktywne kontynuowanie badań nad Nowymi lekami i ich kombinacjami Leczeniem sekwencyjnym Eskalacją dawki Rolą chirurgii Leczeniem neo-adjuwantowym i adjuwantowym Szybsze wdrażania standardów międzynarodowych przez NFZ

30 Dlaczego rak nerki to pole bitwy współczesnej onkologii bo angiogeneza nie jest swoista tylko dla raka nerki