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C. Collaborators Lancet 1999;353:14-7 IFNa + VBL/ VBL : med survival difference 6 months (p<0.05) Pyrhonen S JCO 1999;17:2859 IFNa + VBL / IFNa :no difference Fossa SD Ann Oncol 1992;3:301-5>Z=Z1ZDZ!Z"Z$Z!! .Ov-1Ov         L      '       $RCC - INTERFERON-a0   RESULTS : RR not impressive Long remissions in complete responders Survival advantage in 2 randomized trials Toxicity / good patient selectionD  !@t@v          RCC - High Dose IL-2L FDA approval through 7 phase II trials with 255 patients from 21 centers 600000-7200001u/kg; 15 min infusion q 8 hrs x 14 doses 2 cycles; 5-9 days apart; 6-12 weeks break in responsive/stable pts ci / dose ci or sc IL-2 to decrease toxicity VK8I04                      RCC - High Dose IL-2L  Fisher ve Rosenberg (Cancer Sci Am 2000) RR 15%; 7% CR and 8% PR med response duration 54 months (3-131) (!) med complete response duration 80+ months (!) No relapse in CR pts with PFI>20 months or those in CR after surgical salvage med OS 16. 3 months 5-year OS 10-20%D))OvrN!%                     RCC - High Dose IL-2L (Negrier (Cancer Sci Am 2000) IL-2 long term results: European experience 1987-1990 281 pts ci IL-2 phase II data 1991-1995 425 pts IL-2/IFN/IL-2+IFN RR 15% Med OS 10 months 1-year survival 41% 2-year 22% 5-year 8% 5-year OS in CR patients 60%, PR patients 18% No predictive factors .VqOv.VC.!                                    IL-2 dosing and schedule (?)Z   dose iv bolus : long term response / cure? dose ci : RR 6-29% / response duration? / toxicity? dose sc : RR 16.8% / toxicity$ / response duration? dose iv bolus : RR 8.8% / toxicity $ pts RR (%) Randomized 56 dose iv bolus 16 NCI trial 55 dose iv bolus 4 53 dose sc 11 Yang JC, Rosenberg SA Cancer Sci Am 1997;3:S79-84 !%p(!- ! =     4                                )   RCC - High Dose IL-2L |RESULTS : Toxicity / cost (50-75% i.c.u.) Survival benefit only in CR Careful patient selection Factors predictive for CR, s !s~        $Patient selection for high dose IL-2  ,PS 0, perfect cardiopulmonary status Lung, lymph node, soft tissue mets Only one mets region Nephrectomy DFI>6 months post-nephrectomy Nonsarcomatoid histology IL-2 dose in the first cycle Rebound lymphocytosis Tm erithropoietin production Posttreatment thyroid dysfunction Posttreatment TNF increase-P-                              :RCC - IL-2 / IFNa comparison $ >    2French Immunotherapy Group IFNa IL-2 Pts CR/PR RR 1year EFS - 18mu ci 138 2/7 6.5 % 15 % 6 mu sc 18mu ci 140 1/25 18.6 % 20 % 18 mu sc - 147 0/11 7.5 % 12 % No difference between single agents No survival advantage and increased toxicity with the combination Negrier S NEJM 1998; 338: 1273-8 Z~Z !lB!                                                   >RCC - IL-2 + IFN a combinations 2   Phase II: 1670 pts, RR 19.3 % (CR 4.6 %) Phase III data: IL-2 + IFN a / IL-2 : 99 pts, RR 16 vs 11%, OS ns iv bolus Atkins MB JCO 1993;11:661-70 IL-2 + IFN a / IL-2 : 2 trials, low pts no sc IL-2 + IFN a + TMX / TMX : 128 pts; no difference OS (11.8 vs 13.3 months) Henriksson R Br J Cancer 1998;77:1311-7092*,R-BBBB '  !+!!)             C &          .RCC - IL-2 + IFN a + FU TPhase II, 11 trials 836 pts RR 25.3% (CR 6.8%) med OS 11.9- 42 months Phase III comparison to IFN a in EORTC/MRC study2c2    !           53&RCC  Immunotherapy&  RESULTS : Standard immunotherapy choices are high dose iv bolus IL-2 or IFNaP C !!AOv     97 RCC - Future"86RCC - Vaccines"DC (monocyte derived, GM-CSF and IL-4) feasible but clinical benefits minimal Tumor-lysate pulsed DC / DC-tm cell hybrids some durable CR, ongoing trials of efficacy Peptide-based vaccines (G250-derived peptide) ongoing trial to test T-cell responses Immature DC+autologous tm lysate prolonged stabilization of disease Autologous tm cell vaccine 558 pts, early results reduction in risk of progression after nephrectomy as adjuvant Jocham D. The Lancet 2004;363;594-599'(,-.(!$&FOvOv(,Ov-.Ov(!Ov$OvW*            ,Allogeneic stem cell transplantation +/- DLI    T-cell reactivity against minor histocompatibility AG causing graft vs host disease and antitumor effect (GVT) DLI may be used to augment the GVT     $Allogeneic stem cell transplantation    6 trials evaluating safety, feasibility, clinical results Childs R. N Engl J Med 2000;343:750 Rini BI. J Clin Oncol 2002;20:2017 Pedrazzoli P. Cancer 2002;94:2409 Bregni M. Blood 2002;99:4234 Hentschke P. Bone Marrow Transplant 2003;31:253 Ueno NT. Blood 2003;102:3829 RR 0-56%, duration of response for CR is long 33% transplant-related mortality Toxicity is substantially due to GVHD T-cell depleted marrow: may facilitate engraftment Subsequent DLI : GVT effect # GVHD p::B8              $Allogeneic stem cell transplantation   poor PS, elderly pts progressive with immunotherapy > 90 % multiple metastatic sites expectation for survival$qVt         :8Monoclonal antibodies to G250V  iChimeric Moab WX-G250 Selective tumor targeting ADCC, complement-mediated cell lysis, cell lysis due to epitope binding Guiding toxic substances to tm cells 131I-WX-G250 (phase I level) Brouwers AH. Clin Cancer Res 2003;9:3953s Unconjugated WX-G250 Phase II, 36 pts Weekly iv injections One CR, One PR, 10 SD Med OS 15 months Bleumer I. Br J Cancer 2004;90:985*M#  *M#          ;9IL-6: Proliferation Prognostic Paraneoplastic symptoms (fever-wt loss) 20 mg/day x 21 days PR and symptom control, # PSBK1K,^    {Phase II trial Progressive with immunotherapy 5 mg/kg wks 0,2,6,14,22,30 16% PR, 16% SD 1 year OS % 55 Non-toxic treatment  !  <:Heat Shock Protein 90< Purified prep of selected HSP isolated from cancers lead to protective immunity Strivastava PK. Curr Oncol Rep 2005;7:104 Ongoing phase III trial of HSPPC-96 vs placebo as adjuvant treatment in 644 pts at high risk for recurrence after nephrectomyBQ*Q*      =;RCC - Angiogenesis" (& Thalidomide Trial Thalidomide mg Pts RR Minor 400-1200 29 4% Daliani 200-1200 20 10% Escudier 400-1200 40 5% Motzer 200-800 26 0% Stebbing 200-600 25 8% Eisen 100 18 17% 5.2%"&d  )'Thalidomide + Immunotherapy0  IFNa + thalidomide 22 pts RR 14% IL-2 (sc) + thalidomide 33 pts RR 9% IL-2 (sc) + thalidomide 36 pts RR 36% IFNa +/- thalidomide ECOG Phase III, 353 pts RR % 7.6 vs % 3.1 PFS / OS ns"(b  b bb    $b$(((( ,b,@0000!              ><Neovastat (AE-941)"  6Homogenization and purification of shark cartilage VEGF inhibitor + endothelial cell apoptosis promoter Phase II trials promising Batist G. Ann Oncol 2002;13:1259 Batist G. Proc ASCO 2002;abstr 1907 Phase III, 300 pts refractory to immunotherapy No survival benefit Escudier B. Proc ASCO 2003;22:211 abstr 844pE/,ED,          ?=@>Bevacizumab combinations0  Erlotinib + bevacizumab 62 pts 21% PR, 66 SD (21% minorR) PFS 67% at 6 months, 50% at one year G 3-4 toxicity: rash (13%) diarrhea (10%) emezis (10%) Hpt (8%) Bleeding (5%) TZ[ZCZffX    A?B@PTK787/ZK222584Oral selective inhibitor VEGFR-1, VEGFR-2, PDGFRb TKs Inhibits VEGF induced endothelial cell proliferation Phase I-II trial, 42 pts 2 PR, 6 MR, 60% SD med TTP 6.2 months med OS 21.5 months, 1 year OS % 67(L0       CADBCCI-779 (Temsirolimus).  Specific inhibitor of mTOR RR 7%, MR 26% Mild toxicity Combination with IFNa feasible Phase III trial IFNa vs CCI-779 vs combined in poor risk metastatic RCC (poor PS, # LDH) completed / results awaited0K^    *(EGFR inhibition" Gefitinib (ZD1839) Phase II trial, 21 pts, 500 mg/day, 1 minor R Lapatinib (GW 572016) Dual inhibition of EGFR and Her-2 Phase III in refractory metastatic RCC ongoing/Q`b  bbQ             ,*Novel Treatment Strategies  V  ECL   0` ̙33` ` ff3333f` 333MMM` f` f` 3>?" dd@$f?" dd@  " @ ` n?" dd@   @@``PR    @ ` ` p>> rj(    6, "P  T Click to edit Master title style! !$  0X "  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  0 "``  X*  0* "`   Z*  0L "`   Z*P  s *޽h ?"` ̙33 ,Blank Presentation.pot 0 +#0 ( }@\@  l  C 8ϛ  l  C כ ~ v  ^B  6D1  6xp jy  [Sevil BAVBEK, M.D. Prof. University of Istanbul Institute of Oncology Div. 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̙33___PPT10i.d p+D=' l= @B +  0 x(  r  S fa,M  a r  S Xga@w a LB  c $DzIzH  0޽h ? ̙33___PPT10i.঄C+D=' l= @B + 0 b Z  (    c $aJ  a = Bevacizumab   0a  " Randomized phase II trial ZN LB  c $D7,   <a"6B  "   <|a8:M  OR    6a   _R& Ov    <a_  lPlacebo n=37 "  <a   v 3 mg/kg n=39 .  <as g  w 10 mg/kg n=40.RB  s *D RB  s *D  RB  s *D    0a   jTTP longer in high dose PFS at 8 months is 14% vs 5% 10% PR , one lasting 2 years OS ns Hpt / proteinuriakkff   2  6fԔ"`C ,$D  0H  0޽h ? ̙33___PPT10.3f+D' = @B D?' = @BA?%,( < +O%,( < +Dv' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?dCB0-#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*+  0  $>(  $x $ c $aw  a r  $ S 8a/EO a LB $ c $D7,  $ 0Щac vi  XjIFNa + bevacizumab/placebo 2 ongoing phase III trials<6ffff H $ 0޽h ? ̙33___PPT10i.P+D=' l= @B +;  0 R J 0(  0 0 6@a ,z 8SUO11248 0 0\F I P(Oral, multiple TK inhibitor (PDGFR, VEGFR, KIT, and Flt3), 50 mg/day x 4 wks, 2 wks rest Phase II trial, MSKCC: 63 pts, 86 % clear cell PR 24% SD 46% (clinical benefit 70%) Response duration 4+ to 12+ months in PR pts med TTP 8.3 months, 1-year OS 65% Motzer RJ. Proc ASCO 2004;22:14s Randomized trial IFNa +/- SUO11248ZZZZ!Z#Zff!  ffffffB $ '  LB 0 c $DzzH 0 0޽h ? ̙33___PPT10i. Q+D=' l= @B +  0  4(  4r 4 S {aM  a r 4 S F a LB 4 c $Dzz 4 <4 F6 < ,$ 0 Phase III underwayff0H 4 0޽h ? ̙33___PPT10b.&+DD' l= @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*4%(D' =-o6Bdissolve*<3<*4+8+0+40 + 0 0 8H(  8 8 6F P Bay 43-9006 (sorafenib) N L 8 0(F  Oral inhibitor of Raf-1 kinase VEGFR-2, VEGFR-3, PDGFR, FLT-3, c-kit also 2 phase II trials Ahmad T. Clin Cancer Res;2004:10:6388 Ratain MJ. J Clin Oncol 2004;22:14s-4500 Toxicity: gr I-II rash, hand-foot synd, fatigue, Hpt, diarrea^\R?\O7~    LB 8 c $Dl c   8 #"6   8 <F?   c8 @` 8 <JF?@   d50 @` 8 <HSF? @  d42 @` 8 <\F?   d89 @` 8 <F?   d30 @` 8 <PfF?@   d30 @`  8 <8oF? @  d40 @`  8 <|F?   d41 @`  8 <F?c   hPG (%) @`  8 <8?@ c   hSD (%) @`  8 <t8?c @  hRR (%) @` 8 <48?c   vPts no" @``B 8 0o ?c c ZB 8 s *1 ?  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