黑色素瘤的过去和未来课件

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,#,Clique para editar o estilo do ttulo mestre,Clique para editar os estilos do texto mestre,Segundo nvel,Terceiro nvel,Quarto nvel,Quinto nvel,15/11/2019,#,Treatment of Advanced MelanomaPast, Present and Future,Antonio C. Buzaid, MD,Chairman,Oncology,Center,Treatment of Advanced Melanoma,1,Early 80s,DTIC,Early Trials of combination Chemo,IFN,Trials with HD IL-2 were started,Early 80sDTIC,2,High-Dose IL-2as First Line,High-Dose IL-2as First Line,3,黑色素瘤的过去和未来课件,4,HD IL-2 and LAK Cells,NCI Experience,N=25,7 with metastatic melanoma,Other cancers included RCC, colon, sarcomas, etc.,%ORR = 44%,%CR = 3%,Rosenberg et al. N Engl J Med 313:1485, 1985,HD IL-2 and LAK CellsNCI Expe,5,Annals of Surgery, 1998; Vol. 228, No. 3, 307-319,Annals of Surgery, 1998; Vol.,6,N=182,CR=6.6% (n=12),PR=8.2%,%ORR = 14.8%,NCI Experience with HD IL-2,Annals of Surgery, 1998; Vol. 228, No. 3, 307-319,N=182NCI Experience with HD IL,7,OS for Patients in CR,NCI Experience,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,12,24,36,48,60,72,84,96,108,120,132,144,156,Years,Probability,N=12,Rosenberg et al. Ann Surg 228:307, 1998,OS for Patients in CRNCI Expe,8,Journal of Clinical Oncology, Vol 19, No 15 (August 1), 2001: pp 3477-3482,Journal of Clinical Oncology,9,N=374,All with metastatic melanoma,%ORR = 15.5%,%CR = 5.1%,%PR = 10.4%,Predictors of Response to HD IL-2,NCI Experience,Phan et al. J Clin Oncol 19:3477, 2001,N=374 Predictors of Response t,10,Site of Metastase,N,%ORR,Skin and/or SC,28,53.6,Skin and or LND,23,27.7,Visceral only,69,11.6,Visceral and skin,61,14.8,Bone and other,30,16.7,Brain and other,21,5,Phan et al. J Clin Oncol 19:3477, 2001,Predictors of Response to HD IL-2,NCI Experience,Site of MetastaseN%ORRSkin and,11,High-Dose IL-2after PD on Biochemo,High-Dose IL-2after PD on Bio,12,High-Dose IL-2 after PD on Biochemo,Pittsburgh Cancer Institute Experience,High-Dose IL-2 after PD on Bi,13,J Clin Oncol, 2007; 25:3802-3807.,J Clin Oncol, 2007; 25:3802-38,14,N=26,%ORR = 19,2%,There were four,complete responses, lasting,4, 4,26+,and,41+ months,Pittsburgh Cancer Institute Experience,Tarhini et al. J Clin Oncol 25:3802, 2007,N=26Pittsburgh Cancer Institut,15,High-Dose IL-2 after PD on Biochemo,Our Experience,High-Dose IL-2 after PD on Bi,16,Melanoma Research 2011, 21:370375,Melanoma Research 2011, 21:370,17,N=38,%ORR = 23,6%,Two patients (5.2%) achieved a CR that lasted,for more,than,11.8+,and,36+ months,Our Experience,Buzaid et al. Melanoma Res 21:370, 2011,N=38Our ExperienceBuzaid et al,18,HD IL-2 after PD on Biochemotherapy,Buzaid et al. Melanoma Res 21:370, 2011,HD IL-2 after PD on Biochemoth,19,Buzaid et al. Melanoma Res 21:370, 2011,Buzaid et al. Melanoma Res 21,20,09/26/2006,01/04/2013,01/27/2007,60 yo female treated with HD IL-2 after PD on biochemotherapy,Buzaid et al. Melanoma Res 21:370, 2011,09/26/200601/04/201301/27/2007,21,Early 90s,Biochemotherapy studies (CDDP/VBL/DTIC with IL-2 and IFN were started,Biochemo and,HD IL-2 remained one of the few options with curative potential,Early 90sBiochemotherapy studi,22,Biochemotherapy,Phase II Studies,ORR in the range of 30 to 50%,Long term survival from 8 to 10%,High toxicity,BiochemotherapyPhase II Studi,23,OS of Metastatic Melanoma Patients (n,= 264,) Treatedwith Various Biochemotherapy Protocols at MDACC,Bedikian AY et al. J Immunotox 2008; 5: 201-207,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,Proportion Surviving,0,12,24,36,48,60,72,84,96,108,120,132,144,156,168,180,192,Months,Response,No. patients,% ORR,Median Survival,(months),CR,34,12.9,152.5,PR,104,39.4,13.5,SD,68,25.8,10.5,PD,58,21.9,7.0,CR,SD,PR,PD,P ,2 years (4 BCT, 4 BCT +,surgery for residual disease),(,29+, 30+, 51+, 69+, 71+, 80+, 97+ months),William WN, Schmerling RA, Belfort FA, Fonseca HE, Buzaid AC, ASCO 2006,1998-2005 n=57 William,28,05/MAR/11,29/JUL/09,PET/CT - AS,Patient was treated with 4 cycles of biochemotherapy,05/MAR/1129/JUL/09PET/CT - AS,29,67 yo male with Metastatic Melanoma with Adrenal Metastasis Treated with Biochemo,L adrenal gland was removed via laparoscopy. Path only a few scattered cells of melanoma were identified.,NED 11 years,67 yo male with Metastatic Mel,30,Biochemotherapy,Randomized trials show no difference in OS except for the MDACC study,Patient Selection,vs,Physician Selection,BiochemotherapyRandomized tria,31,The Brain Challenge,The Brain Challenge,32,HD IL-2 and the brain,HD IL-2 and the brain,33,Early 2000,The start of target therapy,Initial trials with Ipilimumab,Early 2000The start of target,34,The Start of Target Therapy,The Start of Target Therapy,35,Oncogenic Mutations Define Clinically Relevant Melanoma Molecular Subsets,Arising from Skin,Without Chronic,Sun Damage,Arising from Skin,With Chronic,Sun Damage,Arising from,Mucosal,Surfaces,Arising from,Acral,Surfaces,Uveal Melanoma,Curtin et al. NEJM 2005; Curtin et al. JCO 2006; Van Raamsdonk et al., NEJM 2010Courtesy of Dr. A. Ribas,50% BRAF,20% NRAS,10% BRAF,10% NRAS,5% BRAF,15% NRAS,15% BRAF,15% NRAS,25% GNAQ 55% GNA11,0% KIT,2% KIT,20% KIT,15% KIT,Oncogenic Mutations Define Cli,36,BRAF,Mutation Rate by Age,N=308. Mutations other than V600K include,V600E and,V600K,V600E and,L597V, K601E, V600_K601E, D594N, T599dup, and V600R.,90% V600E,55% V600E,Long GV, et al. Presented at: SMR. 2012.,Menzies AM, et al.,Clin Cancer Res,. 2012;18:3242-3249,.,BRAF Mutation Rate by AgeN=308,37,Vemurafenib Blocks the Activity of V600-Mutated BRAF,1,Cell proliferation,Cell survival,RAS,Tumor regression,RTK,Vemurafenib,selectively,binds,and,inhibits,oncogenic BRAF,MEK,ERK,Vemurafenib,Constitutive signaling arrested,ERK=extracellular signalregulated kinase; MEK=mitogen-activated protein/ERK; RTK=receptor tyrosine kinase.,50%-65% of melanomas have mutated BRAF,90% of these mutations are V600E,BRAF,BRAF,V600,1. Sala E, et al. Mol Cancer Res. 2008;6:751-759,.,Vemurafenib Blocks the Activit,38,Phase 3 Study of Vemurafenib in Treatment-Naive BRAF,V600E,MutationPositive Unresectable Stage IIIC or IV Melanoma (BRIM3),Stratified according to,Disease stage,Serum LDH,ECOG PS,Geographic region,Primary endpoints: OS, PFS,Treatment continued until disease progression,*,unacceptable toxicity, and/or consent withdrawal,Vemurafenib,960 mg po bid,(n=337),Dacarbazine (DTIC),1000 mg/m,2,IV q3w,(n=338),1:1,Treatment nave,AJCC unresectable stage IIIC or IV,ECOG PS 0/1,BRAF,V600E,mutationpositive (by cobas,4800 BRAF V600 Mutation Test),(N=675),*,Treatment could be continued if it was considered in the best interest of the patient in the judgment of the investigator and the sponsor.,Chapman P, et al. N Engl J Med. 2011;364:2507-2516. ZELBORAF,(vemurafenib) prescribing information. South San Francisco, CA: Genentech, Inc.; 2011,.,Phase 3 Study of Vemurafenib i,39,Change From Baseline in Sum of Tumor Diameters, %,Disease Stage,M1a,M1b,M1c,Unresectable stage IIIC,50,0,50,100,50,0,50,100,Dacarbazine,:,BORR=,5.5,% (95% CI, 2.8%-9.3%),PR=5.5,%,n=12,Vemurafenib,BORR=48.4,% (95% CI, 41.6%-55.2%),CR=0.9,%, n=2,PR=47.4,%,n=104,100,BRIM3: Best,Tumor Response,by Individual Patient,Chapman,PB, et al. N Engl J Med 2011;364:2507-2516.,100,Median time to response: 1.5 months,Median time to response: 2.7 months,Change From Baseline in Sum of,40,Targeting BRAF,V600E,mutant melanoma with vemurafenib leads to rapid response,Day,15,Baseline,Flaherty et al, N Engl J Med 2010;363:809,Targeting BRAFV600E mutant mel,41,BRIM3 2012: PFS, Censored at Crossover,(Cutoff: February 1, 2012),100,90,80,70,60,50,40,30,20,10,0,PFS, %,0,6,12,18,24,338,337,63,186,22,77,3,16,0,0,100,269,37,113,14,49,0,3,Number at risk,1.6,6.9,HR=0.38 (95% CI, 0.32-0.46);,Log-rank,P,0.001 (post hoc),Dacarbazine (n=338),Vemurafenib (n=337),Time, Months,Dacarbazine,Vemurafenib,Chapman,P, et al. Presented at: ASCO. 2012 (abstr LBA8502).,Median follow-up: DTIC=9.5 months, vemurafenib=12.5 months.,BRIM3 2012: PFS, Censored at C,42,BRIM3 2012: OS, Censored at Crossover,(Cutoff: February 1, 2012),100,90,80,70,60,50,40,30,20,10,0,OS, %,0,6,12,18,24,Vemurafenib (n=337),Median follow-up: 12.5 months,Dacarbazine (n=338),Median follow-up: 9.5 months,338,337,173,280,79,178,24,44,0,1,244,326,111,231,50,109,4,7,9.7,13.6,HR=0.70 (95% CI, 0.57-0.87);,P, 95% power,to detect HR of 0.33,Screened,N=733,Dabrafenib,150 mg twice daily,n=187,DTIC,1000 mg/m,2,IV every 3 weeks,n=63,Enrolled,n=250,3:1 randomization,Stratification factors: unresectable stage III, stage IV; M1a+M1b,vs,M1c,Secondary objectives:,OS, ORR in both groups and after cross-over, PFS2 (after cross-over), duration of response, safety/tolerability and BRAF mutation assay validation,Cross-over allowed at radiologic PD,Dabrafenib,150 mg twice daily,n=28,(68% of PD patients),BREAK-3: study designPrimary e,Mechanisms of Resistance to B-Raf inhibitors,Survival,BRAF,V600E,MEK,ERK,P,P,BRAF inh,PDGFRb or IGF1R,PI3K,AKT,Nazarian et al.,Nature 2010,Villanueva et al.,Cancer Cell 2010,MEK-independent,progression,Nazarian et al.,Nature 2010,NRAS,Q61,COT,Johannessen et al.,Nature 2010,CRAF,Wagle et al.,JCO 2011,MEK-dependent,progression,Poulikakos et al.,Nature 2011,MEKi,PI3Ki or AKTi,Mechanisms of Resistance to B-,46,BRAFi (Dabrafenib) + MEKi (Trametinib): Combination Rationale,pERK,BRAF,MEK,Proliferation,Survival,Invasion,Metastasis,BRAFi (Dabrafenib),MEKi (Trametinib),RAS,1,Data presented at ASCO 2010,Tumor Type,% BRAF Mutant,Melanoma,50%,Colorectal,5%,NSCLC,3-5%,Cholangioca,15%,Thyroid,50%,Goals of Combination,Synergy in combination,Prevent/overcome potential monotherapy resistance,Potentially decrease incidence of BRAFi-induced hyper-proliferative skin lesions,BRAFi (Dabrafenib) + MEKi (,47,Delayed resistance with BRAF/MEK combination versus single-agent BRAF inhibition,Flaherty KT et al. N Engl J Med. 2012 Nov;367(18):1694-703.,Delayed resistance with BRAF/M,48,Target Therapy is a Reality in Melanoma,Target Therapy is a Reality in,49,The Start of Novel Immunotherapy,Checkpoint Inhibitors,The Start of Novel Immunothera,50,Ipilimumab,Ipilimumab,51,T Lymphocyte,CD28,Dendritic Cell,CTLA4 Receptors are “Up-Regulated” After T Lymphocyte Activation,MHC,B7,TCR,CTLA4,Antigen,T LymphocyteCD28Dendritic Cell,52,CTLA4 Downregulates T cell Activation,MHC,B7,TCR,CD28,CTLA4,CTLA4 binds to B7 with greater affinity than CD28 and send an inhibitory signal in the T lymphocyte,Dendritic Cell,T Lymphocyte,Antigen,CTLA4 Downregulates T cell Act,53,CTLA4 Blockade Removes the Break of T Lymphocyte Activation,MHC,B7,TCR,CD28,Antigen,CTLA4,Dendritic Cell,T Lymphocyte,CTLA4 Blockade Removes the Bre,54,TCR,CD28,CTLA4,B7,Dendritic Cell,T Lymphocyte,Antigen,MHC,CTLA4 Blockade Removes the Break of T Lymphocyte Activation,TCRCD28CTLA4B7Dendritic CellT,55,MDX010-20 Study Schema,Screening,Induction:,Ipilimumab at 3 mg/kg, with or without gp100, every 3 weeks for 4 treatments,Reinduction:,Patients with SD for 3 months duration from week 12, or a confirmed CR or PR, could receive additional therapy with their assigned treatment regimen upon PD,Ipilimumab,+ gp100,n=,403,Ipilimumab,alone,n=137,gp100 alone,n=,136,Ipilimumab + gp100,Ipilimumab alone,gp100,alone,1,Re-induction,(eligible patients),Induction,Previously treated, HLA-A2*0201,+,patients with,advanced melanoma,(N=676),R,A,N,D,O,M,I,Z,E,Follow- up,PD,PD,PD,3:1:1,Hodi FS, et al. N Engl J Med. 2010;363:711-23,MDX010-20 Study SchemaScreenin,56,Kaplan-Meier Analysis of Survival,Years,Ipilimumab + gp100 (A),Ipilimumab alone (B),gp100 alone (C),1,2,3,4,Comparison,HR,P,-value,Arm A,vs,C0.680.0004,Arm B,vs,C0.660.0026,Arm A,vs,B1.040.7575,Survival Rate,Ipilimumab + gp100,Ipilimumab alone,gp100 alone,1-year,44%,46%,25%,2-year,22%,24%,14%,Kaplan-Meier Analysis of Survi,57,Most Common Immune-Related Adverse Events* (irAEs; All Grades),% of Patients,irAE,Ipi + gp100,N=380,Ipi + pbo,N=131,gp100 + pbo,N=132,All grades,Any,58.2,61.1,31.8,Dermatologic,40.0,43.5,16.7,GI,32.1,29.0,14.4,Endocrine,3.9,7.6,1.5,Hepatic,2.1,3.8,4.5,*Across entire study duration,Hodi FS, et al. N Engl J Med. 2010;363:711-723.,Most Common Immune-Related Ad,58,Baseline,Tumor Assessment,First Scheduled Tumor Assessment,Study 024: Design,Screening,Ipilimumab 10 mg/kg,Q12W,Ipilimumab 10 mg/kg,Q3W X4,Week 12,Week 24,Week 1,INDUCTION,MAINTENANCE *,* in absence of progression or dose-limiting toxicity,Dacarbazine 850 mg/m,2,Q3W x8,Previously,Untreated,Metastatic,Melanoma,(N=502),Placebo,Q3W X4,Placebo,Q12W,R,R,= blinded,randomization,(1:1),Dacarbazine 850 mg/m,2,Q3W x8,Baseline First Scheduled Tumor,59,Study 024: Overall Survival,Estimated Survival Rate,1 Year,2,Years,3,Years*,Ipilimumab +,DTIC n=250,47.3,28.5,20.8,Placebo +,DTIC n=252,36.3,17.9,12.2,*3-year survival was a post-hoc analysis,Ipilimumab + DTIC,Placebo + DTIC,Study 024: Overall Survival Es,60,ipi,ipi,ipi Exposure,ipi,ipi,ipi,ipi,T-cell activation,T-cell response beyond Wk 12 has not been characterized,Immune-cell activation and proliferation begins early,Measurable clinical effect occurs at variable time points,SD,PR,CR,PD,Patterns ofresponse,Baseline,Total Tumor Volume (%)*,*Tumor volume can include immune-cell infiltrates and tumor cells.,25,50,100,SD,PR,CR,Immunotherapy: Evolution of an Anticancer Effect,ipi,ipiipiipi Exposureipiipiipiipi,61,Evolution of Response: Patient Example,Screening,Week 12,:,swelling & progression,Week 14:,improved,Week 16:,continued improvement,Week 72:,complete remission,Week 108:,complete remission,Fonte: CA184-043,Evolution of Response: Patien,62,49 yo WF,on Ipilimumab 3 mg/kg,Baseline,After 1 cycle,After 4 cycles,49 yo WF on Ipilimumab 3 mg/kg,63,R.M.S.H., 47 yo WF,23/02/2007 (Baseline),R.M.S.H., 47 yo WF,64,R.M.S.H., 47 anos.,23/07/2012,R.M.S.H., 47 anos.,65,C.P. 64 yo treated with Ipi 10 mg/kg,Nov/08,Fev/09,Abr/12,C.P. 64 yo treated with Ipi 10,66,IL-2,vs,Ipilimumab,Category,IL-2,Ipilimumab,Rapidity,of Response,Rapid,Slow,Impact of Response,Only CRs,are durable,CRs, PRs and SD may be durable,Toxicity,Acute,Subacute,Pseudoprogression,Not Applicable,Yes,IL-2 vs IpilimumabCategoryIL-2,67,The Future,The Future,68,Better Immunotherapy,Better Immunotherapy,69,Anti-PD1,Anti-PD1,70,Anti-CTLA4 & Anti PD-1 New Complementary Immunotherapies,Ribas, NEJM, 2012,Anti-CTLA4 & Anti PD-1 New Com,71,Anti-PD1 Phase I Trial in Solid Tumors,Topalian et al. N Engl J Med 366:2443, 2012,Phase I dose escalation trial in solid tumors with 296 patients,94 patients had metastatic melanoma,Anti-PD1 Phase I Trial in Soli,72,Anti-PD1 Activity in Melanoma,Dose,Level,(mg/kg),N,ORR %,Duration of response (months),0.1,14,29,7.5+, 5.6 +,5.6, 5.6,0.3,16,19,3.8+, 2.1+, 1.9+,1,27,30,24.9+, 22.9+, 20.3+, 19.3+, 18.4+, 7.6+, 5.6+,5.3+,3,17,41,22.4+, 18.3+, 15.2+,12.9, 11.1, 9.3, 9.2+,10,20,20,24.6+, 23.9+, 18.0+, 17,All doses,94,28,Topalian et al. N Engl J Med 366:2443, 2012,Anti-PD1 Activity in MelanomaD,73,黑色素瘤的过去和未来课件,74,Lambrolizumab in Advanced Melanoma: Phase I Study,Lambrolizumab (MK-3475): humanized IgG4 antiPD-1 antibody,Patients with advanced melanoma,Ipilimumab naive (n = 87),Previously treated with ipilimumab (n = 48),Lambrolizumab dosing until progression or intolerable,10 mg/kg IV q2w,10 mg/kg IV q3w,2 mg/kg IV q3w,Primary endpoint: safety,Hamid O, et al. N Engl J Med. 2013;Epub ahead of print. Ribas A, et al. ASCO 2013. Abstract 9009.,Lambrolizumab in Advanced Mela,75,Lambrolizumab in Advanced Melanoma: Efficacy,Hamid O, et al. N Engl J Med. 2013;Epub ahead of print. Ribas A, et al. ASCO 2013. Abstract 9009.,Cohort,ORR by RECIST, %,No Previous Ipilimumab,Previous Ipilimumab,10 mg/kg q2w (n = 52),49,62,10 mg/kg q3w (n = 45),26,27,2 mg/kg q3w (n = 20),25,-,Percent Change From Baseline in Longest Diameter of Target Lesion,160,140,120,100,80,60,40,20,0,-20,-40,-60,-80,-100,Individual Patients Treated With Lambrolizumab,Previous ipilimumab treatment,No previous ipilimumab treatment,Lambrolizumab in Advanced Mela,76,Nivolumab + Ipilimumab: Efficacy,Clinical activity in concurrent regimen,Clinical activity in sequenced regimen (n = 30),ORR: 20% (1 CR, 5 PR),4 patients had 80% tumor reduction at first scheduled 8-wk tumor assessment,Wolchok JD, et al. N Engl J Med. 2013;Epub ahead of print. Wolchok JD, et al. ASCO 2013. Abstract 9012.,Cohort,Nivolumab,+,Ipilimumab, mg/kg,Response Evaluable,P,atients,n,CR,n,PR,n,ORR,%, 80% Tumor,Reduction at 12 Wks, n (%),1,0.3 + 3,14,1,2,21,4 (29),2,1 + 3,17,3,6,53,7,(41),2a,3 + 1,15,1,5,40,5 (33),3,3 + 3,6,0,3,50,0,All,-,52,5,16,40,16 (31),Nivolumab + Ipilimumab: Effica,77,Better Target Therapy,Better Target Therapy,78,Melanoma oncogenes,CRAF,BRAF,MEK,ERK,P,P,NRAS,alternative splicing,amplification,c-kit,NF1,Melanoma oncogenesCRAFBRAFMEKE,79,Melanomas without activating BRAF or NRAS mutations commonly have NF1 mutations,Cancer Genome Atlas Research Network et al. TCGA symposium 2012,200,Melanomas without activating B,80,Conclusion,Biochemotherapy,may produce long term survivors in about 8 to,10%,High-dose IL-2 may also produce long term survivors in about 4,% even in biochemo failures,These treatments are very toxic,ConclusionBiochemotherapy may,81,Ipilimumab results,in improvement in overall survival and long term survival in,aproximately 25% of the patients,AntiPD1 is also a novel type of immunotherapy which has significant activity in metastatic melanoma even in prior Ipilimumab treated patients,The combination of Ipilimumab + antiPD1 showed promissing preliminary results,Conclusion,Ipilimumab results in improvem,82,BRAF inhibitors and more recently MEK inhibitors improve overall survival in metastatic melanoma,The combination of BRAF + MEK inhibi