El futuro del tratamiento del cáncer renal metastásico: inmunoterapia y terapias blanco dirigidas

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Futuro del tratamientodel cáncer renal metastásico: papel de la inmunoterapia y las terapias blanco dirigidas Mauricio Lema Medina MD Clínica de Oncología Astorga, Clínica SOMA, Medellín Simposio ACHO GU, Septiembre 23-24 de 2016, Bogotá

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ο άνθρωπος είναιτο μέτρο όλων των πραγμάτων Πρωταγόρας

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εὐδαιμονία “Florecer” Avanzar Mejorar Adquirir bienestar

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εὐδαιμονία ο άνθρωποςείναι το μέτρο όλων των πραγμάτων Πρωταγόρας

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Timeline of Developmentof Targeted Agents for RCC US Food and Drug Administration. Sorafenib [advanced RCC] Sunitinib (advanced RCC) Pazopanib (advanced RCC) Bevacizumab + IFN-α (metastatic RCC) Temsirolimus (advanced RCC) Immunotherapy with IFN-α or IL-2 201120102009200820072006200520042003200220012000 2012 2013 2014 2015 Everolimus (advanced RCC after failure of sorafenib or sunitinib) Axitinib (advanced RCC after failure of 1 systemic therapy) VEGFpathway inhibitors mTORinhibitors

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Currently (2014) ApprovedRCC Therapies Tumor cell membrane VEGFR P13K AKT mTOR Raf Mek Ras VEGFR P P P P Erk Nucleus Transcription Factors Cell adhesion Cell survival Cell proliferation Apoptosis Cell differentiation Angiogenesis Tumor blood vessel endothelial cell membrane P P P PDGFR PP PP P EGFR PDGFR P P P PPP P P Pericyte Bevacizumab VEGF-A Sunitinib Axitinib Pazopanib Sorafenib Temsirolimus Everolimus Modified from Rini BI, et al. J Clin Oncol. 2005;23:1028-1043.

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Primary Endpoint: PFS(Independent Review) N Median PFS, Mos (95% CI) Pazopanib 557 8.4 (8.3-10.9) Sunitinib 553 9.5 (8.3-11.1) HR: 1.047 (95% CI: 0.898-1.220) Motzer RJ, et al. ESMO 2012. Abstract 2325. Pts at Risk, n 557 553 361 351 245 249 136 147 105 111 61 69 46 48 19 18 13 10 1 3 Pazopanib Sunitinib 1.0 0.8 0.6 0.4 0.2 0 ProportionofPtsProgressionFree 0 4 8 12 16 20 24 28 32 36 40 Mos

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AXIS Trial: AxitinibSuperior to Sorafenib in Second-line mRCC Therapy Rini BI, et al. Lancet. 2011;378:1931-1939. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 16 18 20 ProbabilityofPFS Axitinib Sorafenib Median PFS, Mos (95% CI) 6.7 (6.3-8.6) 4.7 (4.6-5.6) Stratified HR: 0.665 (95% CI: 0.544-0.812; P < .0001) Pts at Risk, n Axitinib Sorafenib 256 224 361 362 202 157 145 100 96 51 64 28 38 12 20 6 10 3 1 1 0 0 Months

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Progression-Free Survival Median PFS,Mos Everolimus: 4.0 Placebo: 1.9 P < .0001 Motzer RJ, et al. Lancet. 2008;372:449-456. 100 80 60 40 20 0 0 2 4 6 8 10 12 ProbabilityofPFS(%) Everolimus Placebo Pts at Risk, n Everolimus Placebo 132 32 272 138 47 4 8 1 2 0 0 0 0 0 Mos

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PD-L2–mediated inhibition of TH2T cells Stromal PD-L1 modulation of T cells Reprinted from Clinical Cancer Research. 2013;19(5):1021-1034. Sznol M, et al. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. With permission from AACR. Blockade of PD-1 Binding to PD-L1 (B7-H1) and PD-L2 (B7-DC) Revives T Cells  PD-L1 expression on tumor cells is induced by γ-interferon  In other words, activated T cells that could kill tumors are specifically disabled by those tumors PD-1 PD-L1 PD-L2 T-cell receptor MHC-1 CD28 Shp-2 B7.1 IFN-γ–mediated upregulation of tumor PD-L1 PD-L1/PD-1–mediated inhibition of tumor cell killing Priming and activation of T cells Immune cell modulation of T cells Tumor cell IFN-γR IFN-γ Tumor-associated fibroblast M2 macrophage Treg cell Th2 T cell Other NFκB P13K CD8+ cytoxic T lymphocyte T-cell polarization TGF-β IL-4/13 Can you generate tumor-killing T cells? Dendritic cell Antigen priming Can the T cells get to the tumor? T-cell trafficking Can the T cells see the tumor? Peptide-MHC expression Can the T cells be turned off? Inhibitory cytokines Can the T cells be turned off? PD-L1 expression on tumor cells

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Immunocompetent Mice RejectTumors Originating in Immunodeficient Mice Shankaran V, et al. Nature. 2001;410:1107-1111. In other words, competent immune systems force the tumors to figure out how to survive in hostile environments

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Median OS forPatients With mRCC Treated With Nivolumab 1-yr OS: 70% 2-yr OS: 50% Drake CG, et al. ASCO 2013. Abstract 4514. 100 80 60 40 20 0 OS(%) Mos Since Treatment Initiation 510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Pts at Risk, n 034 33 28 28 23 19 14 12 8 8 8 8 8 5 2 0 0 Died/Treated 15/34 Median, Mos (95% CI) > 22 (13.60 - NE)

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CheckMate 025: A randomized,open-label, phase III study of nivolumab versus everolimus in advanced renal cell carcinoma Padmanee Sharma, Bernard Escudier, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman, Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Howard Gurney, Frede Donskov, Petri Bono, John Wagstaff, Thomas C. Gauler, Takeshi Ueda, Li-An Xu, Ian M. Waxman, Robert J. Motzer, on behalf of the CheckMate 025 investigators

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29 Study design andendpoints Disease assessments • Every 8 weeks from randomization through 12 months • Then every 12 weeks until progression or treatment discontinuation Primary endpoint • Overall survival (OS) Enrolled patients • Previously treated advanced or metastatic clear- cell RCC • 1 or 2 prior antiangiogenic treatments Randomize1:1 Nivolumab (N = 410) 3 mg/kg every 2 weeks intravenous Everolimus (N = 411) 10 mg/day oral • Treat until progression or intolerable toxicity • Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted Randomized, open-labeled phase III study to compare nivolumab with everolimus in patients with advanced RCC after prior systemic therapy (NCT01668784)

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30 Overall survival HR, hazardratio; NE, not estimable. Median OS, months (95% CI) Nivolumab (N = 410) 25.0 (21.8–NE) Everolimus (N = 411) 19.6 (17.6–23.1) HR (98.5% CI), 0.73 (0.57–0.93) P = 0.0018 0 3 6 129 15 18 21 24 27 30 33 0.0 0.3 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0 OverallSurvival(Probability) Nivolumab Everolimus  The risk of death was reduced by 27% in patients in the nivolumab treatment group compared with those in the everolimus group  Study stopped after planned interim analysis (398 deaths) because assessment by an independent data monitoring committee concluded that the study met its primary endpoint, demonstrating superior OS for nivolumab This means that patients are more likely to live when treated with nivolumab versus everolimus Months

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25 5 0 8 15 23 30 Nivolumab Everolimus 31 Objective responserate ObjectiveResponseRate(%) P < 0.0001  Patients on nivolumab treatment had a significantly better objective response rate than those on everolimus treatment This means that more patients responded to treatment with nivolumab than to treatment with everolimus

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▪ CheckMate 025met its primary endpoint, demonstrating OS superiority with nivolumab versus everolimus ▪ This is the only phase III trial to demonstrate a survival advantage in previously-treated patients with mRCC versus standard therapy ▪ Nivolumab was associated with a greater number of objective responses than everolimus ▪ The survival improvement and favorable safety profile demonstrated in this phase III trial provides evidence for nivolumab as a potential new treatment option for previously treated patients with mRCC ▪ Based on the positive results of this trial, nivolumab was granted a breakthrough therapy designation from the FDA for advanced RCC, reinforcing the importance of these results in a patient population with large unmet medical need 33 Key conclusions

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Cabozantinib in Relapsedor Refractory RCC: PFS Choueiri TK, et al. ASCO 2012. Abstract 4504. 1.00 0.75 0.50 0.25 0 0 5 10 15 20 ProportionProgressionFree Mos From First Dose Median PFS, Mos 95% CIEvents, n 14.7 7.3, – 8

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Cabozantinib versus Everolimusin Advanced Renal-Cell Carcinoma Choueiri TK, NEJM, 2015

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Overall survival inMETEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma Choueiri TK, Proc ASCO 2016, Abstract 4506

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Long-term overall survivalwith nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. McDermott DF, Proc ASCO 2016, Abstract 4507

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Fig 4. Probabilityof being the best treatment in terms of overall survival according to the four Bayesian models, as a function of time since the beginning of therapy. Wiecek W, Karcher H (2016) Nivolumab versus Cabozantinib: Comparing Overall Survival in Metastatic Renal Cell Carcinoma. PLoS ONE 11(6): e0155389. doi:10.1371/journal.pone.0155389 http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0155389

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New agents andnew targets in RCC • Angiopoietins • ALK-1 • IL-8 • MDM2 • HIF-2 alpha • Neurofibromin-2 (Merlin) and Hippo Philips GK, ASCO Ed Book, 2014

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ALK1: Activin Receptor-likeKinase I Gupta S, Curr Oncol Rep, 2015

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Interleukin-8 mediates resistanceto antiangiogenic agent sunitinib in ccRCC Huang D, Cancer Res, 2010

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Neurofibromin-2 A whole-genome sequencingstudy of a large cohort of primary RCC tumors and cell lines, found that a notable fraction (33%) of VHL wild- type clear cell RCCs contained inactivating mutations of the tumor suppressor gene NF2 Dalgliesh GL, Nature, 2010

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Working hypothesis forthe role of YAP and the Hippo pathway during tumor progression and metastasis. John M. Lamar et al. PNAS 2012;109:14732-14733 ©2012 by National Academy of Sciences

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1st-line antiangiogenic TKI 2nd-lineantiangiogenic TKI mTOR inhibitor To be defined… Today

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1st-line antiangiogenic TKI 2nd-lineantiangiogenic TKI Cabozantinib mTOR inhibitor (?) Tomorrow Nivolumab Sequence?

El futuro del tratamiento del cáncer renal metastásico: inmunoterapia y terapias blanco dirigidas

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