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Dr. Carlos Silva Hospital Británico de Buenos Aires-Hospital Universitario Austral

INMUNO-ONCOLOGIA Estado actual y futuro Cáncer Renal, Melanoma, Cáncer de Pulmón y Medicina de Precisión. Dr. Carlos Silva Hospital Británico de Buenos Aires-Hospital Universitario Austral Universidad Católica Argentina. Declaración de Intereses.

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Dr. Carlos Silva Hospital Británico de Buenos Aires-Hospital Universitario Austral

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  1. INMUNO-ONCOLOGIAEstado actual y futuroCáncer Renal, Melanoma, Cáncer de Pulmón y Medicina de Precisión Dr. Carlos Silva Hospital Británico de Buenos Aires-Hospital Universitario Austral Universidad Católica Argentina

  2. Declaración de Intereses • Doy o he dado conferencias convocado por: Astra Zéneca, Bristol Myers, MSD, Pfizer, Roche. • Pertenezco o he pertenecido a AdvisoryBoards de Astra Zéneca, Bristol Myers, MSD, Pfizer, Roche. • He percibido honorarios por estas actividades. • No he sido ni soy medical advisor de ningún laboratorio. • He asesorado al Ministerio de Salud de la República Argentina. • He sido auditor de uno de los tres sistemas privados de salud más grandes de Argentina (SPM-Galeno).

  3. Agenda • Bases biológicas de la InmunoOncología • Impacto de la InmunoOncología en el tratamiento del cáncer • Tratamiento del Cáncer Renal avanzado primera línea • Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada • Tratamiento del Cáncer de Pulmón en segunda línea • Biomarcadores • Futuro no tan futuro

  4. Agenda • Bases biológicas de la InmunoOncología • Impacto de la InmunoOncología en el tratamiento del cáncer • Tratamiento del Cáncer Renal avanzado primera línea • Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada • Tratamiento del Cáncer de Pulmón en segunda línea • Biomarcadores • Futuro no tan futuro

  5. Hoy encontramos 10 hitosfundamentalesrelacionados con la formación del cáncer Inhibidores vía EGFR Inhibidores quinasas dependiente ciclinas Evadiendo señales supresoras Señal proliferativa sostenida Activación Inmune Anti CTLA4 Inhibidores glicólisis aerobia Metabolismo celular desregulado Evadiendo inmunidad Inhibidores telomerasa Resistencia muerte celular Pro-apoptóticos BH3 miméticos Pemitiendo Inmortalidad replicativa Inflamación promovida por tumor Inestabilidad y mutación genómica Drogas antiinflamat selectivas Inhibidores PARP Activación Invasión y metástasis Inducción angiogénesis Inhibidores HGF/c-Met Inhibidores vía VEGF Hanahan & Weinberg. Cell 2011

  6. ¿QUE ES INMUNO-ONCOLOGĺA? • La Inmuno-Oncología comprende el desarrollo y utilización de nuevos componentes que aprovechan el sistema inmune del propio paciente para combatir el cáncer • Impulsan las propiedades únicas del sistema inmune(especificidad, memoria, adaptabilidad, efectos sistémicos) • Distintos de la cirugía, radioterapia, y modalidades citotóxicas/modalidades blanco que impactan al tumor • Se ha identificado un número blancos terapéuticos basado en nuestra mejor comprensión del sistema inmune en el cáncer y los mecanismos que el tumor utiliza para evadirlo • El objetivo es volcar el balance en favor de la inmunidad, llevando a la erradicación del tumor o la supresión por largo tiempo del crecimiento tumoral • Tiene el potencial de proveer sobrevida durable y a largo témino con una buena calidad de vida para los pacientes con varios tumores sólidos y hematológicos • Tiene el potencial de volverse una modalidad nueva e innovadora y los cimientos sobre los cuales construir nuevas estrategias de tratamiento Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9; De Vita VT, et al. N Engl J Med. 2012;366:2207–2214;Eggermont A. AnnOncol. 2012;23 Suppl 8:viii53–viii57.

  7. Somatic Mutations May Give Rise to Patient-Specific Tumor Neoantigens Presented By Leisha Emens at 2015 ASCO Annual Meeting

  8. ACTIVACIÓN DE LINFOCITOS T CITOTÓXICOS MODELO DE LAS TRES SEÑALES

  9. Agenda • Bases biológicas de la InmunoOncología • Impacto de la InmunoOncología en el tratamiento del cáncer • Tratamiento del Cáncer Renal avanzado primera línea • Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada • Tratamiento del Cáncer de Pulmón en segunda línea • Biomarcadores • Futuro no tan futuro

  10. MDX010-20: 1- and 2-Year Survival Rates, OS1 Survival Rate Median OS, mo 1 Year 2 Year (95%CI) Ipi + gp100 44% 22% 10.0 (8.5, 11.5) Ipi + pbo 46% 24% 10.1 (8.0, 13.8) gp100 + pbo 25% 14% 6.4 (5.5, 8.7) 1.0 0.8 0.6 0.4 0.2 0.0 Proportion alive 0 1 2 3 4 Years Patients at risk Ipi + gp100 403 297 223 163 115 81 54 42 33 24 17 7 6 4 0 Ipi + pbo 137 106 79 56 38 30 24 18 13 13 8 5 2 1 0 Gp100 + pbo 136 93 58 32 23 17 16 7 5 5 3 1 0 0 0 1. Hodi FS, et al. N Engl J Med 2010;363:711-23.

  11. Ipilimumab: Association of Response With Survival in Melanoma 1.0 0.9 0.8 0.7 0.6 0.5 Proportion Alive 0.4 0.3 0.2 CR/PR/SD (by WHO criteria)irPR/irSD (by the irRC)PD and unknown response 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 13 Mos Wolchok JD, et al. Clin Cancer Res. 2009;15:7412-7420.

  12. Consistent Survival Benefit in Subpopulations1Pre-specified Subgroups in MDX010-20 Favors: Ipi + gp100 gp100 Ipi gp100 0.2 0.5 1 2 5 0.2 0.5 1 2 5 Hazard Ratio and 95% CI 1. Hodi FS, et al. N Engl J Med 2010;363:711-23.

  13. Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma 1.0 0.9 N = 1861 Median OS (95% CI): 11.4 mo (10.7-12.1) 3-year OS Rate (95% CI): 22% (20% to 24%) 0.8 0.7 0.6 0.5 Proportion Alive 0.4 0.3 0.2 0.1 Ipilimumab CENSORED 0.0 0 12 24 36 48 60 72 84 96 108 120 Months Patients at Risk Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0 Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.

  14. Nivolumab: Duration of Response 1.0 0.9 0.8 Med., mo. (95%CI) NSCLC (n=22) 17.0 (9.7 - NE) Melanoma (n=33) 24.0 (17.0 - NE) RCC (n=10) 12.9 (11.4 - NE) 0.7 Censored 0.6 0.5 0.4 0.3 Proportion progression-free 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 Months since initiation of response No. at Risk 22 21 16 14 12 8 5 2 2 1 1 0 33 33 30 27 19 15 12 9 5 0 0 0 10 10 10 9 5 3 2 2 2 1 0 0 NSCLC MEL RCC Topalian SL, et al. ASCO 2013. Abstract 3002.

  15. Ways to enhance T cell attack Presented By Michael Postow at 2017 ASCO Annual Meeting

  16. Human tumour Traditional tumour therapy Novel tumour immunotherapy Conventional immunotherapy • Surgical debulking • Radiation therapy • Chemotherapy • Anti-angiogenic therapy Targeting regulatory T cells: • Depleting (Denileukin diftitox, CD25-specific antibody, cyclophosphamide) • Blocking trafficking (CCL22-specific antibody) • Blocking differentiation and signalling (blocking FOXP3 signal) Targeting suppressive molecules: • Blocking suppressive molecules (B7-H1, B7-H4, IDO, arginase) on APCs • Blocking suppressive molecules (CTLA4, PD1) on T cells • Blocking soluble suppressive molecules (TGFβ, IL-10, VEGF, COX2 • Tumour-associated antigens (tumour peptides) • APC vaccination (dendritic cells) • Adoptive T-cell transfusion (effector T cells) • Cytokine and/or chemokine administration (IL-7, IL-15 and IL-21) Combinatorial therapy PERSPECTIVAS DE LA INMUNOTERAPIA PARA EL CÁNCER Weiping Zou 2006. Nat Rev. Immunol. 6:295-307.

  17. Agenda • Bases biológicas de la InmunoOncología • Impacto de la InmunoOncología en el tratamiento del cáncer • Tratamiento del Cáncer Renal avanzado primera línea • Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada • Tratamiento del Cáncer de Pulmón en segunda línea • Biomarcadores • Futuro no tan futuro

  18. ¿Todos los pacientes deben ser tratados de inicio?

  19. Treatment Patterns: Untreated Patients • In a large prospective cohort of mRCC patients, median time to treatment initiation was 7.2 months, and 20% of patients remained untreated at 4 years • Factors predicting later initiation of targeted therapy: • History of radiation therapy • Older age at time of metastatic disease • Presence of brain metastases only • Presence of bone metastases • Indolent disease • High number of metastatic sites . Bains P et al. Poster presentation at ASCO GU 2015. 424.

  20. ¿Cuál es la evidencia de la efectividad de la inmunoterapia para frenar la enfermedad?

  21. Long-Term Overall Survival With Nivolumabin Patients With mRCC 1.0 0.9 • In CheckMate 003, minimum follow-up was 50.5 months 0.8 0.7 0.6 Overall Survival (Probability) 0.5 38% 34% 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Months Number of patients at risk Nivolumab . McDermott DF et al. Oral presentation at ASCO 2016. 4507.

  22. CA209-025/CheckMate 025 Phase III, randomized, open-label trial of nivolumab vs everolimus in subjects with advanced or metastatic clear cell RCC who have received prior antiangiogenic therapy1 N=822 • Key Inclusion Criteria • Advanced/metastatic clear cell RCC • No more than 3 total prior regimens in advanced/metastatic setting • 1 or 2 prior antiangiogenic therapy regimens in advanced/metastatic setting • Karnofsky PS ≥70% • No CNS metastases • No prior therapy with mTOR inhibitor • No autoimmune disease Nivolumab 3 mg/kg IV q2w Until progression*, unacceptable toxicity, withdrawal of consent, or end of trial R 1:1 Everolimus 10 mg PO qd • Primary Outcome Measure: OS • Secondary Outcome Measures: PFS, ORR, duration of objective response, duration of OS by PD-L1 status, safety, disease-related symptom progression rate Start Date: September 2012 Estimated Trial Completion Date: September 2016 Estimated Primary Completion Date: May 2015Status: Ongoing but not recruiting Trial Director: Bristol-Myers Squibb * Patients may continue treatment beyond progression (RECIST 1.1) if investigator-assessed clinical benefit is achieved and treatment is well-tolerated.2 Clinicaltrials.gov. NCT01668784. https://clinicaltrials.gov/ct2/show/NCT01668784?term=NCT01668784&rank=1. Accessed on October 2, 2015. CA209-025 clinical protocol. August 27, 2014.

  23. OS in Patients With mRCC Median OS was 25 months and 19.6 months in the nivolumab and everolimus groups, respectively 1.0 0.9 0.8 0.7 0.6 Nivolumab 0.5 Overall Survival (Probability) 0.4 Everolimus 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 Months # of patients at risk Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0 Everolimus 411 115 366 324 287 265 241 187 61 20 2 0 Motzer et al. N Engl J Med. 2015;373(19):1803-1813.

  24. Duration of Response (DOR) in Patients With mRCC Majority of patients showed a response at first assessment Off treatment Nivolumab On treatment Everolimus Ongoing response First response Responders Motzer et al. N Engl J Med. 2015;373(19):1803-1813. 0 16 32 48 64 80 96 112 128 Time (Weeks)

  25. Landmark Overall Survival Analysis in Patients Treated and Not Treated Beyond Progression • In a landmark analysis beginning from 4 weeks post-progression, median OS was 20.4 months (95% CI, 17.3–NE) in patients treated with nivolumab beyond progression and 11.4 months (95% CI, 9.4–14.6) in patients not treated beyond progression Overall survival with nivolumab 1.0 0.9 0.8 0.7 Treated beyond progression 0.6 Overall Survival (Probability) 0.5 0.4 0.3 Not treated beyond progression 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 Months Number of patients at risk TBP 153 153 146 142 132 123 96 65 30 17 2 0 NTBP 145 131 113 101 84 69 54 29 16 3 0 0 Escudier B et al. Poster presentation at ASCO 2016. 4509.

  26. ¿En primera línea y en combinación es superior que el actual standard de cuidado?

  27. Overall Survival and Progression-free Survival among IMDC Intermediate- and Poor-Risk Patients. RJ Motzer et al. N Engl J Med 2018;378:1277-1290.

  28. ¿Qué pasa si combinamos con antiangiogénicos?

  29. ¿Cuál es el rol en adyuvancia y neoadyuvancia?

  30. Agenda • Bases biológicas de la InmunoOncología • Impacto de la InmunoOncología en el tratamiento del cáncer • Tratamiento del Cáncer Renal avanzado primera línea • Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada • Tratamiento del Cáncer de Pulmón en segunda línea • Biomarcadores • Futuro no tan futuro

  31. Decision Point…. Immunotherapy PD-1/CTLA-4 Combination PD-1 alone

  32. Time to Response and Durability of Response in Patients Who Discontinued Due to Adverse Events (Pooled Analysis of Checkmate 067 and 069 Patients On treatment Off treatment First response Ongoing response 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Weeks Minimum 18-month follow-up, median 21.3-month follow-up. Adapted from Schadendorf D et al. J ClinOncol. 2017;35:3807-3814.

  33. Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV Melanoma: Updated Results from a Phase 3 Trial (CheckMate 238) Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5C. Lance Cowey,6Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15Reinhard Dummer,16 Veerle de Pril,17 Anila Qureshi,17 Abdel Saci,17 James Larkin,18* Paolo A. Ascierto19* 1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute, Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas, USA; 7Hospices Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France; 12Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology, University Hospital of Siena, IstitutoToscanoTumori, Siena, Italy; 15Gallipoli Medical Research Foundation and University of Queensland, Brisbane, Australia; 16University Hospital Zurich, Switzerland; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust, London, UK; 19Istituto NazionaleTumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study. Abstract Number 9502

  34. Primary Endpoint: RFS in All Patients 100 90 80 70 60 aMedian estimate not reliable or stable due to few patients at risk. RFS (%) 70% 50 66% 40 63% 30 20 60% 10 53% 50% 0 0 3 6 9 12 15 18 21 24 27 30 33 Months NIVO IPI Number of patients at risk 453 394 353 331 311 291 280 264 205 28 7 0 NIVO 453 363 314 270 251 230 216 204 149 23 5 0 IPI

  35. Future Directions • A new partner for PD-1 • Less toxic than ipi • More effective than PD-1 alone • Overcoming Resistance • Making ”cold” tumors “hot” • Patient selection • Role of biomarkers

  36. Making Tumors “Hot” Responsive to Immunotherapy + Combination CPIs + Immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + IDO or macrophage inhibitors + Targeted therapies Bring T-cells into tumors: Vaccines TCR engineered ACT CAR engineered ACT Generate T-cells:

  37. Biomarkers • Approximately 50% of melanomas contain mutations in the BRAF gene, a critical component of the growth promoting MAP kinase pathway1 • Some melanomas have activating mutations in the human KIT, NRAS, and other genes1-3 • Only BRAF is currently recommended to be tested in melanoma patients except in clinical trials • BRAF is an activating mutation that is mutually exclusive with NRAS or c-KIT1 • All of these activate the MAP-kinase pathway that promotes tumor growth1-3 • Younger patients are more likely to have mutations5 Biomarker-based stratification of patients is evolving in clinical trials. The NCCN expert panel supports obtaining tissue samples for genetic analysis4 Sources Sosman JA ASCO, 2011: Educational Book pages 367-372. Curtin JA et al. J Clin Oncol. 2006;24:4340-4346. Van Raamsdonk CD et al. N Engl J Med. 2010;363:2191-2199. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v2.2013. Hacker E et al. J Invest Dermatol 2010;130(1):241-248.

  38. Agenda • Bases biológicas de la InmunoOncología • Impacto de la InmunoOncología en el tratamiento del cáncer • Tratamiento del Cáncer Renal avanzado primera línea • Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada • Tratamiento del Cáncer de Pulmón en segunda línea • Biomarcadores • Futuro no tan futuro

  39. But despite these advances, unmet needs remain NSCLC EGFR ALK ROS1 BRAF No actionabledriver mutation How can we improve outcomes for the majority ofNSCLC patients who have no actionable driver mutation?

  40. Agenda • Bases biológicas de la InmunoOncología • Impacto de la InmunoOncología en el tratamiento del cáncer • Tratamiento del Cáncer Renal avanzado primera línea • Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada • Tratamiento del Cáncer de Pulmón en segunda línea • Biomarcadores • Futuro no tan futuro

  41. Examples of Prognostic Implications of Immune Response Correlation with Positive Outcome: Presence of TILs Associated with Increased Recurrence-Free Survival1 Correlation with Negative Outcome: Higher NSCLC-Infiltrating Tregs Associated with Worse Recurrence-Free Survival2 1.0 Recurrence-Free Survival (%) 1.0 P=0.011 0.9 0.8 0.8 0.7 0.6 0.6 0.5 Recurrence-Free Survival (%) 0.4 0.4 0.3 0.2 0.2 FoxP3+ cell <3 TIL+ 0.1 TIL– FoxP3+ cell ≥3 0.0 0.0 0 12 24 36 48 60 0.0 10 20 30 40 50 60 Survival Time (Months) Survival Time (Months) Patients with Stage Ia NSCLC with Surgical Resection (N=273)1 Patients with Stage I–III NSCLC with Surgical Resection (N=100)2 FoxP3 cell < (≥) 3 = lower (higher) levels of FoxP3; TILs = tumor-infiltrating lymphocytes; Tregs = regulatory T cells. 1. Shimizu K, et al. J ThoracOncol. 2010;5:585-590. 2. Horne ZD, et al. J Surg Res. 2011;171:1-5.

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