1 - Presentación Dr. Silva

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
• Doy o he dado conferencias convocado por: Astra Zéneca, Bristol
Myers, MSD, Pfizer, Roche.
• Pertenezco o he pertenecido a Advisory Boards 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).
Agenda
• Bases biológicas de la Inmuno Oncología
• Impacto de la Inmuno Oncología 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
Agenda
• Biomarcadores
Hoy encontramos 10 hitos fundamentales
relacionados con la formación del cáncer
Inhibidores Inhibidores quinasas
vía EGFR dependiente ciclinas
Señal Evadiendo
Inhibidores proliferativa señales Activación Inmune
sostenida supresoras
glicólisis aerobia Anti CTLA4
Metabolismo Evadiendo
celular inmunidad
desregulado
Pro-apoptóticos Resistencia Pemitiendo Inhibidores

muerte Inmortalidad telomerasa
BH3 miméticos celular replicativa
Inestabilidad Inflamación
y mutación promovida
genómica por tumor
Inhibidores Activación
Drogas antiinflamat
PARP Inducción Invasión y selectivas
angiogénesis metástasis
Inhibidores Inhibidores
vía VEGF HGF/c-Met
Hanahan & Weinberg. Cell 2011

¿QUE• LaES INMUNO-ONCOLOGĺA?
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. Ann Oncol. 2012;23 Suppl 8:viii53–viii57.
6
Somatic Mutations May Give Rise to Patient-Specific Tumor Neoantigens
Presented By Leisha Emens at 2015 ASCO Annual Meeting

ACTIVACIÓN DE LINFOCITOS T
CITOTÓXICOS
MODELO DE LAS TRES SEÑALES
Agenda
• Biomarcadores
State-of-the-Art Patient Care in Solid Tumors
clinicaloptions.com/oncology
MDX010-20: 1- and 2-Year Survival Rates, OS1
1.0 Survival Rate Median OS, mo

1 Year 2 Year (95%CI)
0.8 Ipi + gp100 44% 22% 10.0 (8.5, 11.5)
Ipi + pbo 46% 24% 10.1 (8.0, 13.8)
0.6 gp100 + pbo 25% 14% 6.4 (5.5, 8.7)
0.4
Proportion alive
0.2
0.0
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.
For internal use only. Any external use requires appropriate medical/legal/regulatory approvals as per local regulations. 13
Ipilimumab: Association of Response With Survival in

Melanoma
1.0
0.9
0.8
0.7
Proportion Alive
0.6
0.5
0.4
0.3
0.2
CR/PR/SD (by WHO criteria)
0.1 irPR/irSD (by the irRC)
PD and unknown response
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1516 171819 2021 22232425 26 27 2829 30 3132 33 34
Mos
Wolchok JD, et al. Clin Cancer Res. 2009;15:7412-7420.
Consistent Survival Benefit in Subpopulations 1
Pre-specified Subgroups in MDX010-20

Favors: Ipi + gp100 gp100 Ipi gp100
ALL PATIENTS
Gender Male
Female
Age < 65 years
≥ 65 years
Female < 50 years
Female ≥ 50 years
M-stage at Study Entry M0, M1A, M1B
M1C
Baseline LDH ≤ ULN
> ULN
≤ 2x ULN
> 2x ULN
Prior Use of IL-2 Yes
No
0.2 0.5 1 2 5 0.2 0.5 1 2 5

1. Hodi FS, et al. N Engl J Med 2010;363:711-23. Hazard Ratio and 95% CI
For internal use only. Any external use requires appropriate medical/legal/regulatory approvals as per local regulations. 15
Immunotherapy in Cancer: From Principles to Practice
Ipilimumab: Pooled Survival Analysis from Phase II/III

Trials in Advanced Melanoma
1.0
0.9
0.8 N = 1861
0.7 Median OS (95% CI): 11.4 mo (10.7-12.1)
Proportion Alive
3-year OS Rate (95% CI): 22% (20% to 24%)

0.6
0.5
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.

Immunotherapy in Cancer: From Principles to Practice
Nivolumab: Duration of Response

1.0 Med., mo. (95%CI)
Proportion progression-free 0.9 NSCLC (n=22) 17.0 (9.7 - NE)
Melanoma (n=33) 24.0 (17.0 - NE)
0.8 RCC (n=10) 12.9 (11.4 - NE)
0.7
Censored
0.6
0.5
0.4
0.3
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
NSCLC 22 21 16 14 12 8 5 2 2 1 1 0
MEL 33 33 30 27 19 15 12 9 5 0 0 0
RCC 10 10 10 9 5 3 2 2 2 1 0 0
Topalian SL, et al. ASCO 2013. Abstract 3002.
Ways to enhance T cell attack
Presented By Michael Postow at 2017 ASCO Annual Meeting

PERSPECTIVAS DE LA INMUNOTERAPIA PARA EL CÁNCER
Human tumour
Traditional Novel tumour Conventional

tumour therapy immunotherapy immunotherapy
• Surgical debulking Targeting regulatory T cells: • Tumour-associated antigens

• Radiation therapy • Depleting (Denileukin diftitox, CD25-specific antibody, cyclophosphamide) (tumour peptides)
• Chemotherapy • Blocking trafficking (CCL22-specific antibody) • APC vaccination
• Anti-angiogenic therapy • Blocking differentiation and signalling (blocking FOXP3 signal) (dendritic cells)
• Adoptive T-cell transfusion
Targeting suppressive molecules: (effector T cells)
• Blocking suppressive molecules (B7-H1, B7-H4, IDO, arginase) on APCs • Cytokine and/or chemokine
• Blocking suppressive molecules (CTLA4, PD1) on T cells administration
• Blocking soluble suppressive molecules (TGFβ, IL-10, VEGF, COX2 (IL-7, IL-15 and IL-21)
Combinatorial therapy
Weiping Zou 2006. Nat Rev. Immunol. 6:295-307.

Agenda
• Biomarcadores
¿Todos los pacientes deben ser
tratados de inicio?
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
Initiation of
N=920
therapy within:
6 months 47% Factors predicting later initiation of targeted
1 year 57% therapy:
2 years 68% • History of radiation therapy
3 years 74% • Older age at time of metastatic disease
4 years 80% • Presence of brain metastases only
5 years 83% • Presence of bone metastases
• Indolent disease
• High number of metastatic sites
.
Bains P et al. Poster presentation at ASCO GU 2015. 424.
¿Cuál es la evidencia de la
efectividad de la inmunoterapia
para frenar la enfermedad?
Long-Term Overall Survival With Nivolumab
in Patients With mRCC
1.0
0.9 Median OS, months

(95% CI)
0.8
Nivolumab 22.4 (12.5–NE)
Overall Survival (Probability)

0.7
0.6
0.5
38%
0.4 34%
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 34 28 24 18 14 13 12 12 11 8 6 6 2 1 0
• In CheckMate 003, minimum follow-up was 50.5 months

.
McDermott DF et al. Oral presentation at ASCO 2016. 4507.
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 therapy 1
N=822
Key Inclusion Criteria
• Advanced/metastatic clear cell RCC
• No more than 3 total prior regimens in Nivolumab Until
advanced/metastatic setting 3 mg/kg IV q2w progression*,
• 1 or 2 prior antiangiogenic therapy R unacceptable
regimens in advanced/metastatic toxicity,
1:1 withdrawal of
setting
Everolimus consent, or end
• Karnofsky PS ≥70%
10 mg PO qd of trial
• No CNS metastases
• No prior therapy with mTOR inhibitor
• No autoimmune disease
Start Date: September 2012 • Primary Outcome Measure: OS
Estimated Trial Completion Date: September 2016 • Secondary Outcome Measures: PFS, ORR, duration of
Estimated Primary Completion Date: May 2015 objective response, duration of OS by PD-L1 status,
Status: Ongoing but not recruiting safety, disease-related symptom progression rate
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
1. Clinicaltrials.gov. NCT01668784. https://clinicaltrials.gov/ct2/show/NCT01668784?term=NCT01668784&rank=1. Accessed on October 2, 2015.
2. CA209-025 clinical protocol. August 27, 2014.
OS in Patients With mRCC
Median OS was 25 months and 19.6 months in the nivolumab and everolimus groups,
respectively
Median OS,
1.0 months
(95% CI)
0.9
Nivolumab 25.0 (21.8–NE)
0.8 Everolimus 19.6 (17.6–23.1)
0.7
0.6
Nivolumab
0.5
0.4
0.3 Everolimus
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30 33
# of patients at risk Months
Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0
Everolimus 411 366 324 287 265 241 187 115 61 20 2 0
Motzer et al. N Engl J Med. 2015;373(19):1803-1813.

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

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
Median OS, months (95% CI)

Treated beyond progression 28.1 (23.2–NE)
Overall survival with nivolumab Not treated beyond progression 15.0 (12.1–18.2)
1.0 HR (95% CI), 0.41 (0.29–0.57)

0.9
0.8
0.7
Treated beyond progression
0.6
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
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.

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

¿Qué pasa si combinamos con
antiangiogénicos?
¿Cuál es el rol en adyuvancia y
neoadyuvancia?
Agenda
• Biomarcadores
Decision Point….
Immunotherapy
PD-1/CTLA-4
PD-1 alone
Combination
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 Clin Oncol. 2017;35:3807-3814.
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,5
C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10
Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15
Reinhard Dummer,16 Veerle de Pril,17 Anila Qureshi,17 Abdel Saci,17 James Larkin,18* Paolo A. Ascierto19*
1
NYU 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;
12
Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology,
University Hospital of Siena, Istituto Toscano Tumori, 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 Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study.
Abstract Number 9502

Primary Endpoint: RFS in All Patients
NIVO IPI
Events/patients 171/453 221/453
100 Median (95% CI) 30.8 (30.8, NR)a 24.1 (16.6, NR)
HR (95% CI) 0.66 (0.54, 0.81)
90 Log-rank P value <0.0001
80 Median estimate not reliable or stable due to few patients at risk.

a
70%
70 66%
63%
60
RFS (%)
60%
50
53%
40 50%
30
20
NIVO
10 IPI
0
0 3 6 9 12 15 18 21 24 27 30 33

Months
NIVO 453 394 353 331 311 291 280 264 205 28 7 0
IPI 453 363 314 270 251 230 216 204 149 23 5 0
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
Making Tumors “Hot”
Responsive to Immunotherapy
+ Combination CPIs
+ Immune activating antibodies
Bring T-cells or cytokines
into tumors: + TLR agonists or oncolytic
viruses
+ IDO or macrophage inhibitors
+ Targeted therapies
Generate Vaccines
T-cells: TCR engineered ACT
CAR engineered ACT
Biomarkers
• Approximately 50% of melanomas contain

Frequency of genetic mutation1
Site of mutations in the BRAF gene, a critical component
melanoma BRAF GNA11 GNAQ KIT NRAS of the growth promoting MAP kinase pathway1
• Some melanomas have activating mutations in the
Acral surfaces 15% 15% 15%
human KIT, NRAS, and other genes1-3
Mucosal
surfaces
5% 20% 15% • Only BRAF is currently recommended to be tested
in melanoma patients except in clinical trials
Skin with
chronic sun 10% 2% 10% • BRAF is an activating mutation that is mutually
damage exclusive with NRAS or c-KIT1
Skin without  All of these activate the MAP-kinase pathway
chronic sun 50% 20% that promotes tumor growth1-3
damage
 Younger patients are more likely to have
Uvea 55% 25% mutations5
Biomarker-based stratification of patients is evolving in clinical trials.

The NCCN expert panel supports obtaining tissue samples for genetic analysis 4
Sources
1. Sosman JA ASCO, 2011: Educational Book pages 367-372.
2. Curtin JA et al. J Clin Oncol. 2006;24:4340-4346.
3. Van Raamsdonk CD et al. N Engl J Med. 2010;363:2191-2199.
4.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v2.2013. 45
5.Hacker E et al. J Invest Dermatol 2010;130(1):241-248.
Agenda
• Biomarcadores
But despite these advances, unmet needs remain
NSCLC
EGFR
ALK
ROS1
BRAF
No actionable
driver mutation
How can we improve outcomes for the majority of

NSCLC patients who have no actionable driver mutation?
Agenda
• Biomarcadores
Examples of Prognostic Implications
of Immune Response
Correlation with Positive Outcome: Correlation with Negative Outcome:

Presence of TILs Associated with Higher NSCLC-Infiltrating Tregs Associated
Increased Recurrence-Free Survival1 with Worse Recurrence-Free Survival2
1.0 P=0.011 1.0
Recurrence-Free Survival (%)

Recurrence-Free Survival (%)
0.9
0.8 0.8
0.7
0.6 0.6
0.5
0.4 0.4
0.3
0.2 0.2
FoxP3+ cell <3
TIL+ 0.1
TIL– 0.0 FoxP3+ cell ≥3
0.0
0.0 10 20 30 40 50 60 0 12 24 36 48 60
Survival Time (Months) Survival Time (Months)
Patients with Stage Ia NSCLC with Patients with Stage I–III NSCLC
Surgical Resection (N=273)1 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 Thorac Oncol. 2010;5:585-590. 2. Horne ZD, et al. J Surg Res. 2011;171:1-5.
Respuestas a terapias Anti PD-1/PD-L1:
Papel de la Histología, expresión de PDL-1 y estado mutacional
Para los 3 anticuerpos disponibles actualmente:
 La expresión de PD-L1 está fuertemente asociada con mejores tasas

de respuesta.
 Las respuestas ocurren independientemente de la histología,
antecedente de tabaquismo y estado mutacional (EGFR/K-ras).
Tumor Mutational Burden (TMB)
Tumors with more mutations are more likely to respond to immunotherapies,
because of the increased likelihood that they will have neoantigens that can
be targeted by the immune system.
TMB is a measurement of the total number of coding somatic base

substitution and indel mutations occurring in a tumor specimen, per
megabase of coding genome assessed.
TMB IS A BIOMARKER FOR RESPONSE TO IMMUNOTHERAPY
Cancer immunology. Mutational landscape determines sensitivity to

Genetic Basis for Clinical Response to CTLA-4 PD-1 blockade in non-small cell lung cancer.
Blockade in Melanoma Rizvi et al., Science, 2015
Snyder et al., NEJM, 2014
©2016 Foundation Medicine, Inc. 56

Conclusiones
• La caracterización molecular del Cáncer nos ha mostrado realmente

la muy compleja heterogeneidad de esta enfermedad y gracias a esto
hemos entendido las fallas anteriores en decisiones terapéuticas.
Muy probablemente, los estudios clínicos que hemos realizado ya no
tendrán, dentro de poco, una gran validez científica pues hay que
entender que “one size fits all” no aplica en esta enfermedad.
• Es solo a través del conocimiento de las mutaciones genéticas
específicas y el desarrollo de terapias dirigidas a ellas que lograremos
cambiar la historia natural de la enfermedad.
Mensajes
• El cáncer es una enfermedad causada por alteraciones genéticas generalmente
múltiples, heterogéneas, intercambiables.
• La detección de quien conduce la enfermedad al inicio y en cada momento de la
misma seria determinante para conducir el tratamiento y a veces corregir el
rumbo.
• Las plataformas genómicas pueden detectar alteraciones potencialmente blanco
de tratamientos específicos.
• Los futuros estudios deberían incluir con mas frecuencia estas determinaciones.
• La accesibilidad y su validación en más estudios clínicos permitiría seleccionar
pacientes que podrían beneficiarse de tratamientos específicos así como
determinar quienes no tendrían beneficios de tratamientos establecidos.
Agenda
• Biomarcadores
Combinatorial immunotherapy
Chemotherapy
anti-CD137 Radiotherapy
Vaccination
IDO inh
anti-OX40 anti-CTLA4
anti-PD1
anti-PDL1
Adoptive T-cell anti-CD40

immunotherapy Anti-angiogenic
therapy
Clinical standard Treg depletion/

Clinical trials
Preclinical studies inactivation
Perez Gracia, et al. Curr Opinion Immunol 2014

65
What Is Being Tested in the Immune Checkpoint Inhibitor Perioperative trials?<br />
Presented By Naomi Haas at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Slide 19
Presented By Naomi Haas at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
The future of Immuno Oncology in RCC (4)
Presented By Bernard Escudier at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary
Care
Feces composition differs between responders and non responders to IO
Care
Feces modification by antibiotics may negatively impact efficacy of IO
Care
The future of Immuno Oncology in RCC (4)
Care
PROBLEMAS IMPORTANTES
• Necesitamos comprender los mecanismos de resistencia y desarrollar nuevas estrategias para
sortearlos.
• Los pacientes que responden son importantes pero preocupan los que no responden.
• Necesitamos mejores biomarcadores para seleccionar los pacientes que se beneficiaran.
• La toxicidad es manejable salvo la toxicidad financiera que es de grado ¾ con alto riesgo de
transformarse en grado 5 matando al sistema y limitando el acceso de los pacientes a los nuevos
tratamientos.
Slide 19
Presented By Ravi Madan at 2014 ASCO Annual Meeting

Slide 28
Presented By Ravi Madan at 2014 ASCO Annual Meeting

Conclusiones
• La inmunoterapia puede enlentecer el crecimiento de los tumores
más que alterar su progresión a corto término.
• La inmunoterapia puede ejercer su efecto por un largo periodo de
tiempo.
• Combinaciones terapéuticas diseñadas racionalmente pueden lograr
efectos sinérgicos de alto impacto.
• Hoy logramos contener la evolución de muchos tipos de tumores
• Tal vez estemos curando algunos.
Muchas Gracias
Dr. Carlos Silva
Hospital Británico de Buenos Aires-Hospital Universitario Austral
Universidad Católica Argentina

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INMUNO-ONCOLOGIA

Estado actual y futuro

Dr. Carlos Silva

Pro-apoptóticos Resistencia Pemitiendo Inhibidores

Hanahan & Weinberg. Cell 2011

Presented By Leisha Emens at 2015 ASCO Annual Meeting

MDX010-20: 1- and 2-Year Survival Rates, OS1

1.0 Survival Rate Median OS, mo

Ipilimumab: Association of Response With Survival in

Pre-specified Subgroups in MDX010-20

0.2 0.5 1 2 5 0.2 0.5 1 2 5

Ipilimumab: Pooled Survival Analysis from Phase II/III

3-year OS Rate (95% CI): 22% (20% to 24%)

Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.

Nivolumab: Duration of Response

Presented By Michael Postow at 2017 ASCO Annual Meeting

Traditional Novel tumour Conventional

• Surgical debulking Targeting regulatory T cells: • Tumour-associated antigens

Weiping Zou 2006. Nat Rev. Immunol. 6:295-307.

0.9 Median OS, months

Overall Survival (Probability)

• In CheckMate 003, minimum follow-up was 50.5 months

Motzer et al. N Engl J Med. 2015;373(19):1803-1813.

Motzer et al. N Engl J Med. 2015;373(19):1803-1813.

Median OS, months (95% CI)

Overall Survival (Probability)

Escudier B et al. Poster presentation at ASCO 2016. 4509.

RJ Motzer et al. N Engl J Med 2018;378:1277-1290.

Abstract Number 9502

80 Median estimate not reliable or stable due to few patients at risk.

Number of patients at risk

• A new partner for PD-1

• Approximately 50% of melanomas contain

Biomarker-based stratification of patients is evolving in clinical trials.

How can we improve outcomes for the majority of

Correlation with Positive Outcome: Correlation with Negative Outcome:

1.0 P=0.011 1.0

Recurrence-Free Survival (%)

Para los 3 anticuerpos disponibles actualmente:

 La expresión de PD-L1 está fuertemente asociada con mejores tasas

TMB is a measurement of the total number of coding somatic base

Cancer immunology. Mutational landscape determines sensitivity to

©2016 Foundation Medicine, Inc. 56

• La caracterización molecular del Cáncer nos ha mostrado realmente

Adoptive T-cell anti-CD40

Clinical standard Treg depletion/

Perez Gracia, et al. Curr Opinion Immunol 2014

Presented By Ravi Madan at 2014 ASCO Annual Meeting

Presented By Ravi Madan at 2014 ASCO Annual Meeting

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