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Tratamiento actual del cáncer renal
Guillermo de Velasco MD, PhD
Medical Oncologist
University Hospital 12 de Octubre@H12O_GUCancer@g_develasco
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Índice
1. Intro
2. Opciones terapeuticas y por qué usarlas
3. Qué fármacos hay disponibles. Beneficios/riesgos
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Índice
1. Intro
2. Opciones terapeuticas y por qué usarlas
3. Qué fármacos hay disponibles. Beneficios/riesgos
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Epidemiología
• 2-3% de todos los tumores
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Molecular Abnormalities of Kidney Cancer
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Clear cell Non-clearcell
Eble JN, 2006;
2006 2014
Delahunt B et al. Urology 2014
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Índice
1. Intro
2. Opciones terapéuticas y por qué usarlas
3. Qué fármacos hay disponibles. Beneficios/riesgos
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Opciones terapéuticas
ENFERMEDAD LOCALIZADA
ENFERMEDAD METASTÁSICA
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Advanced/Metastatic RCC
• ~20% of patients present with metastatic disease
• ~30% of individuals treated for localized disease
experience recurrence with distant disease
– Metastases: Lung, lymph node, bone, liver, brain…
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Nomogramas
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ASSURE Trial
N. Haas, et al. Lancet 2016.
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S-TRAC
A. Ravaud et al. NEJM 2016
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Opciones terapéuticas para cáncer renal metastásico
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Opciones terapéuticas para cáncer renal metastásico
Observación Cirugía
Tratamiento sistémico
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Opciones terapéuticas para cáncer renal metastásico
Observación Cirugía
Tratamiento sistémico
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Rini et al. Lancet Oncol 2016 16
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Opciones terapéuticas para cáncer renal metastásico
Observación Cirugía
Tratamiento sistémico
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Metástasis Tumor Primario
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Metástasis Tumor Primario
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Factores Pronósticos
Motzer RJ et al J Clin Oncol 1999; 17:2530-40
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Cytoreductive Nephrectomy in Patients withSynchronous Metastases from Renal Cell
23
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Seleccionar los casos
24
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Opciones terapéuticas para cáncer renal metastásico
Observación Cirugía
Tratamiento sistémico
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Índice
1. Intro
2. Opciones terapeuticas y por qué usarlas
3. Qué fármacos hay disponibles. Beneficios/riesgos
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Rapid drug development provides more choices
Presented By Thomas Hutson at 2016 ASCO Annual Meeting
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Tratamientos sistémicos 1L
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Tratamientos sistémicos 2L
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Tipos de tratamientos
Citocinas Antiangiogénicos
Inhibidores de mTOR Inmunoterapia
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Tipos de tratamientos
Citocinas Antiangiogénicos
Inhibidores de mTOR Inmunoterapia
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High dose IL-2 for RCC
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Estudios con IL2 y ORR
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Biomarker?Drugs Biomarker Clinically
indicated
HD-IL2 CAIX NO
VEGF/VEGFR PBRM1/BAP1 NO
mTOR pathway TSC1/TSC2/mTOR NO
PD1/PDL1 abs PD1/PD-L1 NO
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Tipos de tratamientos
Citocinas Antiangiogénicos
Inhibidores de mTOR Inmunoterapia
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RCC Is a Highly Vascular Tumor
Presented By Thomas Hutson at 2016 ASCO Annual Meeting
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Regulation of HIF by pVHL
Signoretti, Choueiri and Kaelin. Molecular Abnormalities in Kidney Cancer, in The Molecular Basis of Cancer, 4th Edition (Chapter 39).
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The Cancer Genome Atlas
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CJ Creighton et al. Nature 000, 1-7 (2013) doi:10.1038/nature12222
Somatic alterations in ccRCC.
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Therapeutic biological pathways in renal-cell carcinoma
Rini et al. Lancet Oncology 2009
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Targeted Agents for Advanced RCCFirst line
Agent Target Efficacy in Randomized Phase III Trials
Comparison No. ORR PFS OS
Bevacizumab VEGF IFN-alfa +/- bevacizumabIFN-alfa +/- bevacizumab
649732
31 vs 1326 vs 13
10.2 vs 5.48.5 vs 5.2
Sunitinib VEGF-R Sunitinib vs IFN-alfa 750 37 vs 9 11.1 vs 5
Sorafenib VEGF-R Sorafenib vs Placebo 903 10 vs 2 5.5 vs 2.8
Pazopanib VEGF-R Pazopanib vs Placebo 435 30 vs 0 11.1 vs 2.8
Pazopanib VEGF-R Pazopanib vs Sunitinib 1110 31 vs 24 10.5 vs 10.2
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Con tantos fármacoscomo elegimos?
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Phase III non-inferiority Trial of Pazopanib vs. Sunitinib (N=1110)
PazopanibSunitinib
N Median PFS (95% CI)
Pazopanib 557 8.4 mo (8.3, 10.9)Sunitinib 553 9.5 mo (8.3, 11.1)
HR (95% CI ) 1.047 (0.898,1.220)
Motzer, Hutson and Choueir i. NEJM 2013
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Hair color changeWeight decreasedSerum ALT increasedAlopeciaUpper abdominal painSerum AST increasedFatigueRashPain in extremityConstipationTaste AlterationLDH increasedSerum creatinine increasedPeripheral edemaHand-foot syndromeDyspepsiaPyrexiaLeukopeniaHypothyroidismEpistaxisSerum TSH increasedMucositisNeutropeniaAnemiaThrombocytopenia
Relative Risk in Adverse EventsAE occurrence ≥10% in either arm; 95% CI for RR does not cross 1
Favors pazopanib Favors sunitinibMotzer, Huston and Choueiri, NEJM 2013
Chart1
3.141.0310.783
2.521.180.807
1.740.4320.34
1.650.690.488
1.510.6320.452
1.490.3830.299
0.870.0890.084
0.770.2030.165
0.730.2460.186
0.720.1870.156
0.710.1450.113
0.670.3110.219
0.660.2420.173
0.640.2310.168
0.590.0940.087
0.580.1670.13
0.540.2110.153
0.510.1970.135
0.50.1520.119
0.490.1880.136
0.460.240.152
0.430.1340.105
0.410.130.096
0.360.1590.104
Y-Values
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0.2
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
0.1779661017
Sheet1
X-ValuesY-ValuesSize
3.1410.22.3574.1710.7831.031
2.5220.17796610171.7133.70.8071.18
1.7430.17796610171.42.1720.340.432
1.6540.17796610171.1622.340.4880.69
1.5150.17796610171.0582.1420.4520.632
1.4960.17796610171.1911.8730.2990.383
0.8770.17796610170.7860.9590.0840.089
0.7780.17796610170.6050.9730.1650.203
0.7390.17796610170.5440.9760.1860.246
0.72100.17796610170.5640.9070.1560.187
0.71110.17796610170.5970.8550.1130.145
0.67120.17796610170.4510.9810.2190.311
0.66130.17796610170.4870.9020.1730.242
0.64140.17796610170.4720.8710.1680.231
0.59150.17796610170.5030.6840.0870.094
0.58160.17796610170.450.7470.130.167
0.54170.17796610170.3870.7510.1530.211
0.51180.17796610170.3750.7070.1350.197
0.5190.17796610170.3810.6520.1190.152
0.49200.17796610170.3540.6780.1360.188
0.46210.17796610170.3080.70.1520.24
0.43220.17796610170.3250.5640.1050.134
0.41230.17796610170.3140.540.0960.13
0.36240.17796610170.2560.5190.1040.159
0.3250.17796610170.2320.40.0680.1
To resize chart data range, drag lower right corner of range.
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A Fay et a. JNCCN 2016
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Biomarker?Drugs Biomarker Clinically
indicated
HD-IL2 CAIX NO
VEGF/VEGFR PBRM1/BAP1 NO
mTOR pathway TSC1/TSC2/mTOR NO
PD1/PDL1 abs PD1/PD-L1 NO
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In-vitro potency of VEGFR inhibitors
Presented By Thomas Hutson at 2016 ASCO Annual Meeting
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Drug Exposure (AUC) = > efficacy (RR, PFS, OS)
Presented By Thomas Hutson at 2016 ASCO Annual Meeting
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Segunda línea con antiangiogénicos
• Axitinib
• Cabozantinib
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Role of MET, VEGF, and AXL in RCC
Presented By Toni Choueiri at 2016 ASCO Annual Meeting
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METEOR Study Design
Presented By Toni Choueiri at 2016 ASCO Annual Meeting
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PFS and Response in All 658 Patients
Presented By Toni Choueiri at 2016 ASCO Annual Meeting
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Overall Survival
Presented By Toni Choueiri at 2016 ASCO Annual Meeting
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Tipos de tratamientos
Citocinas Antiangiogénicos
Inhibidores de mTOR Inmunoterapia
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Therapeutic biological pathways in renal-cell carcinoma
Rini et al. Lancet Oncology 2009
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Inhibidores de mTOR
• Everolimus
• Temsirolimus
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Algún biomarcador para inhibidores de mTOR
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Biomarker?Drugs Biomarker Clinically
indicated
HD-IL2 CAIX NO
VEGF/VEGFR PBRM1/BAP1 NO
mTOR pathway TSC1/TSC2/mTOR NO
PD1/PDL1 abs PD1/PD-L1 NO
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Tipos de tratamientos
Citocinas Antiangiogénicos
Inhibidores de mTOR Inmunoterapia
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Targeting VEGFR and FGFR
Lenvatinib Phase II Study (N = 150)Presented By Thomas Hutson at 2016 ASCO Annual Meeting
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Tipos de tratamientos
Citocinas Antiangiogénicos
Inhibidores de mTOR Inmunoterapia
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Immune Checkpoints Inhibitors
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Checkmate-25 Study design
Previously treated mRCC
Stratification factorsRegion
MSKCC risk groupNumber of prior anti-angiogenic therapies
3 mg/kg intravenously every two
weeksNivolumab
Everolimus10 mg orally once daily
Ran
dom
ize
1:1
• PRIMARY EDNPOINT: OS• Treatment beyond progression was permitted if drug was tolerated and
clinical benefit was notedMSKCC, Memorial Sloan-Kettering Cancer Center.
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Overall survivalMedian OS, months (95% CI)
Nivolumab 25.0 (21.8–NE)Everolimus 19.6 (17.6–23.1)
HR (98.5% CI): 0.73 (0.57–0.93)P = 0.0018
0 3 6 129 15Months
18 21 24 27 30 33
No. of patients at riskNivolumab 410 389 359 337 305 275 213 139 73 29 3 0
411 366 324 287 265 241 187 115 61 20 2 0Everolimus
0.0
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Ove
rall
Surv
ival
(Pro
babi
lity)
Nivolumab
Everolimus
Minimum follow-up was 14 months.NE, not estimable. Motzer, NEJM 2015
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Biomarker?Drugs Biomarker Clinically
indicated
HD-IL2 CAIX NO
VEGF/VEGFR PBRM1/BAP1 NO
mTOR pathway TSC1/TSC2/mTOR NO
PD1/PDL1 abs PD1/PD-L1 NO
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Phase 3 combination trials in advanced RCC
Phase III N=1070Co-Primary endpoint: PFS, OS
Checkmate214 - NCT02231749: Combination PD-1 + CTLA-4
inhibition
RANDOMISATION
Nivolumab+
IpilimumabSunitinib
Phase III N=830Co-Primary endpoint: PFS, OS
IMmotion151 - NCT02420821: Combination PD-L1 + VEGF
inhibition
RANDOMISATION
MPDL3280A+
BevacizumabSunitinib
Phase III N=583Primary endpoint: PFS
Javelin Renal 101 - NCT02684006: Combination PD-L1 + VEGFR TK
inhibition
RANDOMISATION
Avelumab+
AxitinibSunitinib
Phase III N=840Co-Primary endpoint: PFS, OS
Keynote426 - NCT02853331: Combination PD-1 + VEGFR TK
inhibition
RANDOMISATION
Pembrolizumab +Axitinib Sunitinib
Phase III N=735Primary endpoint: PFS
CLEAR - NCT02811861:Combination VEGFR TK + mTOR/PD-L1
inhibition
RANDOMISATION
Lenvatinib+
EverolimusSunitinib
Lenvatinib+
Pembro
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Conclusiones La cirugía es muy relevante en el cáncer renal
El cáncer renal metastásico puede ser potencialmente curable
Los antiangiogénicos han cambiado la historiaclínica de estos tumores
La inmunoterapia con ICI siguen trasformando la historia de estos tumores
Combinaciones versus Secuenciación?
No hay ningún biomarcador
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Muchas gracias
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Molecular Abnormalities of Kidney Cancer
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Multistep Kidney Cancer Carcinogenesis
Inactivating mutation
Signoretti, Choueiri and Kaelin. Molecular Abnormalities in Kidney Cancer, in The Molecular Basis of Cancer, 4th Edition (Chapter 39).
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The Cancer Genome Atlas
•
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Número de diapositiva 1ÍndiceÍndiceEpidemiologíaMolecular Abnormalities of Kidney CancerNúmero de diapositiva 6ÍndiceOpciones terapéuticasAdvanced/Metastatic RCCNomogramasASSURE TrialS-TRACOpciones terapéuticas para cáncer renal metastásicoOpciones terapéuticas para cáncer renal metastásicoOpciones terapéuticas para cáncer renal metastásicoNúmero de diapositiva 16Opciones terapéuticas para cáncer renal metastásicoNúmero de diapositiva 18Número de diapositiva 19Número de diapositiva 20Número de diapositiva 21Factores PronósticosCytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell�Seleccionar los casosOpciones terapéuticas para cáncer renal metastásicoÍndiceRapid drug development provides more choicesTratamientos sistémicos 1LTratamientos sistémicos 2LTipos de tratamientosTipos de tratamientosHigh dose IL-2 for RCCEstudios con IL2 y ORRBiomarker?Tipos de tratamientosRCC Is a Highly Vascular TumorNúmero de diapositiva 37Número de diapositiva 38Número de diapositiva 39The Cancer Genome AtlasNúmero de diapositiva 41Therapeutic biological pathways in renal-cell carcinomaTargeted Agents for Advanced RCC�First lineCon tantos fármacos� como elegimos?�Phase III non-inferiority Trial of Pazopanib vs. Sunitinib (N=1110)�Número de diapositiva 46Número de diapositiva 47Biomarker?In-vitro potency of VEGFR inhibitorsDrug Exposure (AUC) = > efficacy (RR, PFS, OS)Segunda línea con antiangiogénicosNúmero de diapositiva 52Role of MET, VEGF, and AXL in RCCMETEOR Study DesignPFS and Response in All 658 PatientsOverall SurvivalTipos de tratamientosTherapeutic biological pathways in renal-cell carcinomaInhibidores de mTORNúmero de diapositiva 60Algún biomarcador para inhibidores de mTORNúmero de diapositiva 62Número de diapositiva 63Número de diapositiva 64Biomarker?Tipos de tratamientosNúmero de diapositiva 67Targeting VEGFR and FGFR
Lenvatinib Phase II Study (N = 150)Tipos de tratamientosNúmero de diapositiva 70Checkmate-25 Study designOverall survivalBiomarker?Número de diapositiva 74Phase 3 combination trials in advanced RCCConclusionesMuchas graciasMolecular Abnormalities of Kidney CancerNúmero de diapositiva 79The Cancer Genome AtlasNúmero de diapositiva 81
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