Tratamiento actual del cáncer renal - doctaforum.com 9.1.pdf · Tratamiento actual del cáncer renal Guillermo de Velasco MD, PhD Medical Oncologist @H12O_GUCancer. University Hospital

Tratamiento actual del cáncer renal

Guillermo de Velasco MD, PhD

Medical Oncologist

University Hospital 12 de Octubre@H12O_GUCancer@g_develasco

Índice

1. Intro

2. Opciones terapeuticas y por qué usarlas

3. Qué fármacos hay disponibles. Beneficios/riesgos

Epidemiología

• 2-3% de todos los tumores

Molecular Abnormalities of Kidney Cancer

Clear cell Non-clearcell

Eble JN, 2006;

2006 2014

Delahunt B et al. Urology 2014

Índice

1. Intro

2. Opciones terapéuticas y por qué usarlas


Opciones terapéuticas

ENFERMEDAD LOCALIZADA

ENFERMEDAD METASTÁSICA

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…

Nomogramas

ASSURE Trial

N. Haas, et al. Lancet 2016.

S-TRAC

A. Ravaud et al. NEJM 2016

Opciones terapéuticas para cáncer renal metastásico


Observación Cirugía

Tratamiento sistémico

Rini et al. Lancet Oncol 2016 16

Metástasis Tumor Primario

Factores Pronósticos

Motzer RJ et al J Clin Oncol 1999; 17:2530-40

Cytoreductive Nephrectomy in Patients withSynchronous Metastases from Renal Cell

23

Seleccionar los casos

24

Índice

1. Intro

2. Opciones terapeuticas y por qué usarlas


Rapid drug development provides more choices

Presented By Thomas Hutson at 2016 ASCO Annual Meeting

Tratamientos sistémicos 1L

Tratamientos sistémicos 2L

Tipos de tratamientos

Citocinas Antiangiogénicos

Inhibidores de mTOR Inmunoterapia

High dose IL-2 for RCC

Estudios con IL2 y ORR

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

RCC Is a Highly Vascular Tumor


Regulation of HIF by pVHL

Signoretti, Choueiri and Kaelin. Molecular Abnormalities in Kidney Cancer, in The Molecular Basis of Cancer, 4th Edition (Chapter 39).

The Cancer Genome Atlas

•

CJ Creighton et al. Nature 000, 1-7 (2013) doi:10.1038/nature12222

Somatic alterations in ccRCC.

Therapeutic biological pathways in renal-cell carcinoma

Rini et al. Lancet Oncology 2009

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

Con tantos fármacoscomo elegimos?

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

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

1

2

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5

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8

9

10

11

12

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20

21

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24

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.

A Fay et a. JNCCN 2016


indicated

HD-IL2 CAIX NO




In-vitro potency of VEGFR inhibitors


Drug Exposure (AUC) = > efficacy (RR, PFS, OS)


Segunda línea con antiangiogénicos

• Axitinib

• Cabozantinib

Role of MET, VEGF, and AXL in RCC

Presented By Toni Choueiri at 2016 ASCO Annual Meeting

METEOR Study Design


PFS and Response in All 658 Patients


Overall Survival


Therapeutic biological pathways in renal-cell carcinoma

Rini et al. Lancet Oncology 2009

Inhibidores de mTOR

• Everolimus

• Temsirolimus

Algún biomarcador para inhibidores de mTOR


indicated

HD-IL2 CAIX NO




Targeting VEGFR and FGFR
Lenvatinib Phase II Study (N = 150)


Immune Checkpoints Inhibitors

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.

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


indicated

HD-IL2 CAIX NO




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


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


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

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

Muchas gracias

Molecular Abnormalities of Kidney Cancer

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).

The Cancer Genome Atlas

•

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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Tratamiento actual del cáncer renal - doctaforum.com 9.1.pdf · Tratamiento actual del cáncer renal Guillermo de Velasco MD, PhD Medical Oncologist @H12O_GUCancer. University Hospital