Algoritmo terapéutico en Cáncer Renal Avanzado

Diego Soto de Prado y Otero

Hospital Clínico Universitario de Valladolid

Segovia, 7 de mayo de 2016

ESQUEMA DE LA CHARLA

1. Introducción

2. Estudios en primera, segunda y tercera línea 3.  Estudios de secuenciación y de series de pacientes

4. Conclusiones

Introducción

●  Al hacer un algoritmo terapéutico establecemos una secuencia de tratamientos.

●  Hoy en día no existe una afirmación categórica sobre cual tiene que ser la secuencia optima de tratamiento en CCRm

●  No obstante, aunque no existe una secuencia definida, nos podemos aproximar a cual puede ser la secuencia más óptima…

Introducción

PiezasdelPuzzleenCCRm

Sunitinib Sorafenib Interferon

Bevacizumab Pazopanib

Axitinib Everolimus Temsirolimus

PiezasdelPuzzleenCCRm

Sunitinib Sorafenib Interferon

Bevacizumab Pazopanib

Axitinib Everolimus Temsirolimus

ALGORITMO ÚTIL EN LA PRÁCTICA CLÍNICA A DÍA 7 DE MAYO DE 2016

QUIZÁ EN EL 2017 ESTE ALGORITMO CAMBIE CON LA INCORPORACIÓN DE NUEVOS

FÁRMACOS

¿Cuando decidimos “nuestro” algoritmo de tratamiento?

1.  Al inicio del tratamiento, teniendo un esquema prefijado (TKI-TKI-mTOR; TKI-mTOR-TKI)

-  En base a la evidencia clínica -  En base a la experiencia personal

2. Durante el tratamiento, en función de la respuesta a los mismos ó de la toxicidad de los fármacos

Posibles algoritmos terapeúticos en Cáncer Renal metastásico

Poor prognosis

mTOR inhibitor

Good/intermediate prognosis

VEGFR-TKI or MAb-VEGF-A

mTOR inhibitor

VEGFR-TKI

Eligible patients

First-line ~100%

Second-line ~40–60%1,2

Third-line <20%3–5

1. Levy et al. Eur J Cancer 2013; 2. Sonpavde et al. Eur Urol 2012; 3. Iacovelli et al. Eur J Cancer 2013; 4. Pal et al. ASCO GU 2013; 5. Heng et al. ASCO 2013

These slides are for internal use only. Should you wish to use externally, please ensure relevant permissions are obtained.

Para conocer la secuencia óptima, hay que saber los resultados de los fármacos en las diferentes

líneas de tratamiento

Primera Línea

Relapseorstage4andmedicallyorsurgicallyunresectablePredominantclear-cellhistology

• Level 1 evidence* –  Sunitinib –  Bevacizumab + IFN-α –  Pazopanib –  Temsirolimus (for poor prognosis† patients)

• Level 2A evidence‡ –  Clinical trial –  High-dose IL-2 (for selected patients) –  Sorafenib (for selected patients) –  Best supportive care§

•  Level 2B evidence** –  Temsirolimus (for selected patients of other risk groups)

2016NCCNguidelinesforclear-cellmRCC:First-linetherapy

Risk status Recommendation Level of evidence

Favorable or intermediate

Sunitinib Bevacizumab + IFN-α Pazopanib

I, A I, A I, A

Poor risk Temsirolimus II, A

First-linetreatmentguidelinesforclear-cellmRCC:ESMO2014

Escudier B, et al. Ann Oncol. 2014;25(Suppl 3):vii49–56.

EnsayosClínicosenprimeralíneaStudy N ORR (%) Median PFS

(months) Final Median OS (months)

Phase III

Sunitinib vs. IFN-α 750 47 vs. 12 11 vs. 5 p<0.001

26.4 vs. 21.8 p=0.051

Bev + IFN-α vs. IFN-α 649 31 vs. 12 10.4 vs. 5.5 p<.0001

23.3 vs. 21.3 p =0.1291

Bev + IFN-α vs. IFN-α 732 25.5 vs. 13.1 8.4 vs. 4.9 p<0.0001

18.3 vs. 17.4 p =0.069

Pazopanib vs. placebo 233 32 vs. 3 11.1 vs. 2.8 p<0.0000001

22.9 vs. 23.55

p=0.525 Temsirolimus vs. IFN-α

626 8.6 vs. 4.8 5.5 vs. 3.1 p<0.001

10.9 vs. 7.3 p=0.0069

Pazopanib vs. sunitinib

1110 31 vs. 25 8.4 vs. 9.5 Non-inferior

28.4 vs. 29.3 Non-inferior

Phase II Sorafenib vs. IFN-α 189 5.2 vs. 8.7 5.7 vs. 5.6

p =0.504 NA

Pivotal Phase III study of sunitinib first-line in mRCC

Eligibility Criteria •  mRCC

•  Clear-cell histology

•  No prior systemic treatment

•  Measurable disease by RECIST

•  ECOG PS of 0–1

•  Adequate organ function

Sunitinib 50 mg/day on schedule 4/2

(4 weeks on/ 2 weeks off)

IFN- α 3 MU s.c. t.i.w. 1st week 6 MU s.c. t.i.w. 2nd week 9 MU s.c. t.i.w. 3rd week

thereafter

(n=750)

(n=375)

R A N D O M I Z A T I O N

Pivotal Phase III study of sunitinib first-line in mRCC

Motzer RJ, et al. N Engl J Med. 2007;356:115–124.

PFS by Independent Central Review

No. at risk Sunitinib: 375 240 156 54 10 1 IFN-α: 375 124 46 15 4 0

HR = 0.538 95% CI (0.439, 0.658) p<0.00001

0 5 10 15 20 25 30 Time, months

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Sunitinib Median: 11.0 months (95% CI: 10.7–13.4)

IFN-α"Median: 5.1 months (95% CI: 3.9–5.6)

COMPARZ Study Design: Phase III, Open-label, Non-inferiority Trial

Motzer RJ, et al. N Engl J Med 2013;369(8):722–731

Pazopanib 800 mg QD Continuous daily dosing Enrolment criteria:

• Locally advanced or mRCC • Clear-cell histology • No prior systemic therapy • Measurable disease (RECIST 1.0) • KPS ≥70 • Adequate organ function Sunitinib 50 mg QD

Schedule 4/2

Randomised 1:1

N=1,110

COMPARZ 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)

Pts at Risk, n 557 553

361 351

245 249

136 147

105 111

Pazopanib Sunitinib

0 Prop

0 4 8 12 16 20 24 28 32 36 40 Mos

Motzer RJ, et al. N Engl J Med 2013;369(8):722–731

Sunitinib 50 mg/day**

RECORD-3 trial confirms first-line TKI is better than mTOR inhibitor

SCREEN

RANDOM I Z E *

Everolimus 10 mg/day

Sunitinib 50 mg/day**

Everolimus 10 mg/day

Study endpoints

Primary • PFS 1st-line Secondary • Combined PFS • ORR 1st-line • OS • Safety

1:1 Cross-over upon progression

N=471 First-line Second-line

*Stratified by MSKCC prognostic factors; **4 weeks on, 2 weeks off.

Motzer RJ et al. ASCO 2013; Abstract 4504.

Median follow-up 22.7 months

RECORD-3: Primary endpoint: First-line PFS

100 90 80 70 60 50 40 30 20 10 0

0 3 6 9 12 15 18 21 24 27 30 33 Time (months)

238 233

164 181

118 145

88 108

Number of patients still at risk Everolimus Sunitinib

Everolimus (events/N=182/238)

Sunitinib (events/N=158/233) Cum

(%) K-M Median PFS (mo)

Everolimus Sunitinib 7.85 10.71

HR = 1.43 Two-sided 95% CI [1.15, 1.77]

RECORD-3: Overall survival 100

0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

EVE→SUN (events/N=108/238)

SUN→EVE (events/N=96/233)

Number of patients still at risk

K-M Median OS (mo) EVE→SUN SUN→EVE

22.41 32.03

HR = 1.24 Two-sided 95% CI [0.94, 1.64]

EVE→SUN SUN→EVE

Primera Línea

SEGUNDA LINEA

After a first-line VEGF-targeted agent, what do you use?

Good/intermediate prognosis mRCC

VEGFR-TKI? mTOR inhibitor?

Eligible patients

First-line ~100%

1. Levy et al. Eur J Cancer 2013; 2. Sonpavde et al. Eur Urol 2012

Secuencia de dos fármacos de la misma familia

Secuencia de dos fármacos con diferente actividad

Inhibidores de mTOR

Everolimus phase III study (RECORD-1): design and enrolment criteria

Everolimus + BSC (n=272)

Placebo + BSC (n=138)

Upon disease progression

R A N D O M I S A T I O N

Escudier B, et al. ESMO 2008

§  Clear cell mRCC §  Disease progression during

or within 6 months of stopping sunitinib and/or sorafenib

§  Prior cytokines and/or VEGFR inhibitors permitted

§  Stratification §  Prior VEGFR-TKI §  MSKCC prognostic

criteria

§  Primary endpoints: PFS (central review) §  Secondary endpoints: Safety, ORR, OS, quality of life

RECORD-1: PFS and OS data

RECORD-1: ¿es representativo de una segunda línea?

●  RECORD-1 80%: patients were treated with everolimus third-line or later

First- line

Second- line

Third- line

Fourth-line

mTOR fifth- line

First- line

Second- line

Third- line

mTOR fourth-

First- line

Second- line

mTOR third- line

First- line

mTOR second-

PFS: EVE: 4.9 months vs. PLC: 1.9 months (p<.001; HR=0.33)

Inhibidores de Tirosina quinasa

Treat until PD, unmanageable AE or withdrawal of consent Stratification: ●  Prior regimen ●  ECOG PS (0 vs 1)

Sorafenib 400 mg b.i.d.

Eligibility criteria: Histologically-confirmed mRCC with clear-cell component Failure of prior first-line regimen containing ≥1 of: • Sunitinib • Bevacizumab +IFN-α •  Temsirolimus • Cytokine(s)

AXIS Phase III Study Design

Starting dose 5 mg BID with option for dose titration to 10 mg BID ●  Primary endpoint: PFS ●  Secondary endpoints: OS, ORR, duration of

response, safety, QoL (FKSI and EQ-5D)

RANDOM I Z A T I ON

Axitinib 5 mg b.i.d.

Rini BI, et al. Lancet 2011;378:1931–1939

AXIS: Axitinib significantly prolonged PFS vs sorafenib

Updated data cut-off requested for SmPC June 03, 2011

Time (months) 0 2 4 6 8 10 12 22 24 26 28 14 16 18 20

p<0.0001 (log-rank) Stratified HR=0.67 (95% CI: 0.56–0.81)

Axitinib Sorafenib

mPFS, months 95% CI 6.8 4.7

6.4–8.3 4.6–6.3

n 361 362

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Axitinib Summary of Product Characteristics, 2012

IRC Assessment

AXIS: axitinib significantly improved PFS vs sorafenib in patients with prior sunitinib treatment

Axitinib SmPC, 2014

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Time (months)

p=0.0063 HR 0.74 (95% CI 0.58–0.94)

Axitinib Sorafenib

mPFS, months 95% CI 4.8 3.4

4.5–6.5 2.8–4.7

n* 194 195

PFS improvement from 3.4 to 4.8 months with axitinib vs sorafenib

*Prior sunitinib subgroup

Patients with mRCC and PD on 1st-line

sunitinib (N=512)

Stratification factors: • Duration of sunitinib therapy (≤ or >6 mo) • MSKCC risk group • Histology (clear cell or non–clear cell) • Nephrectomy status

RANDOMIZE

Temsirolimus 25 mg IV weekly†

(n=259)

Sorafenib 400 mg oral BID†

(n=253)

Treat until PD, unacceptable

toxicity, or discontinuation for any other

reason

INTORSECT* Study Design

N=512 112 sites in 20 countries

CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival.

Temsirolimus Sorafenib

252 72 22 11 6 0 259 96 28 9 5 0

Sorafenib Temsirolimus

Time (months) 0 5 10 15 20 25

Progression-Free Survival (IRC Assessment)

P=0.1933 (log-rank) Stratified HR: 0.87

(95% CI: 0.71, 1.07)

Median PFS, months 95% CI

4.28 3.91

4.01, 5.43 2.80, 4.21

Patients at risk, n

Overall Survival O

253 158 74 34 13 0 259 132 54 22 8 0

Sorafenib Temsirolimus

0 10 20 30 40 50

Temsirolimus Sorafenib

Patients at risk, n Time (months)

P=0.014 (log-rank) Stratified HR: 1.31

(95% CI: 1.05, 1.63)

12.27 16.64

10.13, 14.80 13.55, 18.72

CI, confidence interval; HR, hazard ratio; OS, overall survival.

Median OS, months 95% CI

Second-line median PFS is higher for VEGFR-TKI → VEGFR-TKI vs VEGFR-TKI → mTOR in comparative

retrospective studies

1. Heng et al. ASCO GU 2012; 2. Proskorovsky et al. Ann Oncol 2012; 3. Vickers et al. Urology 2010; 4. Weikert et al. J Clin Oncol 2011; 5. Derosa et al. Ann Oncol 2012; 6. Alimohamed et al. Clin Gen Cancer 2014

*Sunitinib → sorafenib; †Sorafenib → sunitinib

Heng et al. (N=818)

Proskorovsky et al. (N=318)

Vickers et al. (N=216)

Weikert et al. (N=108)

Derosa et al. (N=42)

Alimohamed et al. (N=818)

Real-world experience: Second-line therapy at Institut Gustave Roussy (2005–2009)

●  62% of eligible mRCC patients (n=211) received second-line targeted therapy (most frequent first-line agent was sunitinib)

Median OS from start of second-line therapy

p=0.126

TKI (20.8 months)

mTOR (16.6 months)

Months

0 6 12 18 24 30 36 42 48 54 60 66 72

Levy et al. Eur J Cancer 2013

Segunda Línea

El futuro…..

Nuevos fármacos

Objetivo Primario

Objetivos Secundarios

Tercera Línea

Potential therapeutic algorithms for targeted agents in mRCC

Poor prognosis

mTOR inhibitor

Good/intermediate prognosis

mTOR inhibitor

VEGFR-TKI

Eligible patients

First-line ~100%

Third-line <20%3–5

1. Levy et al. Eur J Cancer 2013; 2. Sonpavde et al. Eur Urol 2012; 3. Iacovelli et al. Eur J Cancer 2013; 4. Pal et al. ASCO GU 2013; 5. Heng et al. ASCO 2013

These slides are for internal use only. Should you wish to use externally, please ensure relevant permissions are obtained.

Inhibidores de mTOR

RECORD-1: NOT representative of a pure second-line trial

The results of RECORD 1 indicate that a reasonable PFS may still be achieved with an mTOR inhibitor in third-line (or later)

1. Zustovich et al. Crit Rev Oncol Hematol 2012; 2. Motzer et al. Cancer 2010

1st- line

2nd- line

3rd- line

4th-line n=82

1st- line

2nd- line

3rd- line

1st- line

2nd- line

1st- line

mTOR 2nd- line

mTOR 3rd- line

mTOR 4th- line

mTOR 5th- line

RECORD-1 data provide a strong rationale for using everolimus after two prior VEGFR-TKIs

1. Calvo et al. Eur J Cancer 2012

n Everolimus Placebo HR (95% CI)

1 prior VEGFR-TKI 308 5.4 1.9 0.32 (0.24–0.43) p<0.001

2 prior VEGFR-TKIs 108 4.0 1.8 0.32 (0.19–0.54) p<0.001

In RECORD-1, 108 patients (26%) had received two previous VEGFR-TKIs1,2

Setting Risk group Standard Option

First line

Good/Intermediate risk Sunitinib [I,A]

Bevacizumab + IFN-α [I,A] Pazopanib [I,A]

High-dose IL2 [III,C] Sorafenib [II,B] Bevacizumab +

low-dose IFN-α [III,A]

Poor risk Temsirolimus [II,A] Sunitinib [II,B] Sorafenib [III,B]

Second line Post cytokines

Axitinib [I,A] Sorafenib [I,A]

Pazopanib [II,A] Sunitinib [III,A]

Post VEGFR-TKI Axitinib [I,B] Everolimus [II,A] Sorafenib [II,A]

Third line

Post two VEGFR-TKIs Everolimus [II,A]

Post VEGFR-TKI and mTOR inhibitor Sorafenib [I,B] Other VEGFR-TKI [IV,B]

Rechallenge [IV,B]

IFN-α, interferon-α; VEGFR, VEGF receptor Escudier et al. Ann Oncol 2014

2014 ESMO clinical practice guidelines

Inhibidores de Tirosina quinasa

GOLD: dovitinib versus sorafenib in VEGFR-TKI and everolimus-treated patients with mRCC

•  Primary endpoint: PFS •  Secondary endpoints: Safety, ORR, OS, QoL

Motzer et al. proc ESMO 2013 AbstrE17-7025

Dovitinib 500 mg PO 5D / 2D

(n=284)

Eligibility •  mRCC (clear cell

component) •  KPS > 70% •  Failed two prior therapies

–  VEGFR-TKI –  mTORi

Stratification, by: •  MSKCC prognostic criteria •  Region

N=570 On disease progression

RANDOM I SA T I ON

Sorafenib 400 mg BID PO

(n=286)

GOLD: progression-free survival

MotzerRJetal.LancetOncol2014;15:286–96.

0 3 6 9 12 15 18 21

Time from randomization (months)

Dovitinib Sorafenib

No. at risk 284 148 41 20 3 1 1 0 286 152 42 12 2 1 0 0

Dovitinib = 3.7 months (n=209) Sorafenib = 3.6 months (n=231)

HR (Dov/Sor) = 0.86 95% CI = 0.72–1.04 P=0.004 (one-sided)

GOLD: overall survival

MotzerRJetal.LancetOncol2014;15:286–96.

Time from randomization (months) 0 3 6 9 12 15 18 21

Dovitinib Sorafenib

No. at risk 284 246 165 102 51 23 9 0 286 242 160 95 52 22 7 0

Dovitinib = 11.1 months (n=130) Sorafenib = 11.0 months (n=135)

HR (Dov/Sor) = 0.96 95% CI = 0.75–1.22

First line

Third line

Rechallenge [IV,B]

Patients who responded well on 1st line sunitinib, may benefit from re-exposure with sunitinib after a while

(RESUME Study)

First-line Median, 18.4 months (95% CI: 12.5–23.7) Rechallenge Median, 7.9 months (95% CI: 5.4–13.2)

95% confidence limits Censored

Time (months) No. of patients at risk

0 10 20 30 40 50 60

52 47 22 6 2 2 2 32 14 3 2 51 27 7 2 1 0 14 4 1 1

61 Oudard et al, Abstract No. 816PD, ESMO 2014

First line

Third line

Rechallenge [IV,B]

Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma:

Results from a large patient cohort

R. Iacovelli et al. European Journal of Cancer 2013;49(9):2134-2142

La secuencia TKI–TKI–mTORi proporcionó mejores resultados que la secuencia TKI–mTORi–TKI

R. Iacovelli et al. European Journal of Cancer 2013;49(9):2134-2142

TKI-TKI–mTORi (n=152)

TKI–mTORi–TKI (n=95)

p value

Mediana PFS 36.5 meses (95% CI,30.5–42.6) 29.3 meses (95% CI, 23.6–34.9) p= 0.059

Mediana SG 50.7 meses (95% CI, 40.6–60.8) 37.8 meses (95% CI, 34.2– 41.5) p = 0.004

Tercera Línea

Conclusiones

CONCLUSIONES

●  En primera línea: Sunitinib y Pazopanib se perfilan como los tratamientos a valorar en la mayor proporción de pacientes

●  En segunda línea: Axitinib a demostrado ser superior a Sorafenib. Everolimus eficaz en segunda línea y posteriores.Estudio INTORSEC

●  Existen nuevos fármacos con eficacia en segunda línea:

ü  La inmunoterapia (Nivolumab) es superior a m-TOR

ü Cabozantanib es eficaz pero cuidado con su toxicidad

●  En tercera línea: Muy pocos pacientes. El tratamiento dependerá de los empleado en segunda línea (m-TOR)

Mi algoritmo terapeútico en Cáncer Renal metastásico

Mal Pronóstico

Temsirolimus

Pronóstico bueno/intermedio

Sunitinib / Pazopanib

Everolimus

Axitinib

Sorafenib

Primera línea

Segunda Linea

Tercera línea

Nivolumab Cabozantanib Axitinib

TKI / mTOR?

Aunque no existe una recomendación clara sobre cual pude ser la

secuencia de tratamiento más beneficiosa, si podemos aproximarnos

a ella….

TKI – TKI (TKI-TKI-mTOR)

MEJORES RESULTADOS QUE

TKI-mTOR (TKI-mTOR-TKI)

GRACIAS

Muchas gracias…

Algoritmo terapéutico en Cáncer Renal Avanzado

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