Tratamiento actual del Cáncer Renal.

Daniel Castellano

Servicio de Oncología Médica

Unidad de Tumores Genito-Urinarios

Hospital Universitario 12 de Octubre

Diagnóstico en CCR

Mejor pronóstico en estadios tempranos.

Muchos pts son mts asintomáticos.

25% a 40% son de hallazgo incidental.

Usualmente se diagnostican x MAP/Urologo

> frecuentemente x MAP y Urologo y secundario a síntomas

relacionados: hematuria, astenia, dolor lumbar

Patogenesis de CCR

Patogenesis de CCR a cel. claras

Síndrome Von Hippel-Lindau se caracteriza por

mutación del gen VHL y desarrollo de tumores

vasculares incluido CCR.

La función normal del gen VHL (pVHL) es ayudar a

destruir HIFa dentro de la célula.

Mutación del genVHL (90% somática) conduce a una

pVHL modificada no funcionante que permite

incremento de niveles intracel. de HIFa y b.

Sobre-expresión de HIFa induce expresión de genes

hipoxia tisular.

Sobre-expresión consecuente de VEGF, PDGF,TGF

promueve angiogenesis tumoral y proliferación.

3

Targeting signaling pathways in RCC

Rini, et al. Lancet Oncol. 2009;10:992-1000.

Cirugía en el CCR

Nefrectomía parcial (AUA, EAU) estadios I/II

Nefrectomía radical casos especiales

Tumorectomía en casos seleccionados (NSS)

Tratamiento ablativo (T < 2 cms.)

Nefrectomía citorreductora en estadios IV

Beneficio OS 2 estudios randomizados (SWOG, EORTC)

Doble nefrectomía + diálisis en casos seleccionados

(valorar trasplante con > seguimiento)

Modelos Integrados de Predicción Pronóstica en CCR avanzado

Appropriate treatment selection: modified risk status in clinical trials

MSKCC criteria

Karnofsky PS <80

Low serum hemoglobin

High corrected calcium

High LDH

Time from diagnosis to

treatment <1 year

Motzer RJ, et al. J Clin Oncol 2002; Hudes G, et al. N Engl J Med 2007

5

VEGFR-2

VEGFR-1

PDGFR-α

VEGFR-3 PDGFR-ß c-KitFlt-3

Overview of targeted agents in mRCC1–5

Anti-angiogenesisBevacizumab

VEGF-A

VEGF-B

VEGF-C

VEGF-D

VEGF-E

Pazopanib SorafenibRaf

Sunitinib

Good and Intermediate risk pts N ORR (%)

Median PFS

(months)

Median OS

(months)

Sunitinib vs IFN-a1 750 47 vs 12 P<0.001

11 vs 5 P<0.001

26.4 vs 21.8 P=0.051

Bevacizumab + IFN-a vs IFN-a2,3 649 31 vs 13 P=0.0001

10.2 vs 5.4 P<0.0001

23.3 vs 21.3 P=0.1291

Bevacizumab + IFN-a vs IFN-a4,5 732 26 vs 13 P<0.0001

8.5 vs 5.2 P<0.0001

18.3 vs 17.4 P=0.069

*Pazopanib vs placebo6,7 435 30 vs 3†

P<0.001

11.1 vs 2.8P<0.0001

22.9 vs 20.5†

P=0.224

Poor risk patients

Temsirolimus vs IFN-a8* 626 8.6 vs 4.8 NS

5.5 vs 3.1P<0.001

10.9 vs 7.3 P=0.008

*Poor risk patients (modified MSKCC criteria); †Includes cytokine refractory and treatment-naïve patients

Recommended targeted agents for first-line treatment of mRCC: Results from pivotal trials

1. Motzer RJ, et al. J Clin Oncol 2009; 2. Escudier B, et al. Lancet 2007; 3. Escudier B, et al. J Clin Oncol 2010;

4. Rini BI, et al. J Clin Oncol 2008; 5. Rini B, et al. J Clin Oncol 2010; 6. Sternberg C, et al. J Clin Oncol 2010;

7. Sternberg C, et al. ESMO 2010; 8. Hudes G, et al. N Engl J Med 2007*Conditionally approved

PFS: Sunitinib > IFN-

0 5 10 15 20 25 30Time (months)

HR=0.538

(95% CI 0.439–0.658)

P<0.000001

SunitinibMedian: 11.0 months(95% CI: 10.7–13.4)

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

Revisión central independiente

No. at risk

Sunitinib: 375 240 156 54 10 1

IFN-: 375 124 46 15 4 0

1.0

0.8

0.6

0.4

0.2

0

Motzer RJ, et al. N Engl J Med 2007; Motzer RJ, et al. ASCO 2007

PF

S p

rob

abili

ty

Supervivencia en pacientes que no recibieron ningún tratamiento post-estudio

HR=0.647

(95% CI: 0.483–0.870)

P=0.0033 (log-rank)

Sunitinib (n=193)

Median 28.1 months

(95% CI: 19.5–NA)

IFN- (n=162)*

Median: 14.1 months

(95% CI: 9.7–21.1)

*Includes 20 patients whocrossed over to sunitinib on study Motzer RJ, et al. J Clin Oncol 2009; Figlin RA, et al. ASCO 2008

Probabilidad de SG

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0Tiempo (meses)

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

Pro

babili

ty o

f surv

ival

Pazopanib vs. Placebo para 1º y 2º linea de CCR avanzado

Eligibility Criteria

• Locally advanced RCC or mRCC

• Predominant clear cell histology

• Measurable disease (≥1 lesion)

• 0 or 1 prior systemic treatment (cytokine based) for locally advanced or mRCC

RANDOMIZATION

2:1

Primary Endpoint: PFS

Final OS data pending

Pazopanib 800 mg/day

n=290

Placebon=145

N=435

• Open-label extension study

(Pazopanib 800 mg; N=71) completed

in April 2009

Sternberg C. ASCO 2009

PFS del grupo global de pts y 1º linea de tratamiento

Treatment naïve subpopulation Overall study population

Sternberg C, et al. J Clin Oncol. 2009;27(Suppl 15s):5021 (Abstract).

Phase III non-inferiority trial of pazopanib vs sunitinib in first-line mRCC (COMPARZ)

www.clinicaltrials.gov (NCT00720941)

*Pazopanib 800 mg/day

Sunitinib50 mg/day

(Schedule 4/2)

Primary endpoint: PFS

Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL

N=876

Eligibility criteria

Locally advanced

or mRCC with

clear-cell histology

No prior systemic

therapy for

advanced mRCC

R

A

N

D

O

M

I

S

A

T

I

O

N

1:1

*Conditionally approved

COMPARZ primary endpoint: PFS (IRC-assessed)

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)

Pro

po

rtio

n p

rog

ressio

n-f

ree

1.0

0.8

0.6

0.4

0.2

0

MonthsNumber at risk

Pazopinib 557 361 245 136 105 61 46 19 13 1

Sunitinib 553 351 249 147 111 69 48 18 10 3

0 4 8 12 16 20 24 28 32 36 40

Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8

*Modified MSKCC poor risk; †Stratification by country and nephrectomy status ‡SD 16 weeks; §p=0.0069

IFN 3 MU-18 MU (n=207)

CR + PR – 7%

CR + PR + SD‡ – 29%

Med. OS 7.3 months§

IFN 6 MU + TEM 15 mg QW

(n=210) CR + PR – 11%

CR + PR + SD – 41%

Med. OS 8.4 months

TEM 25 mg QW (n=209)

CR + PR – 9%

CR + PR + SD – 46%

Med. OS 10.9 months§

Randomize†

3/6 Poor Risk Features

• LDH >1.5 x ULN

• Hgb < LLN

• Ca++ (cor) >10

• KPS <70%

• DFI <1 year

• Multiple sites of metastases

Metastatic RCC (N=626)

Temsirolimus Fase III en CCR avanzado MSKCC mal pronóstico

Parameter

IFN

Arm 1

(n=207)

TEMSR

Arm 2

(n=209)

TEMSR + IFN

Arm 3

(n=210)

Median survival (mos) 7.3 10.9 8.4

Comparisons Arm 2:Arm 1 Arm 3:Arm 1

Stratified log-rank p 0.0069 0.6912

Parameter

IFN

Arm 1

(n=207)

TEMSR

Arm 2

(n=209)

TEMSR + IFN

Arm 3

(n=210)

Median survival (mos) 7.3 10.9 8.4

Comparisons Arm 2:Arm 1 Arm 3:Arm 1

Stratified log-rank p 0.0069 0.6912

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al d

istr

ibu

tio

n f

un

cti

on

0 5 10 15 20 25 30 35Time to death

Arm 3: IFN + Temsirolimus

Arm 2: TemsirolimusArm 1: IFN

Hudes G et al. N Engl J Med. 2007;356:2271–2281.

RECORD-3. Study Design*

Everolimus

10 mg/day

Sunitinib

50 mg/day***

2nd Line

*NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off.

Primary

• PFS-1st line

Secondary

• Combined PFS

• ORR-1st line

• OS

• Safety

Study

endpoints

Cross-over upon

progression

1 : 1

R

A

N

D

O

M

I

Z

E**

Everolimus

10 mg/day S

C

R

E

E

N Sunitinib

50 mg/day***

1st LineN = 471

22

Primary End Point: 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

68

84

44

55

31

42

23

28

12

15

5

9

0

3

0

0

Number of patients still at risk

Everolimus

Sunitinib

Everolimus (events/N = 182/238)

Sunitinib (events/N = 158/233)Cum

ula

tive e

vent-

free p

robabili

ty (

%)

23

K-M Median PFS (mo)

Everolimus Sunitinib

7.85 10.71

Hazard Ratio = 1.43

Two-sided 95% CI [1.15, 1.77]

Overall Survival

100

90

80

70

60

50

40

30

20

10

0

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

Cum

ula

tive e

vent-

free p

robabili

ty (

%)

Time (months)

EVE→SUN (events/N = 108/238)

SUN→EVE (events/N = 96/233)

238

Number of patients still at risk

233

208

220

189

198

165

185

151

164

137

152

103

115

66

71

43

38

15

22

2

6

0

1

0

0

24

K-M Median OS (mo)

EVE→SUN SUN→EVE

22.41 32.03

Hazard Ratio = 1.24

Two-sided 95% CI [0.94, 1.64]

EVE→SUN

SUN→EVE

The challenge of treatment in mRCC

• Benefits of tyrosine kinase inhibitors (TKIs) are

well established; however, there are limitations

– There are few complete responses

– Initial partial responses are followed by progression

– In other cases there is no objective benefit

• Drug resistance remains an ongoing obstacle to

successful treatment of mRCC

– Limits the success of therapy and reduces survival

rates

Motzer RJ, et al. J Clin Oncol 2009; Rini B, et al. J Clin Oncol 2010; Escudier B, et al. J Clin Oncol2010; Escudier B, et al. N Engl J Med 2007; Hudes G, N Engl J Med 2007

Rini, Atkins Lancet Oncology

Resistance to Targeted Therapy in RCC

Clinical trial summary for second-

line therapy after TKIs in RCC

Trial Recruitment Treatment arms

RECORD-1: Phase III, everolimus vs. placebo

after progression to TKIs

410 Everolimus

Placebo

AXIS: Phase III, axitinib vs. sorafenib as

second-line treatment

744 Axitinib

Sorafenib

INTORSECT: Phase III, temsirolimus vs.

sorafenib in patients refractory to sunitinib

480 Temsirolimus

Sorafenib

RECORD-3: Phase II, sequencing sunitinib

after everolimus vs. everolimus after sunitinib

390 Sunitinib

Everolimus

SWITCH: Phase III in sequence of sunitinib

after sorafenib vs. sorafenib and after sunitinib

540 Sunitinib

Sorafenib

NCT00410124; NCT00474786; NCT00678392; NCT00903175; NCT00732914

Agent N ORR (%)

Median PFS

(months)

Median OS

(months)

Everolimus vs placebo410

3.0 % vs

0 %

4.6 vs 1.8

P = .00114.7 vs 14.3

Axitinib vs Sorafenib723

19.4 % vs

9.4 %

6.7 vs 4.7

P < .0001NA

Sorafenib vs placebo 903 10% vs 2%5.5 vs 2.8;

P = .000001NA

*Poor risk patients (modified MSKCC criteria); †Includes cytokine refractory and treatment-naïve patients

Recommended targeted agents for second-line treatment of mRCC: Results from pivotal trials

1. Motzer RJ, et al. J Clin Oncol 2009; 2. Escudier B, et al. Lancet 2007; 3. Escudier B, et al. J Clin Oncol 2010;

4. Rini BI, et al. J Clin Oncol 2008; 5. Rini B, et al. J Clin Oncol 2010; 6. Sternberg C, et al. J Clin Oncol 2010;

7. Sternberg C, et al. ESMO 2010; 8. Hudes G, et al. N Engl J Med 2007*Conditionally approved

Everolimus Estudio Fase III (RECORD-1):

Everolimus + BSC

(n=272)

Placebo + BSC

(n=138)

Upon

disease

progression

Prior treatment

Everolimus

(n=272) %

Placebo

(n=138) %

Nephrectomy

Radiotherapy

VEGFR-TKI therapy

96

31

95

28

Sunitinib 46 44

Sorafenib 28 30

Both 26 26

Other systemic therapy

IFN

IL-2

Chemotherapy

Bevacizumab

50

22

13

9

50

24

16

10

>70

%

R

A

N

D

O

M

I

S

A

T

I

O

N

2:1

Escudier B, et al. ESMO 2008

N=410

Estratificación

Pre VEGFR-TKI:

1 o 2 tratamientos

MSKCC: favorable- vs

intermedio- vs mal

pronóstico

2º Line Treatment

RECORD-1: PFS y OS

0 2 4 6 8 10 12 14

Months

Pro

ba

bili

ty (

%)

Number of patients at risk

Everolimus 277 192 115 51 26 10 1 0

Placebo 139 47 15 6 2 0 0 0

Log rank P value < 0.001

Everolimus (n=277)

Placebo (n=139)

HR=0.33

95% CI [0.25, 0.43]

Median PFS

Everolimus: 4.90 months

Placebo: 1.87 months

PFS*

Analysis on Feb 2008 Data Cut-Off

Motzer R, et al. ASCO GU 2009; Kay et al. EAU 2009

OS

Pro

ba

bili

ty (

%)

100

80

60

40

20

0

Number of patients at risk

Everolimus 277 267 240 204 164 155 131 101 61 30 6 0 0

Placebo 139 131 117 100 86 74 56 43 27 13 3 0 0

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

Months

100

80

60

40

20

0

Log rank P value = 0.177

Everolimus (n=277)

Placebo (n=139)

HR=0.87

95% CI [0.65, 1.17]

Median OS

Everolimus: 14.78 months

Placebo: 14.39 months

Analysis on Nov 2008 Data Cut-Off

* central radiology review

Phase III study of axitinib versus sorafenib in second-line (AXIS)

Primary endpoints: PFS

Secondary endpoints: OS, ORR, safety and

tolerability, duration of response, patient-reported

outcomes

Axitinib

5 mg BID

Sorafenib400 mg BID

Eligibility

mRCC with clear-cell

histology

Failure of one prior

first-line regimen

containing:

Sunitinib

Bevacizumab +

IFN-α

Temsirolimus

Or cytokines

Stratification by prior

regimen and ECOG

PS

N=717

Rini B, et al. ASCO 2011

R

A

N

D

O

M

I

S

A

T

I

O

N

AXIS: Axitinib significantly prolonged PFS versus sorafenib

361 256 202 145 96 64 38 20 10 1 0

362 224 157 100 51 28 12 6 3 1 0

Subjects at risk, n

Axitinib

Sorafenib

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Time (months)

P<0.0001 (log-rank)

Stratified HR 0.665

(95% CI :0.544–0.812)

0 2 4 6 8 10 12 14 16 18 20

Axitinib

Sorafenib

mPFS, months 95% CI

6.74.7

6.3–8.64.6–5.6

Pro

gre

ssio

n-f

ree

su

rviv

al (p

rob

ab

ility

)

Rini B, et al. ASCO 2011

Beyond the second Line:

Understanding resistance mechanisms can allow identification of optimal treatment strategies

Potential approaches to overcoming resistance include

New pathways

Switch from one TKI to another3

Switch from a TKI to an mTOR inhibitor4

Combination of traditional agents with new agents?

Enhancing Immune Responsiveness

Programmed Death (PD)-1 pathway

PD-1 downregulates T-cell function upon binding to its ligand (PD-L1)

PD-L1 has been shown to be overexpressed in RCC

In patients with mRCC, overexpression of PD-L1 has been shown to

be associated with

Adverse pathology

Aggressive tumour behaviour

Poor survival

APC/

tumour

cell

T-cellT-cell

inactivationPD-1

PD-L1

Thompson RH, et al. Clin Cancer Res 2007

Resolving RCC Lytic Bone Metastasis in

Patient Treated With Anti-PD-1 (10 mg/kg)

3/25/08 4/14/09

B7H1Control Ig

Responses may be

correlated with PD-

L1 expression

3/4 PRs in PDL-1+

tumors,

0/5 PDL-1 negative

Brahmer et al, 2010.

Resolving RCC Lytic Bone Metastasis in

Patient Treated With Anti-PD-1 (10 mg/kg)

3/25/08 4/14/09

B7H1Control Ig

Responses may be

correlated with PD-

L1 expression

3/4 PRs in PDL-1+

tumors,

0/5 PDL-1 negative

Brahmer et al, 2010.

Resolving RCC Lytic Bone Metastasis in

Patient Treated With Anti-PD-1 (10 mg/kg)

3/25/08 4/14/09

B7H1Control Ig

Responses may be

correlated with PD-

L1 expression

3/4 PRs in PDL-1+

tumors,

0/5 PDL-1 negative

Brahmer et al, 2010.

Phase III Anti-PD-1 study

Patients with advanced RCC, PD to prior 2 VEGF targeted therapy

Anti-PD-1

N=350

-Primary end point: PFS/OS-Prior Cytokines allowed

Study Design: International, Prospective, Randomized, Open-label, Multicenter

Everolimus

n=350

RANDOMIZATION

1:1

3º Line Treatment

Phase III TKI258 (dovitinib)

Patients with advanced RCC, PD to prior VEGF and m-TOR targeted therapy

Dovitinib

n=275

-Primary end point: PFS-Prior Cytokines allowed

Study Design: International, Prospective, Randomized, Open-label, Multicenter

Sorafenib

n=275

RANDOMIZATION

1:1

3º Line Treatment

Negative

Algoritmo CCRm – 2014?Setting Patients Therapy Options

First-line Favourable- or

intermediate-risk

Sunitinib

Pazopanib

Beva - IFN-α

HD IL-2

Cytokines

Sorafenib

Poor-risk Temsirolimus Sunitinib

Second-line Prior cytokine Axitinib

Pazopanib

Sorafenib

Sunitinib

Prior VEGF–TKI Axitinib Sorafenib

Prior VEGF–TKI Everolimus Clinical trial

Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012,

NCCN guidelines 2013SOGUG 2010

Algoritmo CCRm – 2014?Setting Patients Therapy Options

First-line Favourable- or

intermediate-risk

Sunitinib

Pazopanib

Beva - IFN-α

HD IL-2

Cytokines

Sorafenib

Poor-risk Temsirolimus Sunitinib

Second-line Prior cytokine Axitinib

Pazopanib

Sorafenib

Sunitinib

Prior VEGF–TKI Axitinib Sorafenib

Prior VEGF–TKI Everolimus Clinical trial

Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012,

NCCN guidelines 2013SOGUG 2010

Third-line Prior TKI – TKI Everolimus

Anti-PD1??

Clinical Trial

Prior TKI – mTOR Sorafenib Clinical trial

Achieving a continuum of care in mRCC

• Today, targeted agents are the standard of care for mRCC andlong-term care may be achieved through effective therapymanagement

• But what is the most effective sequencing strategy?

Long-term continuum of care in mRCC

Efficacious

first-line

agents

Efficacious

second-line

agents

Efficacious

third-line

agents

Effective therapy management

INCREASE IN SURVIVAL … >24~36 months

Long-term survival in patients with metastatic renal cell carcinoma (mRCC) in the era of new targeted therapies Five-year follow-up in a single Spanish medical institution

De Velasco G, Sepulveda JM, Ghanem I, Villacampa F, Cortés-Funes H, Castellano D;(Genito-Urinary Tumor Unit, University Hospital 12 de Octubre).

Conclusions: The survival for patients with mRCC who receive multiple lines of targeted therapy has increased to close to 4 years. These results indicate a clear shift in the evolution of mRCC but lack a great deal about what the best sequence.

(days

)

Drug Sunitinib Everolimus Temsirolimus Axitinib Sorafenib Bevacizumab Pazopanib

Pax no.(%) 57(98) 26(45) 9(15) 6(10) 22(38) 13(22) 2(3,5)

Table 2. Drugs

Survival time IC 95%

Media days(months) 1747(58) 1342-2152

Median days Not reached

Favorable risk

Survival time IC 95%

Media days(months) 1248 (41) 1022-1475

Median days 1346 (44) 904-1807

Intermediate risk

Survival time IC 95%

Media days(months) 936 (31) 662-1210

Median 776 (25,8) 157-1394

Poor risk

42

Key Side-effects Associated with Targeted Therapies in mRCC

Gastrointestinal symptoms and oral changes1–6

Fatigue and fatigue-causing side-effects1–6

Hypertension and other cardiovascular toxicities1–6

Skin toxicities1–6

Haematological toxicities1–6

1. Bhojani N, et al. Eur Urol 2008; 2. Kollmannsberger C, et al. Can Urol Assoc J 2007; 3. Pfizer Inc. SUTENT® (sunitinib) Summary of Product Characteristics, February 2009; 4. Bayer Healthcare. Nexavar® (sorafenib) Summary of Product Characteristics, 2008; 5. Wyeth Pharmaceuticals. Torisel® (Temsirolimus) Summary of Product Characteristics, 2009; 6. Roche Products Ltd. Avastin®

(bevacizumab) Summary of Product Characteristics, 2008

The patient’s profile and treatment goals, and the efficacy/toxicity ratio of the targeted agent must be

considered when selecting a first-line strategy in mRCC

43

Most Common Side-effects (≥20%) Reported with the Seven Licensed Agents for mRCC

1. Pfizer Inc. SUTENT® (sunitinib) Summary of Product Characteristics, February 2009; 2. Bayer Healthcare. Nexavar® (sorafenib) Summary of Product Characteristics, 2008; 3. Wyeth Pharmaceuticals. Torisel® (Temsirolimus) Summary of Product Characteristics, 2009; 4. Escudier B, et al. Lancet 2007; 5. Roche Products Ltd. Avastin® (bevacizumab) Summary of Product Characteristics, 2008

Sunitinib/Pazopanib/Sorafenib

Axitinib/Tivozanib

Temsirolimus/Everolimus

Bevacizumab/IFN-α4,5

Fatigue, gastrointestinal disorders, dysgeusia, decreased appetite, hypertension, HFS, skin discolouration, mucosal inflammation, rash

HTA, diarrhea, asthenia, dysphonia.

Asthenia, anemia, rash, gastrointestinal, disorders, oedema, metabolic disorders,

dyspnea, pain, cough, bacterial infections

Anorexia, fatigue/asthenia, hemorrhage, hypertension, influenza-like illness,

headache, diarrhea

• Mecanismo de acción diferente a QT Toxicidad diferente a QT.

• Mecanismo de acción diferente entre ellos Toxicidades diferentes.

• Son tratamientos prolongados Mayor riesgo de toxicidad.

• La toxicidad es muy frecuente, pero pocos G3-4 y reversibles.

• Hay que conocer la toxicidad y optimizar su manejo.

• No reducciones de dosis ni suspensiones prematuras.

Pazopanib/

/

Manejo de Efectos Secundarios

45

Mucositis funcional

Sínd. Mano-Pie

Rash Cutaneo

Baseline

Month 12

Month 5

Month 11

Pneumonitis with Everolimus Therapy

18

Possible areas of unmet medical need

Currently approved treatments are not curative, and patientsdevelop progressive disease

Evolving need for effective therapeutics with unique

mechanisms of action for patients who progress

Non clear cell histologies

Few studies are available to determine efficacy

Biomarkers, new pathways, gene profile,mechanisms of resistance !!!

Molecular Marker Expression Level Predicted Response to TKI-s1

Hypertension High Good response/PFS-OS

Hormonal syndrome Low Good response/PFS

H-Foot syndrome High Good response/PFS-OS

Clinical Marker Predicted Response to mTOR´s

Pneumonitis Good response/PFS

Lymphopenia PFS?

Castellano D, et al. Cancer T Reviews 2012.

Predicting Response to Treatment Based on Clinical Markers

Predicting Response to Treatment Based on Molecular/Genetic Markers

Molecular Marker Expression Level Predicted Response to Treatment

CAIX1 High Good response to immunotherapy

COX-21 High Good response to immunotherapy

HIF-1/HIF-22 High Good response to sunitinib

Genetic Marker Predicted Response to Treatment

Various nsSNPs3-6 Significant sunitinib toxicity/PFS

Loss of chromosomes 4, 9, or 17p4 Non-response to interleukin-2 (IL-2)

VHL loss-of-function mutation5 Good response to VEGF therapy

nsSNPs: nonsynonymous single nucleotide polymorphisms

1. Kim HL et al. J Urol. 2005;173:1496. 2. Patel PH et al. ASCO 2008. Abstract 5008.

3. Faber PW et al. ASCO 2008. Abstract 5009. 4. Jaeger E et al. ASCO 2008. Abstract 5043.

5. Choueiri TK et al. J Urol. 2008; [Epub ahead of print].

6. Garcia-Donas J. Lnacet Oncology 2011. Estudio SUTREN (SOGUG)

Estudios Fase III en Adyuvancia

Estudios Fase III en Adyuvancia

Immunotherapy ref year Numberofpts Medianfollowup

Outcomes Pvalue

IFNvsobservation Pizzocaroetal 2001 247 N/A5-yrOS:66.5%vs66.0%

NS

IFNvsobservation Messingetal 2003 283 124.0MedianOS:5.1vs7.4years

NS

High-doseIL-2vsobservation

Clarketal 2003 69 N/AMedianDFS:19.5vs36.0mo

NS

Tumorcellvaccinevsobservation

Jochametal 2004 558N/A 5-yrPFS:77.4%

vs67.8%0.02

IL-2+IFN+FUvsobservation

Atzpodienetal 2005 203 51.08-yrRFS:39%vs49%

NS

HSPPC-96vsobservation

Woodetal 2006 818 21.01.9-yrRFS:62.3%vs60.2%

NS

IL-2+IFN+FUvsobservation

NCT00053807 2006 550 N/APhaseIIIcompletedresultspending

N/A

Prior immunotherapy trials:IFN and IL2 trials

G. Pizzocaro, et al. Interferon adjuvant to radical nephrectomy in Robson stages II and IIIrenal cell carcinoma: a multicentric randomized study. J Clin Oncol, 19 (2001),p. 425E.M.Messing, etal. Phase IIIstudy of interferon alfa-NL as adjuvant treatmentfor resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol, 21(2003),p. 1214J.I.Clark, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial J Clin Oncol, 21(2003),p. 3133D. Jocham, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet, 363(2004),p. 594J. Atzpodien, et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of theGerman Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN)Br J Cancer, 92(2005),p. 843C. Wood, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96;vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet, 372(2008),p. 145

Phase II Neoadjuvant vs. Adjuvant PD-1 Blockade inNon-metastatic RCC (ECOG 1813)

• Does the preoperative dosing induce greater tumor CD8+ T cell infiltration?

– 54 pts randomized 2:186% power to detect 100% increase

• Address the need for preop doses in a larger phase III trial

Assess:

•

•

T cell infiltratePD-L1 expression

R

a

n

d

o

m

i

z

e

Baselineprimarytumorbiopsy

*Serum samples at baseline, dose 2, dose 4 in arm B,and at nephrectomy

Primary EP: safety/tolerabilitySecondary endpoints:

-CD8 T cell: Treg infiltration of kidney-CD4 T cell: Treg ratio-Tumor PD-L1 expression

Anti-PD13mg/kg x 3 doses

q 2 wks

Partial or RadicalNephrectomy

2: 1n=54

Partial or RadicalNephrectomy

Anti-PD13mg/kg x 3 doses

q 2 wks

Conclusiones La secuenciación de fármacos es la mejor opción terapéutica

en cáncer renal avanzado.

TKI´s son la 1º opcion en 1º linea de MSKCC pronóstico bueno

e intermedio. Temsirolimus en MSKCC pobre pronóstico.

Axitinib y Everolimus son opciones de 2º linea.

Unidad multidisciplinar de diagnóstico y tratamiento

Identificar nuevos factores moleculares asociados a eficacia y/o

toxicidad> Investigación básica y traslacional

Uso adecuado y/o individualizado del arsenal terapéutico> Línea de trabajo asistencial e investigacional

Aplicación real de guías terapéuticas> Generar grupos de expertos para su gestión y aplicación

KIDNEY PROSTATE BLADDERTOXICITIES

RARE TUMORSTRASLATIONAL

Chair : Daniel Castellano

Co-Chair : Nuria Lainez

Executive Secretary: Ignacio Durán

Treasurer : Arantxa González del Alba

Working Groups/Grupos de Trabajo

Grupos Colaboradores/Miembros SOGUG

Collaborate Groups/SOGUG members

Spanish Oncology Genito Urinary Group

X. García

del MuroM.A. Climent A. Font

J. García-

Donás J.L. Perez G.

EDUCATIONAL COMMITTEE/ DOCENCIA

V Symposium SOGUG-2013

Madrid19-21 de noviembre

¡ Estais todos invitados !

Muchas Gracias