¿EXISTE UNA SECUENCIA ÓPTIMA?

ÁLVARO PINTOServicio de Oncología Médica

Hospital Universitario La Paz – IdiPAZ, Madrid

PERSONALIZANDO EL TRATAMIENTO DEL CÁNCER RENAL

PRIMERA LÍNEA

Agent 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

A LA PROGRESIÓN…

• ¿Cambiar a otro antiangiogénico?

• ¿Cambiar a un inhibidor de mTOR?

TKI-mTOR

Everolimus + BSC(n=272)

Placebo + BSC(n=138)

Upon disease progression

RANDOMISATION

2:1

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

N=410

Everolimus Placebo

ORR 1,8 % 0 %

PFS 4,9 meses 1,9 meses

OS 14,8 meses 14,4 meses

TKI-mTOR

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)

N=723

TKI-TKI

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

duration of response, safety, QoL (FKSI and EQ-5D)10

RANDOMIZATION

Axitinib 5 mg b.i.d.

Rini BI et al. ASCO 2011 Abstract 4503

12Post-cytokines Post-Sunitinib

13

PFS by Prior Response to Sunitinib:Axitinib vs Sorafenib

Time (months)

Pro

bab

ilit

y o

f P

FS

Axitinib

Time (months)

Sorafenib

14

1.00

0.80

0.60

0.40

0.20

0

1.00

0.80

0.60

0.40

0.20

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

Non-respondersResponders

0

n 95% CI

4.84.6

4.2–6.72.8–6.3

mPFS mo

145 47

Non-respondersResponders

n 95% CI

3.04.7

2.8–4.62.9–6.6

mPFS mo

143 52

DISEÑO DE LOS ENSAYOSDiseño Axitinib Everolimus

Estudio Randomizado SI (1:1) SI (2:1)

Comparador Sorafenib Placebo

Numero de pacientes 723 416

Población de pacientes

2ª línea tras solo Sunitinib

Segunda línea exclusiva

389 (54%) pacientes 194 en cada brazo

Población Mixta

56 (13%) pacientes43 brazo de everolimus 13 brazo de placebo

MSKCC FavorableIntermedio

PobreNA

28% 37%33% 2%

29% 56%15%

Permita la entrada de pacientes intolerantes a TKI previo

NO SI

AXIS RECORD-1

All Grades ≥ Grade 3 All Grades ≥ Grade 3

ADVERSE EVENTS

Diarrhea 55% 11% Stomatitis 44% 4%

Hypertension 40% 16% Infections 37% 10%

Fatigue 39% 11% Asthenia 33% 3%

Decreased appetite 34% 5% Fatigue 31% 5%

Nausea 32% 3% Diarrhea 30% 1%

Dysphonia 31% 0% Cough 30% <1%

Hand-foot syndrome 27% 5% Rash 29% 1%

Weight decreased 25% 2% Nausea 26% 1%

Vomiting 24% 3% Anorexia 25% 1%

Asthenia 21% 5% Peripheral edema 25% <1%

Constipation 20% 1% Dyspnea 24% 7%

ABNORMAL LABS

Elevated creatinine 55% 0% Anemia 92% 13%

Hypocalcemia 39% 1% Elevated cholesterol 77% 4%

Anemia 35% <1% Elevated triglycerides 73% <1%

Lymphopenia 33% 3% Elevated glucose 57% 15%

AXIS RECORD-1

All Grades ≥ Grade 3 All Grades ≥ Grade 3

ADVERSE EVENTS

Diarrhea 55% 11% Stomatitis 44% 4%

Hypertension 40% 16% Infections 37% 10%

Fatigue 39% 11% Asthenia 33% 3%

Decreased appetite 34% 5% Fatigue 31% 5%

Nausea 32% 3% Diarrhea 30% 1%

Dysphonia 31% 0% Cough 30% <1%

Hand-foot syndrome 27% 5% Rash 29% 1%

Weight decreased 25% 2% Nausea 26% 1%

Vomiting 24% 3% Anorexia 25% 1%

Asthenia 21% 5% Peripheral edema 25% <1%

Constipation 20% 1% Dyspnea 24% 7%

ABNORMAL LABS

Elevated creatinine 55% 0% Anemia 92% 13%

Hypocalcemia 39% 1% Elevated cholesterol 77% 4%

Anemia 35% <1% Elevated triglycerides 73% <1%

Lymphopenia 33% 3% Elevated glucose 57% 15%

AXIS RECORD-1

All Grades ≥ Grade 3 All Grades ≥ Grade 3

ADVERSE EVENTS

Diarrhea 55% 11% Stomatitis 44% 4%

Hypertension 40% 16% Infections 37% 10%

Fatigue 39% 11% Asthenia 33% 3%

Decreased appetite 34% 5% Fatigue 31% 5%

Nausea 32% 3% Diarrhea 30% 1%

Dysphonia 31% 0% Cough 30% <1%

Hand-foot syndrome 27% 5% Rash 29% 1%

Weight decreased 25% 2% Nausea 26% 1%

Vomiting 24% 3% Anorexia 25% 1%

Asthenia 21% 5% Peripheral edema 25% <1%

Constipation 20% 1% Dyspnea 24% 7%

ABNORMAL LABS

Elevated creatinine 55% 0% Anemia 92% 13%

Hypocalcemia 39% 1% Elevated cholesterol 77% 4%

Anemia 35% <1% Elevated triglycerides 73% <1%

Lymphopenia 33% 3% Elevated glucose 57% 15%

Patients with mRCC and PD on first-line sunitinib

(N = 512)Stratification factors: Duration of sunitinib therapy

(≤ or > 6 mos) MSKCC risk group Histology (clear cell or

non–clear cell) Nephrectomy status

RANDOMIZE

Temsirolimus 25 mg IV weekly*

(n = 259)

1:1

Sorafenib 400 mg oral BID*

(n = 253)

Treat until PD, unacceptable toxicity, or discontinuation for any other reason

Primary endpoint:

PFS (per IRC)

ClinicalTrials.gov. NCT00474786.

*Dose reductions were allowed: temsirolimus (to 20 mg, then 15 mg), sorafenib (to 400 mg/day, then every other day).

Estudio INTORSECT

36.5 vs 29.3 months

50.7 vs 37.8 months

CONCLUSIONES• Axitinib y Everolimus con evidencia basada en ensayo

fase III

• Secuencia TKI-TKI• Fase III puro de 2ª línea• Mayor número de pacientes tratados con esta

secuencia en contexto de ensayos clínicos

• AXITINIB como estándar en 2ª línea• Elección en función de:

• Toxicidad de la línea previa – comorbilidades• ¿Respuesta a la 1ª línea? No parece…

MUCHAS GRACIAS POR SU ATENCIÓNÁLVARO PINTO

Servicio de Oncología Médica

Hospital Universitario La Paz – IdiPAZ, Madrid