¿EXISTE UNA SECUENCIA ÓPTIMA? ÁLVARO PINTO Servicio de Oncología Médica Hospital Universitario...
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Transcript of ¿EXISTE UNA SECUENCIA ÓPTIMA? ÁLVARO PINTO Servicio de Oncología Médica Hospital Universitario...
¿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