¿EXISTE UNA SECUENCIA ÓPTIMA? ÁLVARO PINTO Servicio de Oncología Médica Hospital Universitario La Paz – IdiPAZ, Madrid PERSONALIZANDO EL TRATAMIENTO DEL CÁNCER RENAL
PRIMERA LÍNEA AgentNORR (%) Median PFS (months) Median OS (months) Sunitinib vs IFN-a vs 12 P< vs 5 P< vs 21.8 P=0.051 Bevacizumab + IFN-a vs IFN-a 2, vs 13 P= vs 5.4 P< vs 21.3 P= Bevacizumab + IFN-a vs IFN-a 4, vs 13 P< vs 5.2 P< vs 17.4 P=0.069 *Pazopanib vs placebo 6, vs 3 † P< vs 2.8 P< vs 20.5 † P=0.224 Poor risk patients Temsirolimus vs IFN-a 8* vs 4.8 NS 5.5 vs 3.1 P< 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 R A N D O M I S A T I O N 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
EverolimusPlacebo ORR1,8 %0 % PFS4,9 meses1,9 meses OS14,8 meses14,4 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 RANDOMIZATIONRANDOMIZATION Axitinib 5 mg b.i.d. Rini BI et al. ASCO 2011 Abstract 4503
12 Post-cytokinesPost-Sunitinib
13
PFS by Prior Response to Sunitinib: Axitinib vs Sorafenib Time (months) Probability of PFS Axitinib Time (months) Sorafenib Non-responders Responders 0 n 95% CI – –6.3 mPFS mo Non-responders Responders n 95% CI – –6.6 mPFS mo
DISEÑO DE LOS ENSAYOS DiseñoAxitinibEverolimus Estudio RandomizadoSI (1:1)SI (2:1) ComparadorSorafenibPlacebo Numero de pacientes Población de pacientes 2ª línea tras solo Sunitinib Segunda línea exclusiva 389 (54%) pacientes 194 en cada brazo Población Mixta 56 (13%) pacientes 43 brazo de everolimus 13 brazo de placebo MSKCC Favorable Intermedio Pobre NA 28% 37% 33% 2% 29% 56% 15% Permita la entrada de pacientes intolerantes a TKI previo NOSI
AXISRECORD-1 All Grades≥ Grade 3All Grades≥ Grade 3 ADVERSE EVENTS Diarrhea55%11%Stomatitis44%4% Hypertension40%16%Infections37%10% Fatigue39%11%Asthenia33%3% Decreased appetite34%5%Fatigue31%5% Nausea32%3%Diarrhea30%1% Dysphonia31%0%Cough30%<1% Hand-foot syndrome27%5%Rash29%1% Weight decreased25%2%Nausea26%1% Vomiting24%3%Anorexia25%1% Asthenia21%5%Peripheral edema25%<1% Constipation20%1%Dyspnea24%7% ABNORMAL LABS Elevated creatinine55%0%Anemia92%13% Hypocalcemia39%1%Elevated cholesterol77%4% Anemia35%<1%Elevated triglycerides73%<1% Lymphopenia33%3%Elevated glucose57%15%
AXISRECORD-1 All Grades≥ Grade 3All Grades≥ Grade 3 ADVERSE EVENTS Diarrhea55%11%Stomatitis44%4% Hypertension40%16%Infections37%10% Fatigue39%11%Asthenia33%3% Decreased appetite34%5%Fatigue31%5% Nausea32%3%Diarrhea30%1% Dysphonia31%0%Cough30%<1% Hand-foot syndrome27%5%Rash29%1% Weight decreased25%2%Nausea26%1% Vomiting24%3%Anorexia25%1% Asthenia21%5%Peripheral edema25%<1% Constipation20%1%Dyspnea24%7% ABNORMAL LABS Elevated creatinine55%0%Anemia92%13% Hypocalcemia39%1%Elevated cholesterol77%4% Anemia35%<1%Elevated triglycerides73%<1% Lymphopenia33%3%Elevated glucose57%15%
AXISRECORD-1 All Grades≥ Grade 3All Grades≥ Grade 3 ADVERSE EVENTS Diarrhea55%11%Stomatitis44%4% Hypertension40%16%Infections37%10% Fatigue39%11%Asthenia33%3% Decreased appetite34%5%Fatigue31%5% Nausea32%3%Diarrhea30%1% Dysphonia31%0%Cough30%<1% Hand-foot syndrome27%5%Rash29%1% Weight decreased25%2%Nausea26%1% Vomiting24%3%Anorexia25%1% Asthenia21%5%Peripheral edema25%<1% Constipation20%1%Dyspnea24%7% ABNORMAL LABS Elevated creatinine55%0%Anemia92%13% Hypocalcemia39%1%Elevated cholesterol77%4% Anemia35%<1%Elevated triglycerides73%<1% Lymphopenia33%3%Elevated glucose57%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 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. NCT *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 ATENCIÓN ÁLVARO PINTO Servicio de Oncología Médica Hospital Universitario La Paz – IdiPAZ, Madrid