LOGROS Y RETOS EN LA 1ª LÍNEA DE TRATAMIENTO DEL CARCINOMA RENAL

Transcripción

1 LOGROS Y RETOS EN LA 1ª LÍNEA DE TRATAMIENTO DEL CARCINOMA RENAL Hospital Universitario Central de Asturias Servicio de Oncología Médica Emilio Esteban González

2 26-212: Complete change in RCC treatment paradigm Approved agents in RCC Sorafenib (US 25, EU 26 3,4 SuniSnib (US & EU 26 3,4 High- dose IL- 2 approved in the US (1995. High treatment- related toxicity; small number of durable responses 2 Temsirolimus and Bevacizumab plus IFN (US & EU 27 3,4 Axitinib (US & EU 29 Early 194s: experiments with cytotoxic chemotherapy 1 Everolimus (US & EU 29 3,4 Cabozantinib Nivolumab 215 Early 198s: IFN- α and high- dose IL- 2 used for RCC treatment Pazopanib (US 29, EU 21 3,4 1. Abeloff MD, et al. Clinical Oncology 4th ed. Philadelphia, PA. 2. Coppin C, et al. Cochrane Database Syst Rev 25;1:CD U.S. Food and Drug AdministraSon ( 4. European Medicines Agency (hxp://

3 Tabla 2. Grupos Pronóstico CRm Criterios MSKCC Mediana Criterios de Heng (13 Mediana Tratamiento con CK (12 SG (meses Tratamiento con Antiangiogénicos SG (meses Factores Pronóstico 1. KPS < 8 2. Diagnostico al tratamiento < 1año 3. Anemia 4. Hipercalcemia 5. Elevación LDH 1. KPS < 8 2. Diagnostico al tratamiento < 1año 3. Anemia 4. Hipercalcemia 5. Neutrofilia 6. Trombocitosis Grupo Favorable Ningún factor 2 Ningún factor 38 Grupo Intermedio 1-2 factores factores 27 Grupo Malo > 2 Factores factores 8,8 Lactate dehydrogenase (LDH Memorial Sloan Kettering Cancer Center (MSKCC Citokinas (CK(Interferon Supervivencia Global (SG KPS: Estado general por índice de Karnofsky

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5 Tres factores claves para el éxito de la terapia en CCRm Dosis Manejo Efectos Secundarios Eficacia Óptima Duración Tratamiento

6 SUNITINIB Y EXPOSICION A LA DROGA RELACIÓN CON RESULTADOS Time to tumour progression Overall survival 1. High AUC SS (n=67 Low AUC SS (n=79 1. High AUC SS (n=67 Low AUC SS (n= TTP probability OS probability Time (days Time (days 6 Houk et al. Cancer Chemother Pharmacol 21 High AUC SS.8 µg h/ml; low AUC SS <.8 µg h/ml

7 Probability of PFS Some adverse events are biomarkers of KM estimate of PFS by the presence or absence of any-grade asthenia/fatigue 1 Present (n=583 Median, 1.9 months (95% CI:.6, 12. Absent (n=187 Median, 6.4 months (95% CI: 4.7, Time (months treatment efficacy Probability of OS KM estimate of OS by neutropenia severity grade 2 Grade 2 (n=164 Median, 25.2 months (95% CI: 21.3, 32.6 Grade <2 (n=252 Median, 15.7 months (95% CI: 13.,18.6 p< Time (months OS probability KM estimate of OS by HFS status 3 With HFS (n=179 Median: 38.2 months Without HFS (n=591 Median: 18.9 months p<.1 p<.1 With hypertension (n=442 Median OS, 3.9 months (95% CI: 27.9 to 33.7 Without hypertension (n=92 Median OS, 7.2 months (95% CI: 5.6 to Time (months Time (months 1. Davis MP, et al. ESMO 211; Abstract 1139; 2. Donskov F, et al. ESMO 211; Abstract 1141; 3. Puzanov I, et al. ESMO 211; Abstract 1444.

8 Pazopanib: Mayor concentración plasmática (Cmin1 mejor Supervivencia Libre de Progresión 1. Week 4 C min 2.6 (n = 62 Week 4 C min > 2.6 (n = Log-rank P =.41 Proportion surviving Median PFS = 2.3 Median PFS = Time, weeks! Week 4 plasma pazopanib C min >2.6 µg/ml was associated with significantly better PFS than C min 2.6 µg/ml (p= Suttle et al. J Clin Oncol 21; 28(Suppl: Abstract 348 and poster. 8

9 Relación entre la concentración plasmática de pazopanib y la incidencia de toxicidad 8 Week 12 pazopanib C min 6 Q1 Q2 Q3 Q4 Patients (% 4 2 All patients started on 8 mg/day dose 1. Lin et al. ASCO GU 211; Abstract 345 (Poster. 9

10 RECORD-3 trial confirms first-line TKI is better than mtor inhibitor S C R E E N R A N D O M I Z E * 1:1 Everolimus 1 mg/day Sunitinib 5 mg/day** Cross-over upon progression Sunitinib 5 mg/day** Everolimus 1 mg/day Study endpoints Primary PFS 1 st -line Secondary Combined PFS ORR 1 st -line OS Safety N=471 First-line Second-line Median follow-up 22.7 months *Stratified by MSKCC prognostic factors; **4 weeks on, 2 weeks off. Motzer RJ et al. ASCO 213; Abstract 454.

11 RECORD-3 Study Cumulative event-free probability (% Everolimus Sunitinib RECORD-3: Primary endpoint: First-line PFS Time (months Number of patients still at risk Everolimus (events/n=182/238 Sunitinib (events/n=158/ K-M Median PFS (mo Everolimus Sunitinib HR = 1.43 Two-sided 95% CI [1.15, 1.77] Motzer RJ et al. ASCO 213; Abstract 454. Cumulative event-free probability (% EVE!SUN SUN!EVE RECORD-3: Overall survival EVE!SUN (events/n=18/238 SUN!EVE (events/n=96/ Time (months Number of patients still at risk K-M Median OS (mo EVE!SUN SUN!EVE HR = 1.24 Two-sided 95% CI [.94, 1.64] Motzer RJ et al. ASCO 213; Abstract

12 SWITCH Phase 3 open-label study design 365 patients mrcc unsuitable for cytokines and no prior systemic therapy Age >18 and 85 years ECOG PS /1 1 measurable lesion Sorafenib 4 mg Twice daily Randomization 1:1 Sunitinib 5 mg Once daily* Progression or intolerable toxicity Sunitinib 5 mg Once daily* Sorafenib 4 mg Twice daily Primary endpoint Total PFS** Patients enrolled in Germany, Austria and The Netherlands Stratified by MSKCC prognostic group (favourable or intermediate Efficacy assessed every 12 weeks (RECIST v1. and at treatment end*** Michel MS, Oral Presentation at ASCO GU 214

13 SWITCH Study PFS probability (% SWITCH primary endpoint: Total progression-free survival n Median (one-sided 95% CI PFS months So Su (>11.5, <15. Su So (>1.5, <17.2 HR = 1.1 (one-sided 95% CI: <1.27 p value for superiority=.54 PFS probability (% SWITCH: 1st-line progression-free survival n Median (one-sided 95% CI PFS months So Su (>5.5, <7.9 Su So (>7.1, <11.2 HR = 1.19 (one-sided 95% CI: <1.47 p value for superiority=.92 No. patients So Su 182 Su So Months from randomization Michel MS, Oral Presentation at ASCO GU 214 No. patients So Su 182 Su So Months from randomization Michel MS, Oral Presentation at ASCO GU 214

14 Sunitinib has changed mrcc treatment paradigm 32 months Median OS (Months * 213 * RECORD Sequencing SWITCH Sequencing Interferon era TKIs period Escudier B, et al. Lancet 27; Motzer RJ, et al. J Clin Oncol 29; Motzer ASCO 213

15 Sunitinib in the cornerstone to define an optimal treatment sequence in mrcc Overall Survival 32 months 3rd Line 4rd T size 1st Line Sunitinib 2nd Line TKI / Anti-PD-L1 / mtor Anti-PD-L1 / TKI / mtor time Patients on >8 months first-line treatment Patients on <8 months first-line treatment OS 14.3 months 9.9 months P-value p<.1, HR 1.53 (95%CI DuraAon of first- line TTP predicts overall survival from second- line in an analysis of 1.84 pts Heng DYC. ASCO 21

16 Resultados basados en estudios comparasvos 1st-line (mslp 2nd-line (mslp 3rd-line 9-11 m AxiSnib (AXIS 4.8 m 4 m SuniSnib Everolimus (RECORD- 1 Temsirolimus (INTORSECT 4.6 m 4.3 m Everolimus DoviSnib Sorafenib Sorafenib (AXIS/INTORSECT 3.4 /3.9 m SG: 31 m. SG: m. SG: 11 m.

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18 Vacuna AGS-3 inductora de una respuesta adactativa AGS-3 PME-CD4L DC Antigen & CD4L expression Antigen processing MHC Antigen peptide TCR T cell Granzyme B IFN-y CD8 + CD28 + CD45RA? CTL CD4 Digestion CD8/86 CD28 IL-2 TNF-ɑ RNA electroporation IL Amin A, et al. ASCO 214. Abstract 4524 and poster.

19 Inmnoterapia basado en bloqueo de CTLA4 y PD-1 (Célula dendrítica: CTLA4 1. McDermott DF, et al. ASCO-GU 213. Abstract 351 and poster. 2. Keir ME, et al. Annu Rev Immunol 28;26: Pardoll DM. Nat Rev Cancer 212;12:

20 Estudios en CRa con Vacunas Eligibility criteria: Metastatic and/or locally advanced ccrcc Favourable/intermediate risk HLA-A*2-positive No prior systemic therapy N=33 R A N D O M I S E D IMA91 + GM-CSF + sunitinib Sunitinib IMPRINT randomised Phase III trial Study completion: July 215 Diagnosis of advanced kidney cancer Surgery Tumour sample taken N=45 R A N D O M I S E D Sunitinib + AGS-3 Sunitinib ADAPT randomised Phase III trial Study completion: April 216 AGS-3, autonomous dendritic cell product; ccrcc, clear cell renal cell carcinoma; GM-CSF, granulocyte macrophage colony-stimulating factor; IMA91, consists of multiple tumour-associated peptides; SOC, standard of care ADAPT study trial highlights. Available at: Accessed September 19, 214; (NCT ; (NCT126591

21 ESTUDIO IMPRINT Eligibility: Advanced/mRCC with clear-cell histology No prior systemic therapy Candidate for treatment with sunitinib Favourable/ intermediate-risk N=33 R A N D O M I S A T I O N IMA91 plus GM-CSF added to sunitinib* Sunitinib KLM=.4.#<#$=.,J.*G&%N&%CH.%&('>=;'$.-'##%&'N,&*.!%(O.PQL834.?$G*.RQE1BI.'*.'>SG-'&(.!%$$.C=.'??$%=>.J,.'.?=%,>.,J.T.;,&(O*.!O%$=.#,&N&G%&+.(='(;=&(.!%(O.*G&%N&%C.!"#$%&'&$('*+,-./*-+ Overall Survival (S Favorable All patients HR: 1.34; p =.8* Con: Median OS: n.r. Vac: Median OS: 33.1 mo Con: 33.7 mo Vac: n.r. Intermediate HR:.82; p =.59** HR: 1.52; p <.5** :%;'<.=&>?,%&(*@.AB. B=#,&>'<.=&>?,%&(*@.AB.%&.C%,;'D=E>=F&=>.*GC+,G?H.:IBH.(G;,G. =*?,&*=H.*'J=(<.'&>.(,$='C%$%(<H.#=$$G$'.%;;G&,;,&%(,%&+.!!!"#$%&%#'$(%'$*"+,-. / n.r. = not reached *log Rank stratified on risk group **unstratified log Rank Con: n.r. '('+!"#$%&#'((+1234# Vac: 27.8 mo

22 Previsión Nivolumab vs. everolimus 1 Phase 3; Sept 216 Nivolumab vs. nivolumab + bevacizumab vs. nivolumab + ipilimumab 2 Phase 2; Nov 218 Nivolumab + ipilimumab vs. sunitinib 3 Phase 3; Sept Primary completion date 1. NCT NCT Pembrolizumab vs. pazopanib vs. pembrolizumab + pazopanib 4 Phase 1; Apr 22 MPDL328A (anti- PD-L1 + bevacizumab vs. sunitinib Phase 3; Nivolumab + sunitinib vs. sunitinib Phase 3; NCT NCT

23 Conclusiones En 1ª línea sunitinib sigue demostrando la evidencia más robusta de beneficio terapéutico para pacientes con CRA con histología de célula clara y considerados de buen e intermedio pronóstico Poblaciones Especiales La eficacia terapéutica se basa en una optima utilización en dosis y duración del tratamiento El reto presente y futuro la optimización de la antiangiogénis e inmunoterapia