Hospital Universitario Central de Asturias, Oviedo

Transcripción

1 Evidencia y criterios de eficacia para la selección del tratamiento de 1ª línea: Sunitinib Hospital Universitario Central de Asturias, Oviedo Emilio Esteban González

2 Evidencia actual en cáncer renal Recomendaciones de tratamiento? Importancia de la maximizacion de la primera línea de tratamiento Como se translada a la práctica clínica habitual? Eficacia: factor clave en la secuencia de tratamiento

3 2014 NCCN guidelines for clear-cell mrcc: First-line therapy Relapse or stage 4 and medically or surgically unresectable Predominant clear-cell histology Level 1 evidence* Sunitinib Bevacizumab + IFN-α Pazopanib Temsirolimus (for poor prognosis patients) Level 2A evidence Clinical trial High-dose IL-2 (for selected patients) Sorafenib (for selected patients) Best supportive care Level 2B evidence ** Temsirolimus (for selected patients of other risk groups) * Level 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus. Poor prognosis patients, defined as those with 3 predictors of short survival. Level 2A: Uniform NCCN consensus based on lower-level evidence, including clinical experience, that the recommendation is appropriate. Best supportive care can include palliative RT, metastasectomy, biphosphonates or RANK ligand inhibitors for bony metastases. **Level 2B: Non-uniform NCCN consensus (but no major disagreement), based on lower-level evidence, including clinical experience, that the recommendation is appropriate. NCCN = National Comprehensive Cancer Network; RT = radiation therapy. Kidney Cancer, NCCN v Clinical Practice Guidelines in Oncology. Available at

4 First-line treatment landscape Study N Median PFS (months) Final Median OS (months) Phase III Sunitinib vs. IFN-α vs. 5 p<0.001 Bev + IFN-α vs. IFN-α vs. 5.5 p<.0001 Bev + IFN-α vs. IFN-α vs. 4.9 p< Pazopanib vs. placebo vs. 2.8 p< Temsirolimus vs. IFN-α vs. 3.1 p<0.001 Pazopanib vs. sunitinib vs. 9.5 Non-inferior 26.4 vs p= vs p = vs p = vs p= vs. 7.3 p= vs Non-inferior Phase II Sorafenib vs. IFN-α vs. 5.6 p =0.504 NA 1. Motzer RJ, et al. J Clin Oncol. 2009;27: ; 2. Escudier B, et al. J Clin Oncol. 2009;27(Suppl. 15S):5020 (Abstract); 3. Rini B, et al. J Clin Oncol. 2009;27(Suppl. 15S):LBA5019 (Abstract); 4. Sternberg C, et al. J Clin Oncol. 2010;28: ; 5. NICE final appraisal determination 2010; 6. Hudes G, et al. N Engl J Med. 2007;356: ; 7. Motzer RJ et al. N Engl J Med. 2013;369: ; 8. Escudier B, et al. J Clin Oncol. 2009;27:

5 COMPARZ study design: Phase III, open-label, non-inferiority trial Enrolment criteria: Locally advanced or mrcc Clear-cell histology No prior systemic therapy Measurable disease (RECIST 1.0) KPS 70 Adequate organ function N=927 N=1,110 Randomised 1:1 Pazopanib 800 mg QD Continuous daily dosing Sunitinib 50 mg QD Schedule 4/2 Study start: August 2008 VEG Phase III n=927 VEG Phase II (Asia) n=183 COMPARZ: 1,110 patients Motzer RJ, et al. N Engl J Med. 2013;369:

6 Mean change from baseline COMPARZ study: Timing of assessments Week 6 Week 6 Week 6 Sunitinib Pazopanib Disease assessments QoL assessments Week 4 Week 4 Week 4 Time Motzer RJ, et al. N Engl J Med. 2013;369:

7 COMPARZ Study: PFS At a Glance HR: 1.07 ( ) HR: ( ) HR: 1.05 ( ) Análisis Asian Estudio substudy Asiá co (IRC) Análisis Per Por protocol Protocolo (IRC) analysis analysis Pazopanib Sutent Pazopanib Sunitinib Análisis ITT analysis ITT (IRC) Motzer RJ, et al. N Engl J Med. 2013;369: ; Guo et al. J Clin Oncol 31, 2013 (suppl 6; abstr 366)

8 Motzer RJ, et al. N Engl J Med 2013;369(8): COMPARZ Study: AEs Leading To Drug Discontinuation

9 COMPARZ: HRQoL assessments FACIT-F and FKSI-19 only validated HRQoL assessments scales reported 1 Difference (favouring pazopanib if >0) 2 p-value Minimally important difference* FACIT-F 2.32 < FKSI-19 total *Smallest difference in score in the domain of interest that patients perceive as important in either benefit or harm and that would lead clinicians to consider a change in patients therapy Although differences were statistically significant, they were not clinically meaningful Cella. Oncologist 2011; 2. Motzer et al. NEJM 2013; 3. Cella et al. J Rheumatol 2005; 4. Cella et al. Value Health 2007

10 First-line treatment guidelines for clear-cell mrcc: ESMO 2013 Risk status Recommendation Level of evidence Favorable or intermediate Sunitinib Bevacizumab + IFN-α Pazopanib I, A II, A II, A Poor risk Temsirolimus II, A Escudier B, et al. Ann Oncol. 2012;23(Suppl 7):vii65 71.

11 Uso expandido sunitinib: Características de los pacientes* 4564 pacientes incluidos de la práctica clínica habitual Se incluyeron pacientes que tradicionalmente no son incluidos en los estudios de Fase III Total n % 4,371pts** Age, median (range) 59 (19-89) Age >65yrs 1,418 32% Prior nephrectomy 3,873 89% Pts + brain mets 321 7% PS % Nonclear cell % 1 metastatic site % >2 metastatic site 3,489 80% Prior cytokine 2,974 68% Prior antiangogenic 238 5% *characteristics +/- prior cytokine similar * * 4,371 / 4,564pts received 1 cycle Gore et al, Lancet Oncol 2009

12 Uso expandido sunitinib: Supervivencia Libre de Progresión Gore M, et al. Lancet Oncol. 2009; 10: Gore et al, Lancet Oncol 2009

13 Tolerabilidad Sunitinib, EA s Grado 3/4 Motzer JCO 2009 Gore Lancet Oncol 2009 Gore et al, Lancet Oncol

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15 Al iniciar el tratamiento, el paciente debe de ser consciente de los factores que influyen en el resultado Dosis Manejo Efectos Secundarios Eficacia Óptima Duración Tratamiento

16 OS probability Probability of PFS Probability of OS 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, 10.9 months (95% CI: 0.6, 12.0) Absent (n=187) Median, 6.4 months (95% CI: 4.7, 8.0) Time (months) KM estimate of OS by HFS status 3 treatment efficacy With HFS (n=179) Median: 38.2 months Without HFS (n=591) Median: 18.9 months p< 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: 13.0,18.6) p< Time (months) p< With hypertension (n=442) Median OS, 30.9 months (95% CI: 27.9 to 33.7) Without hypertension (n=92) Median OS, 7.2 months (95% CI: 5.6 to 10.7) Time (months) Time (months) 1. Davis MP, et al. ESMO 2011; Abstract 1139; 2. Donskov F, et al. ESMO 2011; Abstract 1141; 3. Puzanov I, et al. ESMO 2011; Abstract 1444.

17 Fraction of patients not progressed Fraction of patients surviving Why the management of sunitinib therapy is important Time to tumor progression OS AUC >Median (N=120) AUC >Median (N=120) 1.0 AUC <Median (N=117) 1.0 AUC <Median (N=117) * Historical placebo median * Historical placebo median p=0.001 Relative risk p=0.014 Relative risk Days Days 600 Houk BE, et al. Cancer Chemother Pharmacol. 2010;66: ; Yang JC, et al. N Engl J Med

18 Concentración de Pazopanib eficacia y toxicidad

19 Una mayor duración de tratamiento con Sunitinib proporciona una mayor respuesta al tratamiento Las tasas de respuesta del fase III se incrementaron con una mayor duración del tratamiento : Sunitinib (n=374) IFN-α (n=373) Análisis Duración, ms (rango) ORR, % (95%CI) Duración, ms (rango) ORR, % (95%CI) p Interino 6 (1 15) 31 (26 36) 4 (1 13) 6 (4 9) <0.001 Final 11 (<1 41) 39 (34 44) 4 (<1 40) 8 (6 12) <0.001 Los pacientes se deben mantener en tratamiento mientras se observe un beneficio Motzer RJ, et al. N Engl J Med 2007; Motzer RJ, et al. J Clin Oncol 2009.

20 Respuestas completas con sunitinib Sunitinib-treated patients: n=59; sorafenib-treated patients: n=5 Long lasting CRs can occur after TKI treatment alone or when combined with local treatment Relapsing patients responded well to further therapy Median time to CR was 12.6 months in patients receiving TKIs alone, highlighting the importance of maintaining therapy Albiges L, et al. J Clin Oncol. 2012;30:

21 RAINBOW Study: Sunitinib management by using individualised schemes Rate (%) Retrospective observational study of mrcc patients administered sunitinib on a 2/1 schedule* Grade 3 toxicities Fatigue Hypertension *Patients moved to 2/1 schedule due to treatment-related toxicities during initial therapy using 4/2 schedule; p<0.001; p= Off-label data presented. Bracarda et al. ASCO GU 2014

22 RAINBOW Study: Eficacia en pacientes que pasaron de sunitinib 50 MG 4:2 a 2:1 Group A (n=208) [4/2 2/1] Group B (n=41) [2/1] Median treatment duration, months Median PFS, months (95% CI) 28.2 [ ] 38.6 ( ) ( ) Potential improvement of PFS with an alternative 2/1 schedule Results observed in the group B should be analyzed taking into account poorer patient characteristics. Bracarda et al. ASCO GU 2014

23 Ajustes de dosis sunitinib no condicionan la eficacia de sunitinib Análisis retrospectivos de estudios de fase II y fase III sunitinib in mrcc 1 Pacientes con reducciones de dosis en esquemas de 4/2 y con reducciones de dosis alcanzan una mayor PFS que aquellos que no tuvieron un ajuste de dosis Fase III trial Fase II trial Con reducción de dosis Sin reducción de dosis Con reducción de dosis Sin reducción de dosis n Eventos, n (%) 107 (55.2) 104 (57.5) 28 (54.9) 58 (61.1) Mediana PFS, meses (95% CI) 14.0 ( ) 8.1 ( ) 13.4 ( ) 5.8 ( ) 1. Khosravan R, et al. ASCO-Genitourinary Cancers Symposium Annual Meeting 2012: Abstract 363

24 RECORD-3 trial S C R E E N R A N D O M I Z E * 1:1 Everolimus 10 mg/day Sunitinib 50 mg/day** Cross-over upon progression Sunitinib 50 mg/day** Everolimus 10 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 2013; Abstract 4504.

25 RECORD-3 Trial Confirms first-line TKI is better than mtor inhibitor

26 The ESPN Trial Nizar M. Tannir et al

27 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 0/1 1 measurable lesion Sorafenib 400 mg Twice daily Randomization 1:1 Sunitinib 50 mg Once daily* Progression or intolerable toxicity Sunitinib 50 mg Once daily* Sorafenib 400 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 v1.0) and at treatment end*** Michel MS, Oral Presentation at ASCO GU 2014

28 SWITCH Study

29 Sunitinib base para la planificación de una secuencia óptima en cáncer renal avanzado 3rd Line T size 1st Line 2nd Line time Sunitinib TKI / mtor mtor / TKI Patients on >8 months first-line treatment Patients on <8 months first-line treatment OS 14.3 months 9.9 months P-value p<0.0001, HR 1.53 (95%CI ) Duration of first-line TTP predicts overall survival from second-line in an analysis of pts Heng DYC. ASCO 2010

30 Experiencia Basada en estudios Comparativos 1st-line 2nd-line (mslp) 3rd-line Axitinib (AXIS) 4.8 m 4 m Sunitinib Everolimus (RECORD-1) Temsirolimus (INTORSECT) 4.6 m 4.3 m Everolimus Dovitinib Sorafenib Sorafenib (AXIS/INTORSECT) 3.4 /3.9 m SG: 30 m. SG: m. SG: 11 m.

31 Conclusiones: Sunitinib en 1ª línea de tratamiento 1. Representa el tratamiento con mayor grado de evidencia y experiencia en pacientes con buen e intermedio pronóstico 2. Su efectividad se reproduce en la práctica clínica y en diferentes grupos de pacientes 3. Prevención y manejo apropiado de los efectos adversos para maximizar la duración del tratamiento y optimizar resultados 4. Sunitinib representa la piedra angular para el tratamiento integral y el resultado global en pacientes con CCRm