Tumores RAS nativo: tratamiento 1ª línea A favor del bevacizumab. P. García Alfonso Sr. Oncología Médica HGU Gregorio Marañón de Madrid

Transcripción

1 Tumores RAS nativo: tratamiento 1ª línea A favor del bevacizumab P. García Alfonso Sr. Oncología Médica HGU Gregorio Marañón de Madrid

2 Time (months) Supervivencia global en el Cáncer Colorrectal metastásico 30 Median OS s 1990s 2000s 2010 BSC 5-FU *Not approved by the EMA or for use in the Czech Republic Irinotecan 1 Capecitabine 2 1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004; 3. Rothenberg, et al. JCO Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012 Oxaliplatin 3 Bevacizumab 4 Cetuximab 5,6 Panitumumab 7 Aflibercept 8 Regorafenib 9 *

3 2012 ESMO consensus guidelines Schmoll HJ et al. Ann Oncol 2012;23:

4 La efficacia depende de la primera línea Parameter 1st line 2nd line Later lines ORR (%)* , , ,9 Median PFS (months)* , , ,9 *Range of results for targeted treatment arms of key Phase II and III trials (KRAS 12/13 wt for EGFR inhibitor trials) Conclusion: 1st linea de tratamiento es crítica en la OS 1. Maughan TS, et al. Lancet 2011;377: ; 2. Saltz LB, et al. J Clin Oncol 2008;26: ; 3. Bokemeyer C, et al. Ann Oncol 2011;22: ; 4. Hurwitz H, et al. New Engl J Med 2004;350: ; 5. Langer C, et al. ESMO 2008 (Abstract No. 385P); 6. Peeters M, et al. J Clin OncoI 2010;28: ; 7. Giantonio BJ, et al. J Clin Oncol 2007;25: ; 8. Grothey A, et al. Lancet 2013;38: ; 9. Karapetis CS, et al. N Engl J Med 2008;359:

5 Con que biológico empezamos? Antiangiogénicos? Anti-EGFR?

6 Cúal es la primera línea de tratamiento más activa para pacientes con CCRm Medicina basada en la evidencia. Eficacia/ Toxicidad 1st line Biomarcadores predictivos 2nd line 3rd line Disponibilidad de los fármacos (costes)

7 Angiogenesis is mediated through the interaction between VEGF and its receptors 1 5 The interaction of the VEGF ligand with VEGF receptors is a key mediator of angiogenesis VEGF VEGF receptor Facilitates survival of existing endothelial cells 1,2,6 8 Contributes to vascular abnormalities 1,2,6,7,9 Stimulates new vessel growth 1,2,6 8,10 Increases vessel permeability 11,12 1. Ferrara. Endocr Rev 2004; 2. Hicklin, Ellis. JCO 2005; 3. Baka, et al. Expert Opin Ther Targets 2006; 4. Morabito, et al. Oncologist 2006; 5. de Vries, et al. Science 1992; 6. Bergers, Benjamin. Nat Rev Cancer 2003; 7. Jain. Science 2005; 8. Gerber, Ferrara. Cancer Res 2005; 9. Jain. Nat Med 2001; 10. Inoue, et al. Cancer Cell 2002; 11. Margolin. Curr Oncol Rep 2002; 12. Hu, et al. Am J Pathol

8 Eficacia de las combinaciones de Bevacizumab

9 Bevacizumab for 1L treatment of mcrc: significant benefit with different chemotherapy regimens in phase III trials Regimen Tx line N Post-study therapy ORR (%) Median PFS (months) Median OS (months) IFL 2L: ~50% IFL + bevacizumab 1 1L 813 2L: ~50% 35 45* * * XELOX/FOLFOX XELOX/FOLFOX + bevacizumab 2 1L 1,401 2L: 53% 2L: 46% * Capecitabine 68% Capecitabine + bevacizumab 3 1L % * Capecitabine 37% Capecitabine + bevacizumab 4 1L % 10 19* * *Statistically significant difference vs the control arm NR = not reported 1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Tebbutt, et al. JCO Cunningham, et al. ASCO GI 2013;

10 Amplia experiencia - Datos de eficacia consistentes en EECC Supervivencia Libre de Supervivenci a Global progresión

11 Bevacizumab-Associated Toxicity Adverse Event Grade 3 ATE Grade 3/4 HTN Incidence With Bev Across Indications, [1] % 2.6 GI perforations Grade 3 hemorrhagic event Wound complications Comments Risk of ATE increased in pts 65 yrs of age or older or with ATE history 5-18* Patients should receive otherwise standard CV prophylaxis and have BP monitored and managed 15 *Predominantly grade 3. May apply more to NSCLC. When surgery conducted during bev therapy. Bev not recommended for pts with serious hemorrhage or recent hemoptysis Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors Discontinue 4-8 wks before surgery; resume 6-8 wks postsurgery Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others. [2,3] 1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; Nalluri SR, et al. JAMA. 2008;300; Hurwitz H, et al. J Clin Oncol. 2011;29:

12 TRIBE: phase III trial comparing bevacizumab + FOLFOXIRI with bevacizumab + FOLFIRI

13 OLIVIA study design Previously untreated, unresectable colorectal cancer with metastases confined to the liver N=80 Criteria for unresectability Stratification factors: Centre Randomization 1:1 ECOG performance status No. of metastatic lesions Bevacizumab + FOLFOXIRI Bevacizumab 5 mg/kg, oxaliplatin 85 mg/m 2, irinotecan 165 mg/m 2, folinic acid 200 mg/m 2 and 5-FU 3200 mg/m 2 46-hr infusion on day 1 q2w Bevacizumab + mfolfox6 Bevacizumab 5 mg/kg, oxaliplatin 85 mg/m 2, folinic acid 400 mg/m 2, bolus 5-FU 400 mg/m 2 then 5-FU 2400 mg/m 2 46-hr infusion on day 1 q2w Patients had to meet at least one of the following criteria: no upfront R0/R1 resection of all hepatic lesions possible less than 30% estimated residual liver after resection disease in contact with major vessels of the remnant liver FDG-PET was performed to exclude extrahepatic metastases Primary endpoint: overall resection rate (R0/R1/R2)

14 OLIVIA: Resection and Response rate and PFS ITT population Variable, n (%) Bev + FOLFOXI RI (n=41) Bev + mfolfo X-6 (n=39) Differ ence (%) P valu e Resection rate R0/R1/R2* 25 (61.0) 19 (48.7) 12.3 R0/R1 21 (51.2) 13 (33.3) 17.9 R0 20 (48.8) 9 (23.1) Overall response rate 33 (80.5) 24 (61.5)

15 Utilización de Bevacizumab en primera línea de CCRm Optional 1st line FU FU + Bev Oxaliplatin-based 1st line Irinotecan-based 1st line Chemotriplet 1st line FOLFOX + Pan or Cet FU/Ox FU/Ox + Bev FU/Iri + Cet FU/Iri FU/Iri + Bev FU/Ox/Iri FU/Ox/Ir +Bev * 2nd line FU/Iri + Bev FOLFIRI + Aflibercept Fu/Iri (FOLF)IRI+ Pan/Cet FU/Ox+ Bev FU/Ox FOLFOX + Cet (Pan) Pan/Cet ± Iri or FU/Bev 3rd line Regorafenib* Pan/Cet ± Iri FU+Bev Regorafenib* Pan/Cet ± Iri FU + Bev Regorafenib* 4th line Regorafenib* Regorafenib* *Not approved by the EMEA or for use in the Czech Republic Schmoll, et al. Ann Oncol 2012 *Falcone, et al. ASCO 2013

16 Qué aportan los tratamientos de mantenimiento con bevacizumab?

17 Tratamiento de Mantenimiento con Bevacizumab Trial 1L 2L SLP1 SLP2 OS MACRO CAIRO-3 SAKK TML XELOX - Beva XELOX - Beva NA 10.4 NA 21.1 XELOX - Beva Beva NA 9.6 NA 20.4 XELOX - Beva XEL - Beva XELOX - Beva XELOX - Beva Observ Quimio- Beva Beva NA 9.5 NA 25.1 Quimio- Beva Observ NA 8.5 NA 22.8 Quimio- Beva Quimio- Beva 5.7 NA 9.8 Quimio- Beva Quimio 4.1 NA 11.2 Está indicado el tratamiento de mantenimiento hasta la progresión. El estándar es bevacizumab más capecitabina

18 CAIRO3: maintenance Beva + capecitabine versus observation Arm A PFS1 PFS2 TTP2 Observation PD1 Beva + XELOX PD2 Previously untreated mcrc (n=558) Beva + XELOX (x6) CR PR SD R Beva + capecitabine PD1 Beva + XELOX PD2 Phase III trial Arm B Primary endpoint: PFS after re-introduction = PFS2 Secondary endpoints: PFS1, OS, TTP2, ORR, safety PFS2 was considered to be equal to PFS1 for patients in whom Avastin + XELOX was not reintroduced after PFS1 for any reason Koopman, et al. ASCO 2013

19 CAIRO3: resultados eficacia

20 Presented By Miriam Koopman, at 2014 ASCO Annual Meeting

21 Presented By Miriam Koopman, at 2014 ASCO Annual Meeting

22 Presented By Dirk Arnold, at 2014 ASCO Annual Meeting

23 Presented By Dirk Arnold, at 2014 ASCO Annual Meeting

24 Presented By Dirk Arnold, at 2014 ASCO Annual Meeting

25 Presented By Dirk Arnold, at 2014 ASCO Annual Meeting

26 Selección de Biológicos por biomarcadores

27 Bevacizumab independiente de RAS Hasta ahora los resultados de eficacia de Bevacizumab resultado independiente del estado mutacional de Kras ha

28 PRIME study RAS analysis KRAS, NRAS and BRAF mutation hotspots EXON 1 KRAS EXON 2 EXON 3 EXON % 5% 6% NRAS EXON 1 EXON 2 EXON 3 EXON % 4% 0% EXON 1 BRAF EXON 15 EXON 16 9% Overall RAS ascertainment rate: 90% Overall RAS and BRAF ascertainment rate: 89% Among WT KRAS exon 2 patients, an additional 17% of tumours with RAS mutations were found Based on Douillard JY, et al. N Engl J Med 2013; 369: ; Oliner KS, et al. EJC 2013; 49 (suppl 3):abstract 2275 (and poster). Percentages have been rounded; 7 patients harboured either KRAS or NRAS codon 59 mutations

29 What data are available to support selection of first-line therapy? Optional 1st line WT RAS Pmab QT Oxali FU WT RAS Cetux QT Oxaliplatin-based 1st line Irinotecan FU + Bev Irinotecan-based 1st line Chemotriplet 1st line FOLFOX + *Pan or **Cet FU/Ox FU/Ox + Bev FU/Iri + Cet FU/Iri FU/Iri + Bev FU/Ox/Iri 2nd line FU/Iri + Bev FOLFIRI + Aflibercept Fu/Iri (FOLF)IRI+ Pan/Cet FU/Ox+ Bev FU/Ox FOLFOX + Cet (Pan) Pan/Cet ± Iri or FU/Bev 3rd line Regorafenib* Pan/Cet ± Iri FU+Bev Regorafenib* Pan/Cet ± Iri FU + Bev Regorafenib* 4th line Regorafenib* Regorafenib* *Oliner, et al. ASCO 2013 **Primrose JN, et al. ASCO 2013 Schmoll, et al. Ann Oncol 2012

30 limitations are head-to-head trials available? CALGB (phase III) Primary endpoint: OS Untreated KRAS WT mcrc (n=1,100) R Bevacizumab + FOLFOX or FOLFIRI Cetuximab + FOLFOX or FOLFIRI PD PD FIRE III (phase III) Primary endpoint: ORR Untreated KRAS WT mcrc (n=520) R Bevacizumab + FOLFIRI Cetuximab + FOLFIRI PD PD PEAK (phase II) Primary endpoint: PFS Untreated, unresectable KRAS WT mcrc (n=285) R Bevacizumab + mfolfox6 Panitumumab + mfolfox6 PD PD

31

32 PEAK study mfolfox6 + panitumumab or bevacizumab in 1 st -line treatment of WT KRAS exon 2 mcrc Metastatic CRC WT KRAS exon 2 (n = 285) 1:1 R mfolfox6 (Q2W) + panitumumab 6 mg/kg (Q2W) mfolfox6 (Q2W) + bevacizumab 5 mg/kg (Q2W) Tumour Assessment Q8W (±7 days); Treatment administered until disease progression, death, or withdrawal from study E n d o f t r e a t m e n t 30 days (+ 3 days) S a f e t y f o l l o w u p P o s t t r e a t m e n t f o l l o w u p Every 3 months (±28 days) until end of study E n d o f s t u d y Study endpoints: PFS (1 ); OS, ORR, safety, exploratory biomarker analysis No formal hypothesis testing was planned Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster); Protocol ID: ; ClinicalTrials.gov identifier: NCT ORR, objective response rate; mfolfox6, modified FOLFOX6

33 PEAK study RAS analysis: PFS

34 PEAK study RAS analysis: OS

35 FIRE-3 study design Stintzing S, et al. Journal of clinical oncology (suppl 3):abstr 445. Pres. at ASCO GI 2014

36 FIRE-3 study results Stintzing S, et al. Journal of clinical oncology (suppl 3):abstr 445. Pres. at ASCO GI 2014

37 RAS: Evaluation of ORR Stintzing S, et al. Journal of clinical oncology (suppl 3):abstr 445. Pres. at ASCO GI 2014

38 RAS: Evaluation of PFS Stintzing S, et al. Journal of clinical oncology (suppl 3):abstr 445. Pres. at ASCO GI 2014

39 RAS: Evaluation of OS Stintzing S, et al. Journal of clinical oncology (suppl 3):abstr 445. Pres. at ASCO GI 2014

40 CALGB/SWOG 80405: <br /> FINAL DESIGN Presented By Alan Venook at 2014 ASCO Annual Meeting

41 CALGB/SWOG 80405: Statistics Presented By Alan Venook at 2014 ASCO Annual Meeting

42 CALGB/SWOG 80405: Overall Survival <br /> Presented By Alan Venook at 2014 ASCO Annual Meeting

43 CALGB/SWOG 80405: Progression-Free Survival<br />(Investigator Determined) Presented By Alan Venook at 2014 ASCO Annual Meeting

44 CALGB/SWOG 80405: Overall Survival<br />FOLFOX Treated Presented By Alan Venook at 2014 ASCO Annual Meeting

45 CALGB/SWOG 80405: Overall Survival<br />FOLFIRI Treated Presented By Alan Venook at 2014 ASCO Annual Meeting

46 Grade 3-4 Toxicities<br /> Presented By Alan Venook at 2014 ASCO Annual Meeting

47 Slide 23 Presented By Alan Venook at 2014 ASCO Annual Meeting

48 Conclusiones La supervivencia global de la QT/Cetuximab no es diferente de la de la QT/Bevacizuab en primera línea de tratamiento en pacientes kras wt. Ambas combinaciones puedes ser considerados opciones terapéuticas en kras wt La SG en ambas ramas es superior a 29 meses, estableciéndose un nuevo baremo para esta enfermedad Análisis detallado de subgrupos y de largos supervivientes pueden ofrecer una valiosa información Hay que esperar a los resultados del estudio evaluados por RAS

49 Evaluación KRAS: Negativos CALGB (phase III) Primary endpoint: OS Untreated KRAS WT mcrc (n=1,100) R Bevacizumab + FOLFOX or FOLFIRI Cetuximab + FOLFOX or FOLFIRI PD PD FIRE III (phase III) Primary endpoint: ORR Untreated KRAS WT mcrc (n=520) R Bevacizumab + FOLFIRI Cetuximab + FOLFIRI PD PD PEAK (phase II) Primary endpoint: PFS Untreated, unresectable KRAS WT mcrc (n=285) R Bevacizumab + mfolfox6 Panitumumab + mfolfox6 PD PD

50 Estudios fase III: Evaluación por RAS total PEAK: RAS total : aumento de PFS Estudio fase II generador de hipótesis FIRE RAS total negativo Incremento de OS!! CALGB RAS total???

51 Personalización en el Tratamiento del CRCm: Consideraciones Extensión de la enfermedad Intención del tratamiento (paliativo vs potencialmente curativo) Performance status Edad Comorbilidades Adyuvancia previa en 1 año Marcadores moleculares Función de órgano: hepatica y renal Riesgo de toxicidad: Enf coronaria o ACA activo, proteinuria, hemorragia activa, heridas no cicatrizadas, alergia a los mac, neuropatia, Enfermedad inflamatoria intestinal, Gilberts Conveniencia Costes/recursos Preferencias del paciente

52 A favor de los antiangiogénicos Los estudios fase III/II y los meta-análisis confirman la eficacia de los antiangiogénicos Perfil de tolerabilidad adecuado Bevacizumab incrementa la supervivencia independientemente del estado de RAS Los estudios comparativos con anti-egfr en pacientes seleccionados por KRAS no encuentran diferencias en eficacia Permiten abordajes terapéuticos que priorizan calidad de vida Pueden mejorar la tasa de R0 en pacientes con metástasis hepáticas en esquemas de tripletes

53 Slide 30 Presented By Alan Venook at 2014 ASCO Annual Meeting

54 Preferencia del paciente y de los efectos secundarios Anti-EGFR? Antiangiogénicos?

55 Muchas Gracias!