mrcc: Tratamiento HOY de segunda línea Pablo Maroto Htal Sant Pau

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1 mrcc: Tratamiento HOY de segunda línea Pablo Maroto Htal Sant Pau

2 El CCRm precisa de una estrategia de tratamiento Los agentes anti-diana constituyen el tratamiento estandar del CCRm. Pero.. Cómo combinarlos? Long-term continuum of care in mrcc Efficacious first-line agents Efficacious second-line agents Efficacious third-line agents Effective therapy management

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4 Secuenciación Óptima. Cómo? Datos preclínicos Datos clínicos Sequencing strategy Guidelines Biomarcadores y Situaciones Clínicas

5 Secuenciación Óptima. Cómo? Datos preclínicos Datos clínicos Sequencing strategy Guidelines Biomarcadores y Situaciones Clínicas

6 Longest tumour axis (mm) RCC is a VEGF-driven tumour: Sorafenib-resistant tumours remain sensitive to repeat sorafenib Day -30: Tumour cells implanted into mice and allowed to grow Day 0: When tumours reached 12 mm, oral sorafenib treatment at 80 mg/kg 6 of 7 days began Length of stabilization (days) Untreated 2.6 ± 1.2 Treated 4.9 ± 1.5 Treated implanted naïve host 8.6 ± 3.1 Treated 2 reimplanted naïve host 9.7 ± Days Zhang et al. PLoS One 2011

7 Resistance in RCC appears to be mediated by angiogenic escape ASL MRI: Rodent model Histopathological correlation of sorafenib-treated tumours with ASL perfusion maps ASL perfusion maps Haematoxylin-eosin staining CD34 staining RCC tumours remain VEGF-driven and should remain a target for continual VEGF suppression ASL, arterial spin labelling; MRI, magnetic resonance imaging Schor-Bardach et al. Radiology 2009

8 Hicklin, D. J. et al. J Clin Oncol; 23:

9 Tumour growth factor expression may support using anti-vegf therapy throughout treatment and specific anti-vegf therapy first line bfgf bfgf TGF -1 bfgf TGF -1 TGF -1 PIGF PIGF PD-ECGF bfgf TGF -1 VEGF VEGF VEGF VEGF VEGF PIGF PD-ECGF Pleiotrophin Tumour growth Adapted from Folkman 2005 Cancer: Principles and Practice of Oncology 2005

10 Secuenciación Óptima. Cómo? Datos preclínicos Datos clínicos Sequencing strategy Guidelines Biomarcadores y Situaciones Clínicas

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12 RECORD-1: Phase III study of everolimus versus placebo in second line: Design Eligibility mrcc (clear-cell component) Prior VEGFR-TKI with RECIST PD 6 months Stratification MSKCC prognostic criteria for patients with previously treated mrcc (favourable, intermediate or poor) Prior VEGFR-TKI therapy (1 vs 2 prior VEGFR-TKIs) N=416 R A N D O M I Z A T I O N Primary endpoint: PFS Everolimus 10 mg q.d. + BSC (n=277) Upon disease progression Placebo + BSC (n=139) Secondary endpoints: OS, ORR, safety and quality of life First Phase III trial in which 100% of patients were previously treated with a TKI However, although all patients were post-tki, they could also have received bevacizumab, cytokines, hormones or chemotherapy 1. Motzer et al. Lancet 2008; 2. Motzer et al. Cancer 2010; 3. Calvo et al. Eur J Can 2012

13 Prior Therapies Prior Treatment Everolimus (n = 272) % Placebo (n = 138) % Nephrectomy Radiotherapy VEGFr-TKI therapy Sunitinib Sorafenib Both Other systemic therapy Interferon Interleukin Chemotherapy Bevacizumab 9 10

14 Probability (%) Probability (%) RECORD-1: PFS and OS results PFS* OS HR=0.33 (95% CI: ) Median PFS Everolimus: 4.90 months Placebo: 1.87 months Log-rank p-value < HR=0.87 (95% CI: ) Median OS Everolimus: months Placebo: months Log-rank p-value = Everolimus (n=277) 20 Everolimus (n=277) 0 Placebo (n=139) 0 Placebo (n=139) Months Months *Central radiology review Motzer R, et al. Cancer 2010

15 Subgroup Analysis of Progression-Free Survival Central Radiology Review 1 1. Motzer et al. J Clin Oncol. 2004;22:

16 RECORD-1: No sólo segunda línea.. In RECORD 1, almost 80% of patients were treated with everolimus in third-line or later 1,2 The results of RECORD 1 indicate that a reasonable PFS may still be achieved with an mtor inhibitor in third-line (or later) Firstline Secondline Thirdline Fourthline mtor fifth-line n=82 Firstline Secondline Thirdline mtor fourthline n=104 79% Firstline Secondline mtor thirdline n=141 Firstline mtor secondline n=89 21% 1. Zustovich et al. Crit Rev Oncol Hematol 2012; 2. Motzer et al. Cancer 2010

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18 Potency: IC50 (nm) 1,000 VEGFR-1 VEGFR-2 VEGFR-3 Less potent More potent 0.1 TivozanibA V-951 Axitinib Cediranib Motesanib AMG-706 Sunitinib ABT-869 Pazopanib Sorafenib Vatalanib PTK787 Vandetanib 0.01 Figure modified using data from Chow LQM, Eckhardt SG. J Clin Oncol. 2007; Eskens FALM, et al. AACR Abstract LB-201; Hu-Lowe DD, Clin Cancer Res 2008

19 Secuencia Sunitinib Sorafenib J Urol Jul;182(1):29-34; Sequential sorafenib and sunitinib for renal cell carcinoma. Sablin MP, Negrier S, Ravaud A, Oudard S, Balleyguier C, Gautier J, Celier C, Medioni J, Escudier B.Inst.Gustave Roussy, Villejuif, France. Conclusions: lack of absolute crossresistance between TKi. Ann Oncol.2011; first published online May 2011 Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma. Data from the Czech registry Camillo Porta 1, Giuseppe Procopio2, Giacomo Cartenì3, Roberto Sabbatini4, Alessandra Bearz5, Isabella Chiappino6, Enzo Maria Ruggeri7 European Urology 54 ( ) Sequential Use of the Tyrosine Kinase Inhibitors Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma: A Retrospective Outcome Analysis Christian Eichelberg a,*,1, Roman Heuer a,1, Felix K. Chun a, Kristin Hinrichs a, Mario Zacharias a, Hartwig Huland a,b, Hans Heinzer Conclusions: The median time from the initialisation of the first TKI until progression under therapy with the second TKI was 17.3 mo.

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21 Potency: IC50 (nm) 1,000 VEGFR-1 VEGFR-2 VEGFR-3 Less potent More potent 0.1 TivozanibA V-951 Axitinib Cediranib Motesanib AMG-706 Sunitinib ABT-869 Pazopanib Sorafenib Vatalanib PTK787 Vandetanib 0.01 Figure modified using data from Chow LQM, Eckhardt SG. J Clin Oncol. 2007; Eskens FALM, et al. AACR Abstract LB-201; Hu-Lowe DD, Clin Cancer Res 2008

22 AXIS: Second-line phase III trial: Axitinib vs Sorafenib Eligibility: mrcc clear-cell histology Failure of one first-line regimen containing: Sunitinib Bevacizumab + IFN-α Temsirolimus, or Cytokines Stratification by prior regimen and ECOG PS N=723 R A N D O M I Z E 1:1 Axitinib 5 mg b.i.d.* Sorafenib 400 mg b.i.d. Primary endpoint: PFS ECOG PS, Eastern Cooperative Oncology Group performance status; *Starting dose 5 mg b.i.d. with option for dose titration to 10 mg b.i.d. Rini et al. Lancet 2011

23 PFS (probability) AXIS: PFS Axitinib Sorafenib n mpfs, months % CI p< (log-rank) Stratified HR=0.67 (95% CI: ) Time (months) Updated data cut-off requested for SmPC June 03, 2011

24 AXIS: Median PFS (m) by prior regimen Prior treatment regimen Axitinib (n=361) Sorafenib (n=362) HR p-value* Cytokines (n=251) IRC < Investigator Sunitinib (n=389) IRC Investigator Temsirolimus (n=24) IRC Investigator Bevacizumab (n=59) IRC Investigator Patient numbers for temsirolimus and bevacizumab are too small to be conclusive *One-sided log-rank test stratified by ECOG PS and prior treatment; IRC, independent review committee Rini et al. Lancet 2011

25 Toxicidad All-causality AEs of most interest Event Axitinib (%) Sorafenib (%) All grade Grade 3/4 All grade Grade 3/4 Diarrhoea Hypertension Fatigue Nausea Dysphonia Vomiting Hypothyroidism 19 <1 8 0 Stomatitis <1 Hand foot syndrome Rash 13 < Alopecia AEs leading to discontinuation dose reduction Rini et al. Lancet 2011

26 Toxicidad All-causality AEs of most interest Event Axitinib (%) Sorafenib (%) All grade Grade 3/4 All grade Grade 3/4 Diarrhoea Hypertension Fatigue Nausea Dysphonia Vomiting Hypothyroidism 19 <1 8 0 Stomatitis <1 Hand foot syndrome Rash 13 < Alopecia AEs leading to discontinuation dose reduction Rini et al. Lancet 2011

27 Secuenciación Óptima. Cómo? Datos preclínicos Datos clínicos Sequencing strategy Guidelines Biomarcadores y Situaciones Clínicas

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29 Longer-term survival ESMO 2012: Guidelines for clear cell mrcc Treatment group Standard recommendation Level of evidence First-line Favourable or intermediate risk Sunitinib Bevacizumab + IFN- Pazopanib I, A II, A II, A Poor risk Temsirolimus II, A Secondline Prior cytokine Prior VEGFR-TKI Axitinib * Sorafenib Pazopanib Sunitinib Axitinib * Everolimus I, A I, A II, A III, A I, A II, A Third-line Post two TKIs Everolimus II, A * Axitinib is indicated for advanced RCC after failure of prior treatment with sunitinib or a cytokine Escudier et al. Ann Oncol 2012

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31 INTORSECT:* Phase III TKI versus mtor inhibitor study in second-line mrcc after first-line sunitinib Patients with mrcc and PD on first-line sunitinib (N=512) Stratification factors: Duration of sunitinib therapy ( or >6 months) Risk factors based on MSKCC data Histology (clear cell or non-clear cell) Nephrectomy status R A N D O M I Z A T I O N 1:1 Temsirolimus 25 mg IV weekly (n=259) N= sites in 20 countries Sorafenib 400 mg oral b.i.d. (n=253) Treat until PD, unacceptable toxicity or discontinuation for any other reason * PACIENTES QUE ABANDONABAN TRATAMIENTO POR INTOLERANCIA NO ERAN PERMITIDOS: SÓLO RESISTENTES (NCT )

32 PFS (probability) Progression-Free Survival (IRC Assessment) Temsirolimus Sorafenib Median PFS, months % CI 4.01, , P= (log-rank) Stratified HR: 0.87 (95% CI: 0.71, 1.07) Patients at risk, n Sorafenib Temsirolimus Time (months) CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival. 32

33 PFS by Subgroup Subgroup N All patients 511 Prior nephrectomy 442 No prior nephrectomy days sunitinib 189 >180 days sunitinib 323 Clear cell histology 422 Non clear cell histol 90 MSKCC favorable 94 MSKCC intermediate subgroup 355 MSKCC poor subgroup 63 HR 95% CI , , , , , , , , , , 1.25 Hazard Ratio Favors temsirolimus Favors sorafenib CI, confidence interval; HR, hazard ratio; MSKCC, Memorial Sloan-Kettering Cancer Center; PFS, progression-free survival

34 INTORSECT: Toxicidades Event, % Temsirolimus (n=249) Sorafenib (n=252) Rash Fatigue Cough Anemia Nausea Diarrhea Decreased appetite Mucosal inflammation Dyspnea Asthenia Pruritus Hand-foot syndrome 4 52 Alopecia 2 31 *All-causality; experienced by >25% of patients in either treatment arm. 27

35 Overall Survival (probability) Overall Survival Temsirolimus Sorafenib Median OS, months % CI 10.13, , P=0.014 (log-rank) Stratified HR: 1.31 (95% CI: 1.05, 1.63) Patients at risk, n Sorafenib Temsirolimus Time (months) CI, confidence interval; HR, hazard ratio; OS, overall survival. 35

36 imtor ITK

37 TKI TKI mtor versus TKI mtor TKI: Retrospective studies (PFS) TKI TKI mtor TKI mtor TKI Calvani et al. (N=33) Iacovelli et al. (N=281) 1. Calvani et al. Med Oncol 2013; 2. Iacovelli et al. Eur J Cancer 2013

38 RECORD 3: Phase II, open-label, non-inferiority study of everolimus versus sunitinib Objective: to determine whether everolimus is non-inferior to sunitinib, as assessed by PFS, for first-line treatment of mrcc Eligibility Patients with advanced RCC No prior systemic therapy for advanced RCC Karnofsky performance status 70% With or without nephrectomy R A Everolimus N 10 mg/day D O N=471 M Cross-over upon 1:1 progression I Z A T I O N Sunitinib 50 mg/day (Schedule 4/2) Sunitinib 50 mg/day (Schedule 4/2) Everolimus 10 mg/day Discontinuation (owing to progressive disease/toxicity) (NCT )

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41 SWITCH: Phase III sequential study of sorafenib and sunitinib Eligibility mrcc with all histologies Stratification ECOG PS 0 or 1 No prior systemic therapy for advanced or metastatic RCC N=346 R A N D O M I Z A T I O N Primary endpoints: overall PFS Sorafenib 400 mg b.i.d. Sunitinib 50 mg/day (Schedule 4/2) Sunitinib 50 mg/day (Schedule 4/2) Sorafenib 400 mg b.i.d. Discontinuation (owing to progressive disease/toxicity) Secondary endpoints: total time to progression, OS, disease control rate and cardiotoxicity Study conducted in Germany and The Netherlands (NCT )

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45 Tumour growth factor expression may support using anti-vegf therapy throughout treatment and specific anti-vegf therapy first line bfgf bfgf TGF -1 bfgf TGF -1 TGF -1 PIGF PIGF PD-ECGF bfgf TGF -1 VEGF VEGF VEGF VEGF VEGF PIGF PD-ECGF Pleiotrophin Tumour growth Adapted from Folkman 2005 Cancer: Principles and Practice of Oncology 2005

46 Motzer ESMO 2013

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49 Secuenciación Óptima. Cómo? Datos preclínicos Datos clínicos Sequencing strategy Guidelines Biomarcadores y Situaciones Clínicas

50 Predictive biomarkers of outcome in mrcc Clinical, biological and radiological biomarkers can be used to identify subsets of mrcc patients more or less likely to respond to a particular therapy Examples include: ECOG PS 0: tivozanib versus sorafenib; axitinib versus sorafenib SNPs: PIK3CA and everolimus; VEGF-A and VEGFR inhibitors HFS and elevated BP for VEGFR inhibitors Pneumonitis for mtor inhibitors Elevated LDH: temsirolimus Elevated IL-6: pazopanib Hypertension: axitinib Further validation of these biomarkers is required to ascertain their clinical utility

51 Correlation between axitinib efficacy and blood pressure Pooled PK/PD analysis of 168 patients with mrcc dbp, mmhg mpfs, months Continuous - HR (95% CI) ( ) p* mos, months < HR (95% CI) ( ) < Univariate Cox Proportional Regression Analysis ( ) ( ) p* < Axitinib efficacy is correlated with dbp 90 mmhg *Based on log rank (score) test at significance level of p=0.1 for inclusion in multivariate model Hazard ratio per 10 mmhg increase of dbp dbp, diastolic blood pressure Rini et al. J Clin Pharmacol 2013

52 Para ir concluyendo: Subgrupos de pacientes 1. Pacientes que abandonan un tratamiento por toxicidad 2. Pacientes auténticamente refractarios a Sunitinib 2.1. Primarios 2.2. Progresión temprana 2.3. Largos respondedores

53 1. Pacientes que abandonan por toxicidad 1 de cada 6 pacientes abandona tratamiento por toxicidad Estos pacientes no están incluídos en ensayos AXIS ó INTORSECT

54 Estos pacientes no van a ser buenos candidatos a un TKi de segunda línea...

55 2. Pacientes que abandonan por progresión 2.1. Refractarios primarios: < 3/6 m? 2.2. Grupo Intermedio: 6-12 m? 2.3. Largos respondedores: >12 m?

56 NO DIFERENCIAS ENTRE mtor y TKi T a progresión: <4m

57 INTORSEC: OS by duration of prior Sunitinib (ITT Population) Prior Sunitinib Use 180 days, n (%) Median OS, mo (95% CI) Temsirolimus (n=259) 97 (38%) 10.1 (8.5, 13.4) Sorafenib (n=253) 92 (36%) 11.4 (8.9, 16.8) HR (95% CI) 1.30 (0.94, 1.81) p value* >180 days, n (%) Median OS, mo (95% CI) 162 (62%) 14.4 (11.3, 16.9) 161 (64%) 17.8 (15.4, 22.9) 1.37 (1.04, 1.80) *Unstratified log-rank test. CI, confidence interval; HR, hazard ratio; ITT, intent to treat; OS, overall survival. 17

58 Finalmente. Considerar la heterogeneidad del CCR Variedad histológica Células claras No células claras ******** Sarcomatoide Tratamiento previo Nº de regimenes Tipo de tratamiento Respuesta y tolerancia Factores pronóstico

59 Gracias