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Introduction

G lobal I nvestigation of therapeutic DE cisions in hepatocellular carcinoma and O f its treatment with sorafe N ib (GIDEON) study. Introduction. Sorafenib is the only systemic therapy indicated to treat HCC 1-4

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Introduction

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  1. Global Investigation of therapeutic DEcisions inhepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study

  2. Introduction • Sorafenib is the only systemic therapy indicatedto treat HCC1-4 • In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with uHCC5-6 • GIDEON allows evaluation of several clinically relevant patient subgroups, including those with more advanced liver dysfunction in whom data were previously limited • GIDEON was the largest prospective study in uHCC ever conducted7 • Over 3000 patients have been enrolled from 39 countries8 uHCC, unresectable hepatocellular carcinoma; OS, overall survival; 1.NCCN Guidelines™: Hepatobiliary Cancers. Available at: http://www.nccn.org/ Accessed May 29,2014. 2. EASL–EORTC ClinicalPracticeGuidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf. 3. Position paper AISF DLD 2013 45(2013) 712-723. 4. AIOM Guidelines. Availableat: http://www.aiom.it/5. LlovetJM, et al. N EnglJ Med. 2008;359(4):378-390. 6. Cheng AL, et al. Lancet Oncol. 2009;10(1):25-34. 7. Lencioni R, et al. Int J ClinPrac. 2010;64(8):1034-1041. 8. Marrero JA et al. Abstract presented at AASLD 2011 Annual Meeting

  3. The GIDEON study:design and objectives • The GIDEON study is a large, global, prospective, non-interventional study of patients with unresectable HCC who are eligible for systemic therapy and for whom the decision has been taken to treat with sorafenib under real-life practice conditions. • Primary objective: The primary objective of GIDEON is to evaluate the safety of sorafenib in uHCC patients under real-life clinical practice conditions and to gather more comprehensive data on the use of sorafenib in patients with Child-Pugh B liver function, who were excluded from the randomised clinical trials. • Secondary objectives: evaluate the efficacy [OS, progression-free survival (PFS), time to progression (TTP), response rate and stable disease rate] of sorafenib; determine the duration of therapy according to various patient characteristics; evaluate methods of patient evaluation, diagnosis and follow-up; assess comorbidities and their influence on treatment and outcome in real-life practice rather than a controlled clinical trial setting and evaluate the practice patterns of the physicians involved in the care of these patients. Lencioni R, et al. Int J Clin Prac. 2010;64(8):1034-1041.

  4. The GIDEON study:design and objectives • Planned subgroup analyses conducted globally, regionally and by country will include: • the impact of baseline characteristics on safety, particularly Child-Pugh B; • the relationship between baseline characteristics and efficacy; • the duration of sorafenib therapy and reasons for discontinuation; • the effect of other treatments for HCC on outcome and the impact of different practice patterns on outcome. Lencioni R, et al. Int J Clin Prac. 2010;64(8):1034-1041.

  5. The GIDEON study: Patient eligibility • Eligibility criteria include: • Patients with histologically or cytologically documented or radiographically diagnosed unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib • life expectancy of > 8 weeks • Have provided signed informed consent. Lencioni R et al. Int J Clin Pract 2010;64:1034–4

  6. The GIDEON study: safety, efficacy, treatment and baseline patient assessments and end-points BCLC, Barcellona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ECOG, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; NCI-CTC, National Cancer Institute-Common Toxicity Criteria; OS, overall survival; PFS, progressio-free survival; RR, rensponse rate; SD, stable disease; TNM, tumor node metastases; TTP, time to progression Lencioni R et al. Int J Clin Pract 2010;64:1034–41

  7. The GIDEON study: timeline and plannedanalyses 2008-2009 2010 2011-2012 2013-2015 Lencioni R et al. Int J Clin Pract 2010;64:1034–41

  8. GIDEON study: regional distribution of patients • A total of 3371 patients were enrolled from 39 countries, across 5 different regions Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  9. ITT, intent to treat; OS, overall survival; TTP, time-to-progression Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126) GIDEON final analysispatients population • 3202 patients in the safety population • Safety population used for analysis of AEs and serious AEs • 3213 patients in the ITT population • ITT population used for analysis of OS and TTP

  10. GIDEON final analysis:baseline patients characteristics by CP status *includes493 non-evaluablepatients BCLC, Barcelona Clinic LiverCancer; ECOG PS, Eastern Cooperative Oncology Group performance status; TNM, tumornodemetastasis Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  11. GIDEON final analysis:overall treatment-emergent safety data by CP status Patients who received >1 dose of sorafenib and had >1 follow-up assessment were included in the safety analysis. aIncludes 493 non-evaluable patients; bAny AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically important event; cTreatment-emergent deaths occurring up to 30 days after last sorafenib dose Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  12. GIDEON final analysis:rate of drug-related AEsa by CP status aRate calculation based on treatment-emergent AEs with >10% incidence and 365.25 days per year; bIncludes 493 non-evaluable patients Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  13. GIDEON final analysis:onset time of AEs > grade 3 by CP status Time to AE onset (days) Child-Pugh A Child-Pugh B • The onset time of AEs was comparable between Child-Pugh A and Child-Pugh B patients, with the majority of AEs occurring within the first 30 days of treatment in both groups Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  14. GIDEON final analysis:sorafenib dosing and treatment duration by CP status • Overall and across Child-Pugh subgroups, the majority of patients received the recommended initial dose of 800 mg • The median daily dose was similar across Child-Pugh subgroups • Duration of treatment was longer in Child-Pugh A patients than in Child-Pugh B patients aIncludes 493 non-evaluable patients Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  15. GIDEON final analysis:duration of sorafenib treatment by CP status Duration of sorafenib treatment Child-Pugh A Child-Pugh B • Overall, the majority of patients received sorafenib for either ,8 weeks (29.5%) or >24 weeks (35.9%), and 31.2% of patients received sorafenib for >28 weeks • In Child-Pugh B patients treated with sorafenib, 25.7% were treated for 24 weeks Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  16. GIDEON final analysis:OS by CP status Overall survival • Median overall survival (OS; months) was longer in Child-Pugh A patients than in Child-Pugh B and C patients (13.6 vs5.2 and 2.6, respectively) CI, confidence interval Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  17. GIDEON final analysis:TTP by CP status Time to progression • Time to progression (TTP) was comparable between Child-Pugh A and B patients The imaging examination interval was at the investigators’ discretion Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  18. GIDEON final analysis:OS by BCLC stage Overall survival • Patients with BCLC stage A had a median OS ~3 times that of patients with BCLC stage C Bronovicki J-P, et al. Presentedat ECC 2013. P 2594

  19. GIDEON final analysis:TTP by BCLC stage Time to progression Bronovicki J-P, et al. Presentedat ECC 2013. P 2594

  20. GIDEON final analysis:OS by TNM stage Overall survival • Median OS (months) was similar across TNM stages IIIA, IIIB, IIIC, and IV (9.5 vs 9.2 vs 10.8 vs 9.1) TNM, tumornodemetastasis Bronovicki J-P, et al. Presentedat ECC 2013. P 2594

  21. GIDEON final analysis:TTP by TNM stage Time to progression TNM, tumornodemetastasis Bronovicki J-P, et al. Presentedat ECC 2013. P 2594

  22. GIDEON final analysis:OS by ECOG performance status Overall survival • MedianOS wasgreater in patients with an ECOG PS of 0 or 1 than in patients with an ECOG PS of 2 or 3 Bronovicki J-P, et al. Presentedat ECC 2013. P 2594

  23. GIDEON final analysis:TTP by ECOG performance status Time to progression Bronovicki J-P, et al. Presentedat ECC 2013. P 2594

  24. Conclusions • The safety profile of sorafenib in uHCC patients appears consistent, irrespective of liver function • AEs observed across Child-Pugh subgroups were in keeping with the known AE profile of sorafenib • Child-Pugh status does not appear to influence the approach to sorafenib dosing, although duration of treatment is shorter in Child-Pugh B patients than in Child-Pugh A patients • Discontinuation of sorafenib due to AEs is higher in Child-Pugh B patients • Consistent with previous reports, Child-Pugh status is a strong prognostic factor for OS in uHCC patients, regardless of treatment with sorafenib • TTP was similar in Child-Pugh A and Child-Pugh B patients, while OS was longer in Child-Pugh A patients Marrero J, et al. J ClinOncol 31, 2013 (suppl; abstr 4126)

  25. GIDEON final analysis: the European subset • A total of 1113 patients in 22 European countries were evaluable for safety • At study initiation the majority of European patients (82.4%) started sorafenibtherapy at the full prescribing dose of 800 mg/day; 15.4% received 400 mg/day of sorafenib and 2.2% received an alternative dose *Alternative doses included 200 and 600 mg/day Daniele B, et al. Presented at ECC 2013. P 2581

  26. GIDEON final analysis - the European subset: baseline patients characteristics by initial dose aBaselinedata collected at study entry, patients may have multiple responses; Daniele B, et al. Presented at ECC 2013. P 2581

  27. GIDEON final analysis - the European subset: baseline patients characteristics by initial dose bAtstudy entry; cNecessary data for scoring were not collected in investigators’ routine practice; dNo record is available, egtransfer from other hospitals, data to assess BCLC are not available; eNo data entry on case report form for missing patients Daniele B, et al. Presented at ECC 2013. P 2581

  28. GIDEON final analysis - the European subset: baseline patients characteristics by initial dose bAtstudy entry; cNecessary data for scoring were not collected in investigators’ routine practice Daniele B, et al. Presented at ECC 2013. P 2581

  29. GIDEON final analysis - the European subset: history of of prior treatmentby prior TACE and ctTACE *Patients in the concomitant TACE groups may also be part of the prior TACE group aChemotherapy, immunotherapy, or others; bRadiotherapy and other locoregionaltherapy ct, concomitant; HAI, hepaticarterialinfusion; LRT, locoregionaltherapy; PEI, percutaneousethanol injection; RFA, radiofrequency ablation P. I. Stal, et al. Presentedat UEGW. P 1196

  30. GIDEON final analysis - the European subset: duration of sorafenib treatment by initial dose Duration of sorafenib treatment • The duration of treatment was greater for the 800 mg/day patient group compared with the 400 mg/day patient group (18.0 vs 13.0 weeks) *Time in weeks from initial visit to last visit date (for ongoing patients) or last dosing date +1 Daniele B, et al. Presented at ECC 2013. P 2581

  31. GIDEON final analysis - the European subset: OS by initial dose Overall survival • Patients who received an initial dose of sorafenib of 800 mg/day had greater median OS (12.1 months; 95% CI 10.5–13.8) than those patients who started on 400 mg/day (9.4 months; 95% CI 6.3–12.6) Daniele B, et al. Presented at ECC 2013. P 2581

  32. GIDEON final analysis - the European subset: OS by TACE and ct-TACE treatment Overall survival • Median OS was greater in patients with prior TACE (464 days, 15.3 months) compared with those who did not receive prior TACE (309 days, 10.2 months) • The same result was seen in patients who received ctTACE (494 days, 16.3 months) compared with no ctTACE (336 days, 11.1 months) P. I. Stal, et al. Presentedat UEGW. P 1196

  33. GIDEON final analysis:OS by underlying liver disease aetiology Overall survival according to hepatitis B as aetiology Overall survival according to hepatitis C as aetiology 11.7 months (358 days) 14.2 months (432 days) Overall survival according to alcohol use While a small advantage in OS was reported for patients with hepatitis C, TTP was comparable for each of the underlying aetiologies 12.9 months (394 days) Ratziu V, et al. Presentedat EASL 2014. P957

  34. GIDEON final analysis:TTP by underlying liver disease aetiology • Median time to progression (TTP) in the intent-to-treat (ITT) population (n=1113) was comparable for patients with known underlying aetiologies Ratziu V, et al. Presentedat EASL 2014. P957

  35. GIDEON final analysis - the European subset:rate of treatment-emergent AEs and SAEs by initial dose • There was an increase in AEs (all grades) in the group receiving an initial dose of 400 mg/day vs 800 mg/day (95.9% vs 87.8%), and an increase in drug-related AEs (73.7% vs 68.8%) and serious Aes(57.3% vs 44.5%) • All other AE categories were comparable between the two groups *Includes 25 patients who received an alternative dose of sorafenib; aAny AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability / incapacity; congenital anomaly / birth defect; medically important event Daniele B, et al. Presented at ECC 2013. P 2581

  36. GIDEON final analysis - the European subset:rate of treatment-emergent AEs and SAEs by prior TACE and ctTACE • Overall, AEs and serious AEs (SAEs) were similar in the prior TACE and no prior TACE populations. The same observation was seen in the ctTACEand no ctTACEpopulations • The incidence of drug-related AEs was greater in patients who received prior TACE (76.4%) than those who received no prior TACE (65.1%) • The same pattern was seen for patients who had received prior ctTACE (86.5%) compared with patients who had received no ctTACE (68.0%) *Patients in the concomitant TACE groups may also be part of the prior TACE group; aAny AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability /incapacity; congenital anomaly / birth defect; medically important event P. I. Stal, et al. Presentedat UEGW. P 1196

  37. GIDEON final analysis - the European subset:rate of drug-related AEs by liver disease aetiology Overview of treatment-emergent AEs according to aetiology of patient’s underlying liver disease • The incidence of AEs (all grades), drug-related Aes(allgrades), seriousAEs (allgrades), and AEsresultingin permanent discontinuation of study drug were comparable in patients with all known underlying aetiologies *Baseline data collected at study entry, patients may have multiple responses; aDeaths while on treatment or within 30 days of last sorafenib dose NASH, non-alcoholic steatohepatitis Ratziu V, et al. Presentedat EASL 2014. P957

  38. Conclusions • In this real-life clinical practice setting, the majority of patients (82.4%) received the recommended initial sorafenib dose of 800 mg/day • Patients on 800 mg/day tended to continue on treatment for longer, have less discontinuations and have a greater median overall survival compared with those patients receiving the lower 400 mg/daydose • Patients treated with ctTACE lived longer than those with no ctTACE. However, it is not clear that this finding is a result of treatment effect or the patients’ selection for ctTACE, due to the limitation and potential bias of an observational study • The incidences of AEs for the 800 mg/day and 400 mg/day sorafenibdosesweresimilar • Adverse event profiles of sorafenib are comparable regardless of history of prior TACE or ctTACE treatment Daniele B, et al. Presented at ECC 2013. P 2581 P. I. Stal, et al. Presentedat UEGW. P 1196

  39. GIDEON final analysis: the Italian subset • Overall, 278 patients have been enrolled in Italy between June ‘09 and April ‘11 Salvatore D’A, et al. Presented at EASL 2014. P 237

  40. GIDEON final analysis - the Italian subset: baseline patients characteristics Salvatore D’A, et al. Presented at EASL 2014. P 237

  41. GIDEON final analysis - the Italian subset: history of of prior treatmentby prior TACE and ctTACE *Patients in the concomitant TACE groups may also be part of the prior TACE group; aChemotherapy, immunotherapy, or others; bRadiotherapyand otherlocoregionaltherapy. HAI, hepaticarterialinfusion; LRT, locoregionaltherapy; PEI, percutaneousethanolinjection; RFA, radiofrequencyablation; TACE, transarterialchemoembolization Vito L, et al. Presented at EASL 2014. P 447

  42. GIDEON final analysis - the Italian subset: OS by BCLC Overall survival • Patients with BCLC stage B had longer OS than BCLC stage C; median OS was not reached for patients with BCLC stage A Salvatore D’A, et al. Presented at EASL 2014. P 237

  43. GIDEON final analysis - the Italian subset: OS by ECOG-PS Overall survival • The majority of patients had an ECOG PS of 0 or 1. Median OS was greater in patients with an ECOG PS of 0 or 1 than in patients with an ECOG PS of 2 Salvatore D’A, et al. Presented at EASL 2014. P 237

  44. GIDEON final analysis - the Italian subset: OS by TACE Overall survival • Median OS was greater in patients with prior TACE (697 days, 22.9 months) compared with those who did not receive prior TACE (341 days, 11.2 months) Vito L, et al. Presented at EASL 2014. P 447

  45. GIDEON final analysis - the Italian subset: OS by ctTACE Overall survival • For the small cohort of patients who underwent ctTACEmOS was not reached whilst for those no ctTACEmOS was 383 days Vito L, et al. Presented at EASL 2014. P 447

  46. GIDEON final analysis - the Italian subset:rate of treatment-emergent AEs and SAEs by prior TACE and ctTACE • The overall incidence of AEs and serious AEs (SAEs) was similar in the prior TACE and no prior TACE populations. The same observation was seen in the ctTACEand no ctTACEpopulations *Patients in the concomitant TACE groups may also be part of the prior TACE group; aAny AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability / incapacity; congenital anomaly / birth defect; medically important event Vito L, et al. Presented at EASL 2014. P 447

  47. Conclusions • The results of the Italian cohort from the GIDEON study are consistent with the global results of the study • Patients treated with prior TACE lived longer than those with no prior TACE possibly because of the earlier stage of disease at initial diagnosis among the first group • Patients treated with ctTACE lived longer than those with no ctTACE. However, due to the small number of patients treated with ctTACE and to the limitation and potential bias of an observational study it is not possible to attribute this difference to a different treatment effect • Adverse event profiles of sorafenib are comparable among the patients with or without prior TACE and ct TACE. Potential differences among those receiving or not ctTACE might be caused by the small number of patients in the ctTACEgroup Salvatore D’A, et al. Presented at EASL 2014. P 237 Vito L, et al. Presented at EASL 2014. P 447

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