global investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with...

Global Investigation of therapeutic DEcisions in

hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study

Introduction

Sorafenib is the only systemic therapy indicatedto treat HCC1

In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with uHCC2-3

Pivotal studies generally included patients with preserved liver function

Investigation of sorafenib in wider patient groups is needed4

GIDEON is the largest prospective study in uHCC ever conducted

Over 3000 patients have been enrolled from 39 countries5

1.NCCN Guidelines™: Hepatobiliary Cancers. Available at: http://www.nccn.org/ Accessed: June 7, 2011. 2. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390. 3. Cheng AL, et al. Lancet Oncol. 2009;10(1):25-34. 4. Lencioni R, et al. Int J Clin Prac. 2010;64(8):1034-1041.5. Marrero JA et al. Abstract presented at AASLD 2011 Annual Meeting

uHCC, unresectable hepatocellular carcinoma; OS, overall survival;

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: to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice conditions.

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.

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.

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

Data are collected at the start of sorafenib treatment, then at intervals normally used by the prescribing physician, until death, withdrawal of consent, or until the patient is lost to follow-up

The GIDEON study: Patient assessment schedule


Visit at entry

Initial visit to startsorafenib

Demografic data

Past medical history Comitant diseaseLiver functionECOG PS

History of HCCInitial stageActiology

Previous treatment

Specilaity of the investigator and previous physician(s)

Baseline data• Current stage• Weight• BP• ECOG PS• Child-Pugh

Sorafenib• Initial dose• Reason for • treatment

Follow-upduring treatment with sorafenib

Follow-up visit• Tumor• Weight• BP• ECOG PS• Child-Pugh• AE

Sorafenib• Given dose• Evaluation

DC ofsorafenib

Sorafenib• Given dose• Reason for DC• Evaluation

Concomitant Treatment• for HCC• for others

Concomitant Treatment• for HCC• for others

Follow-upafter DC ofSorafenib Follow-up visit• Tumor• Weight• BP• ECOG PS• Child-Pugh

Death orFinal visit

Follow-up Oservation• Survival status• Tumor• Weight• BP• ECOG PS• Child-Pugh• Reason for DCof observation

Treatment for HCC

Treatment for HCC

Applicable if patient discontinues therapy, is alive and not lost to follow-upAE, adverse event; BP, blood pressure; DC, discontinuation:ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma

Follow-up visit• Tumor• Weight• BP• ECOG PS• Child-Pugh• AE

Safety

• Adverse events• Relation• Seriousness• NCI-CTC grade• Action taken• Outcome

• Child-Pugh score

• ECOG PS

Efficacy

• OS• TTS• PFS• RR• SD

Treatment for HCC

• Sorafenib therapy• Duration of treatment• Reason for discontinuation

• Other therapies• Prior• Concurrent• Following Sorafenib

Baseline characteristics

•History of HCC• Duration from initial diagnosis• Disease extent

• Stage (BCLC, TNM, CLIP)• Tumor burden, presence of metastasis

• Previous treatment• Aetiology

•Liver disorders• Child-Pugh, cirrhosis

•ECOG PS

•Age, gender, race

•Co-morbidities

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

GIDEON study: regional distribution of patients

Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

The GIDEON study: timeline and planned analyses


Phase IObjectives:

Phase IIObjectives:

Phase IIIObjectives:

Phase IV and VObjectives:

• Site initiation• Study initiation

• Safety assessment in Child-Pugh B• First interim analysis (500 patients)

• Second interim analysis (1500 patients)• Safety assessment in Child-Pugh B• Efficacy assessment of sorafenib in a board population of patients with HCC• 3000th patient

• Last patient’s last visit 31 December 2013• Analysis of final data - Safety - Efficacy• Provide data to regolatory organizations

2008-2009 2013-20152011-20122010

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

ITT, intent to treat; OS, overall survival; TTP, time-to-progression Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

% of n Child-Pugh A (n=1968)

Child-Pugh B (n=666)

Child-Pugh C (n=74)

total (n=3202)*

Number of patients 615 208 23 100

Male/female 82/18 81/19 82/18 82/18Median age, years 64 61 58 62ECOG PS

0 or 1 88 72 59 83>2 7 21 34 12

TNM stageI 5 4 7 5II 15 9 14 12III 36 43 34 35IV 36 33 30 35

BCLC stageA 8 6 0 7B 22 20 0 20C 57 56 1 52

D 3 5 89 5

*includes 493 non-evaluable patients BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; TNM, tumor node metastasis Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

GIDEON final analysis:baseline patients characteristics by Child-Pugh status

GIDEON final analysis: overall treatment-emergent safety data by CP

% of n Child-Pugh A (n=1968)


Child-Pugh C (n=74)

total (n=3202)a

AEs (all grades) 84 88.6 91.9 85.3

Drug-related AEs (all grades) 68.5 64.4 39.2 66.0

Serious AEsb (all grades) 36.0 60.4 70.3 43.3

Drug-related serious AEs (all grades) 8.8 14.1 2.7 9.3

All grade 3 or 4 32.5 31.6 17.6 31.8

Drug-related grade 3 or 4 25.5 22.0 10.8 23.6

AEs resulting in permanent discontinuation of sorafenib 28.9 40.1 43.2 31.4

Deathsc 17.7 35.9 51.4 23.7

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 Clin Oncol 31, 2013 (suppl; abstr 4126)

GIDEON final analysis: rate of drug-related AEsa by CP status

Rate, event per patient-yeara

Child-Pugh A (n=1968)


Child-Pugh C (n=74)

Total(n=3202)b

Any AE 1.17 25.5 1.41 1.24

Diarrhea 0.48 25.5 0.39 0.51

HFSR 0.54 17.0 0.19 0.50

Fatigue 0.27 14.3 0.49 0.29

Rash / desquamation

0.21 8.6 0.15 0.21

Anorexia 0.18 7.4 0.24 0.18

Nausea 0.09 6.2 0.34 0.12

Pain, abdomen, NOS 0.05 3.6 0.19 0.06

Liver dysfunction 0.03 3.6 0 0.03

aRate calculation based on treatment-emergent AEs with >10% incidence and 365.25 days per year; bIncludes 493 non-evaluable patients


GIDEON final analysis: onset time of AEs > grade 3 by CP status

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

Time to AE onset (days)Child-Pugh A Child-Pugh B


GIDEON final analysis: sorafenib dosing and treatment duration by CP status

aIncludes 493 non-evaluable patients Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

Child-Pugh A (n=1968)


Child-Pugh C (n=74)

total (n=3202)a

Initial dose of 800 mg, % of 84 88.6 91.9 85.3

Initial dose of 400 mg, % of n 68.5 64.4 39.2 66.0

Median daily dose, mg 36.0 60.4 70.3 43.3

Median treatment duration, weeks 8.8 14.1 2.7 9.3

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

GIDEON final analysis: duration of sorafenib treatment by CP status


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

Duration of sorafenib treatment

Child-Pugh A

Child-Pugh B

GIDEON final analysis: OS by CP status

CI, confidence intervalMarrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

Overall survival

Median overall survival (OS; months) was longer in Child-Pugh A patients than in Child-Pugh B and C patients (13.6 vs 5.2 and 2.6, respectively)

GIDEON final analysis: TTP by CP status


Time to progression (TTP) was comparable between Child-Pugh A and B patients

Time to progresion

The imaging examination interval was at the investigators’ discretion

GIDEON final analysis: OS by Child-Pugh B score

Overall survival

Median OS was shorter in patients with a higher Child-Pugh B score


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

global investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with...

Documents

safety of sorafenib

duration of sorafenib

objectivesthe gideon

upthe gideon study

int j clin pract

unresectable hcc

start of sorafenib treatment

duration of therapy