GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) second interim analysis in >1500 patients: clinical findings in patients with liver dysfunction Jorge A. Marrero, M.D., M.S. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States R. Lencioni, M. Kudo, S. L. Ye, K. Nakajima, F. Cihon, A. Venook

Introduction Sorafenib is the only systemic therapy indicated to treat HCC 1 In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with uHCC 2-3 Pivotal studies generally included patients with preserved liver function Investigation of sorafenib in wider patient groups is needed 4 GIDEON is the largest prospective study in uHCC ever conducted In total, 3322 patients have been enrolled from 39 countries 1.NCCN Guidelines™: Hepatobiliary Cancers. Available at: Accessed: June 7, Llovet JM, et al. N Engl J Med. 2008;359(4): Cheng AL, et al. Lancet Oncol. 2009;10(1): Lencioni R, et al. Int J Clin Prac. 2010;64(8): uHCC, unresectable hepatocellular carcinoma; OS, overall survival;

The GIDEON study design and objectives GIDEON is a non-interventional study Primary objective: to evaluate safety of sorafenib in patients with uHCC who are candidates for systemic therapy and for whom the decision to treat with sorafenib was made in clinical practice Secondary objectives: efficacy, duration of therapy; methods of patient evaluation, diagnosis and follow-up; co-morbidities and practice patterns GIDEON will also provide information in patient subgroups where data are currently limited Including patients with Child-Pugh B status who were generally excluded from sorafenib Phase III trials in uHCC Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting. uHCC, unresectable hepatocellular carcinoma;

The GIDEON study: second interim analysis Per protocol the second interim analysis was planned when ~1500 treated patients were followed for ≥4 months 1571 patients in the safety population Includes patients who received ≥1 dose of sorafenib and had ≥1 follow-up assessment after start of treatment 1612 patients in the ITT population ITT population used for analysis of OS and TTP Includes patients who received ≥1 dose of sorafenib >2 days before study entry; excludes patients previously treated with sorafenib All statistical analyses performed were descriptive in nature Lencioni R, et al. Int J Clin Prac. 2010;64(8): Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting. ITT, intent to treat; OS, overall survival; TTP, time-to-progression

Selected patient baseline characteristics by Child-Pugh status at start of therapy a Child-Pugh status unknown for 5 patients; 207 patients are not evaluable and not tabulated ECOG PS, Eastern Cooperative Oncology Group performance status Total a (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) Patients, % of n Male / female, % of n 82 / 1883 / 1781 / 1983 / 17 Median age, years (range) 62 (18-98)64 (18-94)61 (23-86)58 (39-82) ECOG PS, % of n < < Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Selected patient baseline characteristics by Child-Pugh status at start of therapy a Child-Pugh status unknown for 5 patients; 207 patients are not evaluable and not tabulated BCLC, Barcelona Clinic Liver Cancer; TNM, tumor node metastases % of n Total a (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) TNM stage I II III IV BCLC stage A B C D Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Initial sorafenib dose by Child-Pugh status and Child-Pugh B status % of n Total a (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) 800 mg mg mg mg mg<1 00 a Initial dosing data missing for 8 patients; Child-Pugh status unknown for 5 patients Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Sorafenib dosing and average daily dosing by Child- Pugh status a a Data at study entry; b Dosing data missing for 8 patients; Child-Pugh status unknown for 5 patients; c Assessed in the 79% of patients for whom dosing data were available Total b (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) Mean daily dose, mg c Median daily dose, mg c Dose increase, % of n Dose increase to 800 mg from lower initial doses, % of n 6650 Number of dose increases Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Sorafenib dose interruptions and modifications by Child- Pugh status a % of n Total b (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) Dose interruption Dose modification Dose increase Dose reduction a Data at study entry b Dosing data missing for 8 patients; Child-Pugh status unknown for 5 patients Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Duration of sorafenib therapy by Child-Pugh status a Total (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) ≤4 weeks, % >4-8 weeks, % >8-20 weeks, % >20-28 weeks, % >28 weeks, % Median treatment duration, weeks a Data at study entry Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Overview of treatment-emergent safety data by Child-Pugh status a % of n Total b (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) AEs (all grades) Drug-related AEs (all grades) AEs (grade 3/4) Drug-related AEs (grade 3/4) SAEs b Drug-related SAEs c AEs resulting in permanent discontinuation of sorafenib d Deaths e a Data at study entry; b Child-Pugh status missing or not evaluable for 56 patients; c An SAE is defined as any 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; d Any AE; e Treatment-emergent deaths occurring up to 30 days after last sorafenib dose AEs, adverse events; SAEs, serious adverse events Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Overview of treatment-emergent safety data by Child-Pugh B status a % of n Child-Pugh B (7-9) (n=367) Child-Pugh B (7) (n=196) b Child-Pugh B (8) (n=96) b Child-Pugh B (9) (n=69) b AEs (all grades) Drug-related AEs (all grades) AEs (grade 3/4) Drug-related AEs (grade 3/4) SAEs c Drug-related SAEs c AEs resulting in permanent discontinuation of sorafenib d Deaths e a Data at study entry; b Patients with Child-Pugh status available; c An SAE is defined as any 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; d Any AE; e Treatment-emergent deaths occurring up to 30 days after last sorafenib dose AEs, adverse events; SAEs, serious adverse events Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Treatment-emergent drug-related AEs by Child-Pugh status a,b % of n Total Any grade (n=1571) Total G3/G4 (n=1571) Child-Pugh A (<7) (n=957) Child-Pugh B (7-9) (n=367) Child-Pugh C (>9) (n=35) Diarrhea253 / HFSR245 / Fatigue 143 / < Rash / desquamation 122 / < Anorexia91 / Hypertension72 / 0930 Alopecia60 / 0833 Nausea6<1 / 0556 Weight loss5<1 / 0543 Pain, abdomen, NOS 3<1 / 0346 a Incidence ≥5% in any group and any grade; b At start of therapy HFSR, hand-foot skin reaction; NOS, not otherwise specified Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Cause of death a,b while on sorafenib therapy or within 30 days of discontinuing therapy c n (%) deaths Total d (n=343) Child-Pugh A e (<7) (n=154) Child-Pugh B e (7-9) (n=125) Child-Pugh C (>9) (n=13) HCC-related138 (40)61 (40)50 (40)4 (31) HCC- and liver- related 38 (11)15 (10)15 (12)3 (23) HCC- and liver- related, and MOF 9 (3)4 (3)2 (2)1 (8) Liver-related49 (14)22 (14)18 (14)2 (15) HCC-related and MOF 15 (4)8 (5)4 (3)0 MOF22 (6)10 (6)8 (6)1 (8) a Incidence >2% in total group; b Patients may be included in more than one cause of death category; b By Child-Pugh status at study entry; d Child-Pugh status missing for 1 patient; e Data missing for 7 Child-Pugh A and 7 Child-Pugh B patients HCC, hepatocellular carcinoma; MOF, multi-organ system failure Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Preliminary overall survival by Child-Pugh status a at study entry Child Pugh A (<7) (n=984), median (95% CI) 312 (284, 341) days 10.3 months Child Pugh B (7-9) (n=376), median (95% CI) 147 (126, 189) days 4.8 months Child Pugh C (>9) (n=36), median (95% CI) 62 (46, 94) days 2.0 months Time since start of treatment (days) Survival distribution function a 207 patients not evaluable CI, confidence interval Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Preliminary time-to-progression a by Child-Pugh status b at study entry Child Pugh A (<7) (n=984), median (95% CI) 129 (119, 146) days 4.2 months Child Pugh B (7-9) (n=376), median (95% CI) 109 (93, 140) days 3.6 months Child Pugh C (>9) (n=36), median (95% CI) 64 (28, 110) days 2.1 months Time since start of treatment (days) TTP distribution function a TTP was documented radiological disease progression; RECIST v 1.0 used for tumor evaluation; b 207 patients not evaluable TTP, time-to-progression; RECIST, Response Evaluation Criteria In Solid Tumors Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Conclusions (1) Based on the second interim analysis, there is no evidence suggesting that treating physicians use a different dosing strategy for Child-Pugh B patients compared with Child- Pugh A patients Duration of sorafenib therapy was shorter in Child-Pugh B patients than in Child-Pugh A patients Compared with Child-Pugh A patients, Child-Pugh B patients did not have a higher incidence of drug-related AEs, but had a higher incidence of liver-associated AEs In patients with moderate liver dysfunction, no unexpected AEs were observed Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.

Conclusions (2) The vast majority of deaths were due to HCC or underlying liver disorders The differences in patient outcomes across Child-Pugh groups likely reflect differences in prognosis Consistent with previously reported studies, these preliminary data indicate that Child-Pugh status appears to be a useful prognostic factor for overall survival The GIDEON study is ongoing, and the safety, tolerability, and efficacy of sorafenib in HCC patients will continue to be evaluated Adapted from Marrero J, et al. J Clin Oncol. 2011;29(suppl): Abstract 4001; oral presentation at 2011 ASCO Annual Meeting.