1 First interim results of GIDEON: oncologists and non-oncologists appear to use sorafenib differently Alan P Venook, MD University of California, San Francisco, USA R Lencioni, JA Marrero, M Kudo, K Nakajima, F Cihon, SL Ye

2 ASCO conflict of interest disclosure for Alan P Venook Consultant or advisory role –Yes, NCCN Stock ownership and/or employment –No Honoraria received –No Research funding received –Yes, Bayer, Onyx, Genentech, Novartis, Roche, Pfizer, NCCN Expert testimony –No Other remuneration –No

3 Introduction Sorafenib is the only systemic therapy indicated to treat HCC –In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with HCC –Survival was distinctly different across regions The ongoing GIDEON registry study aims to evaluate the use of sorafenib in clinical practice conditions GIDEON goal is to recruit ~3000 patients from >400 sites in >40 countries HCC, hepatocellular carcinoma; OS, overall survival

4 SHARP: OS Adapted from Llovet JM et al. N Engl J Med 2008; 359: Months since randomization Probability of survival Sorafenib Median: 10.7 months (95% CI: ) Placebo Median: 7.9 months (95% CI: ) HR (S/P): 0.69 (95% CI: ) p<0.001 Sorafenib Patients at risk Placebo

5 Asia-Pacific: OS Survival probability HR (S/P): 0.68 (95% CI: ) p= Months since randomization Sorafenib Patients at risk Placebo Adapted from Cheng AL et al. Lancet Oncol 2009; 10: Placebo Median: 4.2 months (95% CI: ) Sorafenib Median: 6.5 months (95% CI: )

6 SHARP 10.7 months 7.9 months Asia-Pacific: OS Survival probability HR (S/P): 0.68 (95% CI: ) p= Adapted from Cheng AL et al. Lancet Oncol 2009; 10: Sorafenib Median: 6.5 months (95% CI: ) Placebo Median: 4.2 months (95% CI: ) Months since randomization Sorafenib Patients at risk Placebo

7 Asia-Pacific Liver Cancer Study and SHARP: baseline patient characteristics Asia-Pacific (n=226) SHARP (n=602) Median age (range), years 51 (23-86)67 (21-89) Hepatitis virus status (HBV/HCV), %73/818/28 Sex (male), %8587 ECOG PS (0/1/2), %26/69/554/38/8 Macroscopic vascular invasion, %3538 Extra-hepatic spread, %6951 BCLC stage (B/C), %4/9617/82 No. of tumor sites, % ≥43513 Sites of disease, % Lung5021 Lymph node3226 BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status

8 Endpoint Asia-PacificSHARP HR (95% CI)p value HR (95% CI)p value OS <0.001 ( )( ) TTSP ( )( ) TTP 0.57 < <0.001 ( ) ( ) PFS 0.62 < <0.001 ( )( ) PFS, progression-free survival; TTSP, time to symptomatic progression; TTP, time to progression Asia-Pacific Liver Cancer Study and SHARP: efficacy

9 The GIDEON registry study The primary objective is to evaluate the safety of sorafenib in patients with HCC under real-life practice conditions GIDEON should: –provide information on treatment patterns and outcomes for patients with HCC –provide data on patients who would not have been eligible for sorafenib clinical trials –enable a greater understanding of practice in the real-world setting GIDEON may: –help explain differences in outcome by region

10 GIDEON first interim analysis The first interim analysis was planned when ~500 patients had been followed for ≥4 months There were no pre-specified interventions Data were collected prior to the start of sorafenib treatment, then patients who received sorafenib were followed up as per physicians’ usual practice 511 patients enrolled (140 sites) 479 patients (safety population) reported here –Results of preplanned subgroup analyses are included

11 GIDEON: first interim analysis distribution of patients a by region a In the safety population (N=479)

12 Table 1. Patients by region and specialty Hep/GI n (%) Med Onc n (%) Surgery n (%) Other a n (%) Asia-Pacific, n= (53)58 (35)6 (4)14 (8) Europe, n=14393 (65)40 (28)2 (1)4 (3) USA, n=11639 (34)62 (53)10 (9)2 (2) Latin America, n=3218 (56) 8 (25)6 (19)0 Japan, n=2110 (48) 011 (52)0 Total, b N= (52) 168 (35)35 (7)20 (4) a Other includes radiology, anesthesiology, and traditional Chinese medicine b Includes all specialties; missing data not tabulated

13 Child-Pugh: classification severity of liver disease Pugh RN et al. Br J Surg 1973; 60: ; Lucey MR et al. Liver Transpl Surg 1997; 3: Measure1 point2 points3 points Bilirubin (mg/dL) < >3.0 Albumin (g/dL)> <2.8 Prothrombin time (sec)< >6.0 AscitesNoneSlightModerate Encephalopathy (grade)NoneI-IIIII-IV GradeTotal pointsSurgical risk2-year survival A (Well-compensated disease) 5-6Good85% B (Significant functional compromise) 7-9Moderate60% C (Decompensated disease) 10-15Poor35%

14 Table 2. Selected patient baseline disease characteristics by specialty Hep/GI (n=248) Med Onc (n=168) Surgery (n=35) Total a (N=479) BCLC, n (%) Stage C129 (52)98 (58)9 (26)253 (53) TNM, n (%) Stage IV 69 (28)78 (46)10 (29)167 (35) Child-Pugh, n (%) A (5-6) B (7-9) 149 (60) 80 (32) 91 (54) 34 (20) 17 (49) 16 (46) 278 (58) 134 (28) Vascular invasion, n (%) 75 (30)20 (12)9 (26)107 (22) Extra-hepatic spread, n (%) 73 (29)77 (46)10 (29)170 (35) TNM, tumor nodes metastasis a Includes all specialties

15 Results: variations in patient characteristics by specialty Most common treating physician specialty by region: –Med Onc in USA –Hep/GI in Asia-Pacific, Europe, and Latin America Patients with more advanced disease (BCLC and TNM) and extra-hepatic spread were most often treated by Med Oncs compared with Hep/GIs The largest proportion of patients with Child-Pugh B status (80 of 134 patients; 60%) were treated by Hep/GIs

16 Table 3. Summary of sorafenib daily dose by specialty and region Median daily dose, mgHep/GIMed OncSurgeryTotal a Asia-Pacific, n=142 b Europe, n=93 b USA, n=96 b Latin America, n=19 b Japan, n=17 b 542.0NA521.0 NA, no specialists in region a Includes all specialties; missing data not tabulated; b Missing data not tabulated

17 Initial sorafenib dose level of 800 mg, n (%) a Hep/GIMed OncSurgeryTotal b Asia-Pacific, n=16782 (93)33 (57)5 (83)133 (80) Europe, n=14371 (76)36 (90)0114 (80) USA, n=11628 (72)32 (52)5 (50)69 (59) Latin America, n=3217 (94)8 (100)6 (100)31 (97) Japan, n=218 (80)NA8 (73)16 (76) Table 4. Summary of initial sorafenib dose level by specialty and region NA, no specialists in region a Denominator for % based on number of patients by specialty in each region; b Includes all specialties

18 Table 5. Summary of sorafenib administration by specialty Hep/GI (n=248) Med Onc (n=168) Surgery (n=35) Total a (N=479) Treatment duration ≤4 weeks, n (%) 53 (21)40 (24)9 (26)106 (22) a Includes all specialties; b Missing data not tabulated Median daily dose, b mg Initial sorafenib dose 800 mg, n (%) 206 (83)109 (65)24 (69)363 (76) Patients with dose interruptions, n (%) 60 (24) 40 (24)11 (31)117 (24) Patients with dose increase, n (%) 35 (14) 33 (20)6 (17)80 (17) Patients with dose reduction, n (%) 77 (31) 54 (32)13 (37)153 (32)

19 Duration of exposure by physicians’ primary specialty: Hep/GI, medical oncology, and surgery a Number of subjects under treatment Time since start of therapy (days) Hepatology / gastroenterology Medical oncology Surgery n=248 n=168 n=35 a Data for radiology (n=6), anesthesiology (n=4), and traditional Chinese medicine (n=10) not shown

20 Results: variations in sorafenib usage by specialty and region In general, a greater percentage of Hep/GIs initiate sorafenib therapy at 800 mg/day Hep/GIs had a higher median daily dose than Med Oncs In Europe and Latin America, the median daily dose of sorafenib used by Hep/GIs and Med Oncs was comparable

21 Table 6. Safety data by specialty (as reported) Hep/GI (n=248) Med Onc (n=168) Surgery (n=35) Total a (N=479) AEs (all grades) 217 (88)149 (89)31 (89)415 (87) AEs (grade 3/4)81 (33)60 (36)13 (37)161 (34) Drug-related AEs (all grades)156 (63)125 (74)26 (74)319 (67) Drug-related AEs (grade 3/4)49 (20) 41 (24)13 (37)109 (23) SAEs b (all grades)117 (47) 59 (35)19 (54)201 (42) Drug-related SAEs b (all grades)28 (11) 14 (8)8 (23)51 (11) AEs resulting in permanent discontinuation of sorafenib c 81 (33) 34 (20)15 (43)133 (28) Deaths d 69 (28) 29 (17)11 (31)114 (24) AE, adverse event; a Includes all specialties; b Serious AE (SAE) is any AE at any dose resulting in any of the following outomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically important event; c Any AE; d Treatment-emergent deaths occurring up to 30 days after last sorafenib dose

22 Table 7. Drug-related AEs (all grades) by specialty (incidence ≥10% in any group) n (%) Hep/GI (n=248) Med Onc (n=168) Surgery (n=35) Total a (N=479) HFSR 56 (23)51 (30)10 (29)124 (26) Diarrhea57 (23)46 (27)8 (23)114 (24) Rash / desquamation 31 (13)27 (16)3 (9)63 (13) Fatigue24 (10)22 (13)2 (6)51 (11) Hypertension12 (5)12 (7)5 (14)29 (6) Thrombocytopenia3 (1)17 (10)2 (6)23 (5) HFSR, hand-foot skin reaction a Includes all specialties

23 Results: no clinically significant difference in AE profiles across specialties Based on reported data, AE profiles across specialties appear to be comparable Med Oncs reported fewer SAEs, discontinuations due to any AE, and deaths on treatment The most common drug-related AEs were HFSR and diarrhea, irrespective of specialty However, follow-up intervals / assessments and dose adjustments were not specified so further analysis of this data will be necessary

24 Conclusions The first interim analysis of GIDEON suggests differential use of sorafenib depending on physician specialty and region No apparent clinically significant differences in the overall AE and drug-related AE profile of sorafenib were seen across specialties in these early analyses

25 In the non-clinical trial setting, what makes dosing of sorafenib different in patients with HCC? –Patient factors: extent of cancer, liver dysfunction, general condition? –Physician specialty? –Physician expectations? –Patient preference / expectations? –Regional differences? Questions

26 Questions Are these findings real or a reflection of physicians selected to participate in GIDEON? Is a registry a ‘real-life’ setting? If true, why do Hep/GIs use more sorafenib than Med Oncs? More mature data from GIDEON as well as additional studies may be useful in providing further data on sorafenib dosing and ensuring its optimal use

27 Acknowledgments The study was supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals