Alan P Venook, MD University of California, San Francisco, USA

1. First interim results of GIDEON:oncologists and non-oncologistsappear 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 interestdisclosure 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 indicatedto 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 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 299303 290295 270272 249243 234217 213189 200174 172143 140108 11183 8969 6847 4831 3723 2414 76 13 00 Sorafenib Median: 10.7 months (95% CI: 9.4-13.3) 1.00 0.75 Placebo Median: 7.9 months (95% CI: 6.8-9.1) Probability of survival 0.50 HR (S/P): 0.69(95% CI: 0.55-0.87)p<0.001 0.25 0 Months since randomization Patients at risk Sorafenib Placebo Adapted from Llovet JM et al. N Engl J Med 2008; 359: 378-390

5. 2 4 6 8 10 12 14 16 18 20 22 0 150 134 103 78 53 32 21 15 13 4 1 0 76 62 41 26 23 15 9 5 4 1 0 0 Asia-Pacific: OS Sorafenib Median: 6.5 months (95% CI: 5.6-7.6) 1.00 0.75 Placebo Median: 4.2 months (95% CI: 3.7-5.5) 0.50 Survival probability HR (S/P): 0.68(95% CI: 0.50-0.93)p=0.014 0.25 0 Months since randomization Patients at risk Sorafenib Placebo Adapted from Cheng AL et al. Lancet Oncol 2009; 10: 25-34

6. Sorafenib Median: 6.5 months(95% CI: 5.6-7.6) Placebo Median: 4.2 months(95% CI: 3.7-5.5) 2 4 6 8 10 12 14 16 18 20 22 0 150 134 103 78 53 32 21 15 13 4 1 0 76 62 41 26 23 15 9 5 4 1 0 0 Asia-Pacific: OS SHARP 10.7 months 7.9 months 1.00 0.75 0.50 Survival probability HR (S/P): 0.68 (95% CI: 0.50-0.93) p=0.014 0.25 0 Months since randomization Patients at risk Sorafenib Placebo Adapted from Cheng AL et al. Lancet Oncol 2009; 10: 25-34

7. Asia-Pacific Liver Cancer Study and SHARP:baseline patient characteristics BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status

8. 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

9. 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

10. GIDEON: first interim analysisdistribution of patientsa by region aIn the safety population (N=479)

11. Table 1. Patients by region and specialty aOther includes radiology, anesthesiology, and traditional Chinese medicine bIncludes all specialties; missing data not tabulated

12. Child-Pugh: classificationseverity of liver disease Pugh RN et al. Br J Surg 1973; 60: 646-649; Lucey MR et al. Liver Transpl Surg 1997; 3: 628-637

13. Table 2. Selected patient baselinedisease characteristics by specialty TNM, tumor nodes metastasis aIncludes all specialties

14. Results: variations in patientcharacteristics 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 byMed 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

15. Table 3. Summary of sorafenibdaily dose by specialty and region NA, no specialists in region aIncludes all specialties; missing data not tabulated; b Missing data not tabulated

16. Table 4. Summary of initial sorafenibdose level by specialty and region NA, no specialists in region aDenominator for % based on number of patients by specialty in each region; bIncludes all specialties

17. Table 5. Summary of sorafenibadministration by specialty aIncludes all specialties; bMissing data not tabulated

18. Duration of exposure by physicians’ primary specialty: Hep/GI, medical oncology, and surgerya 300 Hepatology / gastroenterologyMedical oncologySurgery n=248 200 Number of subjects under treatment 100 n=168 n=35 0 0 100 200 300 400 Time since start of therapy (days) aData for radiology (n=6), anesthesiology (n=4), and traditional Chinese medicine (n=10) not shown

19. Results: variations in sorafenibusage 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

20. Table 6. Safety databy specialty (as reported) AE, adverse event; aIncludes all specialties; bSerious 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; cAny AE; dTreatment-emergent deaths occurring up to 30 days after last sorafenib dose

21. Table 7. Drug-related AEs (all grades) byspecialty (incidence ≥10% in any group) HFSR, hand-foot skin reactionaIncludes all specialties

22. 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

23. 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

24. Questions • 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?

25. 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 ensuringits optimal use

26. Acknowledgments • The study was supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals