1. TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA Universitätsklinik für Innere Medizin III Klin. Abtl. für Gastroenterologie und Hepatologie Christian Müller

2. TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA Universitätsklinik für Innere Medizin III Klin. Abtl. für Gastroenterologie und Hepatologie Christian Müller

3. HEPATOCELLULAR CARCINOMA INCIDENCE  rising incidence  worldwide most frequent malignancy  Austria 9 / 100.000 2% of all tumors Bosch et al. Sem.Liv.Dis. 1999; 19: 271-285.

4. HEPATOCELLULAR CARCINOMA ETIOLOGY OF LIVER DISEASE Anti-HCV+9438% HBsAg+2811% ALCOHOLIC8635% HEMOCHROMATOSIS10 4% PBC 2 1% CRYPTOGENIC29 12% alcoholic Anti-HCV + HBsAg + hemochromatosis PBC cryptogenic

5. HCC STAGE 0 Very early 1 HCC < 2 cm CHILD A PST 0 STAGE A Early 1 HCC < 5 cm or <3 HCC < 3 cm CHILD A/B PST 0 STAGE B Intermediate Multinodular CHILD A/B PST 0 STAGE C Advanced Portal Invasion, N1,M1 CHILD A/B PST 1-2 STAGE D Terminal Portal Invasion M1,N1 CHILD C,PST >2 BCLC HCC STAGING AND TREATMENT Portal Pressure / Bilirubin Associated Diseases ResectionLTXPEI / RFA normal increased noyes TACE Sorafenib Potentially Curative Treatment 5-year survival 50-70% Palliative Treatment – RCT Median survival (untreated) 5-16 mo Supportive Treatment Survival < 3 mo

6. SORAFENIB IN HCC TREATMENT - RATIONALE  RAF kinase overexpressed and activated in HCC  RAF / MEK / ERK signaling pathway implicated in liver tumorigenesis  Sorafenib is a multikinase inhibitor of RAF, VEGFR, and other kinases  Sorafenib induces apoptosis in HCC xenograft models  Sorafenib active in Phase II trial of patients with advanced HCC and CHILD A / B liver function Hwang et al. Hepatol Res 2004;29:113-121 Calvisi et al. Gastroenterology 2006;130:1117-1128 Villanueva et al. Semin Liv Dis 2007; 27:55-76 Liu et al. Cancer Res 2006; 66:11851-11858 Abou-Alfa et al. J Clin Oncol 2006; 24: 4293-4300

7. RAS Endothelial cell or Pericyte Angiogenesis: PDGF-  VEGF VEGFR-2 PDGFR-  Paracrine stimulation Mitochondria Apoptosis Tumor cell PDGF VEGF EGF/HGF Proliferation Survival Mitochondria EGF/HGF HIF-2 Nucleus Autocrine loop Apoptosis ERK RAS MEK RAF Nucleus ERK MEK Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis Wilhelm S et al. Cancer Res. 2004;64:7099-7109 RAF Differentiation Proliferation Migration Tubule formation Sorafenib

8. PHASE III SHARP TRIAL SORAFENIB TREATMENT FOR HCC STUDY DESIGN PRIMARY END-POINT: OVERALL SURVIVAL TIME TO SYMPTOMATIC PROGRESSION SECONDARY END-POINTS: TIME TO PROGRESSION Stratification: Macroscopic vascular invasion and / or extrahepatic spread ECOG PS Geographic region Randomization n = 602 Sorafenib (n=299) 400 mg po bid Continous dosing Placebo (n=303) 2 tablets po bid Continous dosing

9. Sorafenib Median: 46.3 weeks (95% CI: 40.9, 57.9) Survival Probability Weeks Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88). P=0.00058* Placebo Median: 34.4 weeks (95% CI: 29.4, 39.4) 1.00 0 0.75 0.50 0.25 08081624324048566472 02742412051611086738120 Patients at risk Sorafenib: 027622417912678472572 Placebo: 299 303 PHASE III SHARP TRIAL SORAFENIB TREATMENT FOR HCC OVERALL SURVIVAL

10. 01961268050281482 0192101573112821 Probability of progression Hazard ratio (S/P): 0.58. (95% CI: 0.44, 0.74) P=0.000007 546121824303642480 Weeks Sorafenib Median: 24.0 weeks (95% CI: 18.0, 30.0) Placebo Median: 12.3 weeks (95% CI: 11.7, 17.1) 1.00 0 0.75 0.50 0.25 Patients at risk Sorafenib: Placebo: 299 303 PHASE III SHARP TRIAL SORAFENIB TREATMENT FOR HCC TIME TO PROGRESSION

11. PHASE III SHARP TRIAL SORAFENIB TREATMENT FOR HCC Baseline characteristics of patients CharacteristicsSorafenibPlacebo (n=299) (n=303) Age (vears,median) 65 66 Male / Female (%) 87 / 13 87 / 13 Region (Europe / N.America / others;%) 88 / 9 / 3 87 / 10 / 3 Etiology (%) HCV / HBV 29 / 1927 / 18 Alcohol / other 26 / 2626 / 29 Child (A / B; %) 95 / 598 / 2 Prior Therapies (%): Resection 19 21 PAI / RFA / TACE 39 41 BCLC stage (%) Stage B 18 17 Stage C 82 83 ECOG PS (%) ECOG 0 54 54 ECOG 1 38 39 ECOG 2 8 7 Vascular Invasion / Extrahepatic spread (%) 70 70

12. PHASE III SHARP TRIAL SORAFENIB TREATMENT FOR HCC Safety events SorafenibPlacebo (n=299) (n=303) Serious adverse events (SAE;%) 52 54 Adverse events (%)allgrade 3/4allgrade 3/4 Diarrhea39 8/-11 2/- Pain (abdomen) 8 2/- 3 <1/- Weight loss 9 2/-<1 0/- Anorexia14 <1/- 3 <1/- Nausea11 <1/- 8 1/- Hand-foot skin reaction21 8/- 3 <1/- Vomiting 5 1/- 3 <1/- Alopecia14 0/- 2 0/- Liver dysfunction<1 <1/- 0 0/- Bleeding 7 <1/- 4 <1/<1

13. Sorafenib plus doxorubicin in patients with advanced HCC OS (% pts) Time from randomisation (mo) 02.55.07.510.012.515.017.520.0 Median OS (Phase II) Doxorubicin + sorafenib: 13.7 months (95% CI: 10.4–can not be estimated) 100 75 50 25 0 Doxorubicin + placebo: 6.5 months (95% CI: 4.9–9.5) HR=0.45; p=0.0049 Censored treatment Abou-Alfa GK. ECCO 2007 OVERALL SURVIVAL

14. HCC STAGE 0 Very early 1 HCC < 2 cm CHILD A PST 0 STAGE A Early 1 HCC < 5 cm or <3 HCC < 3 cm CHILD A/B PST 0 STAGE B Intermediate Multinodular CHILD A/B PST 0 STAGE C Advanced Portal Invasion, N1,M1 CHILD A/B PST 1-2 STAGE D Terminal Portal Invasion M1,N1 CHILD C,PST >2 BCLC HCC STAGING AND TREATMENT Portal Pressure / Bilirubin Associated Diseases ResectionLTXPEI / RFA normal increased noyes TACE New Agents Potentially Curative Treatment 5-year survival 50-70% Palliative Treatment – RCT Median survival (untreated) 5-16 mo Supportive Treatment Survival < 3 mo

15. Targeted agents in development for HCC Agent Anti-angiogenic targetsAntiproliferative targets Developmental status VEGFVEGFRPDGFREGFRRafmTOR Bevacizumab ● Phase II ongoing Brivanib ● Phase II recruiting Cediranib ● Phase II recruiting Erlotinib ● Phase II complete Gefitinib ● Phase II complete Cetuximab ● Lapatinib ● Phase II ongoing RAD001 ● Phase I/II recruiting Sorafenib* ●●● Phase III complete Sunitinib* ●● Phase II ongoing Thalidomide ● Phase III recruiting TSU-68 ●● Phase I/II recruiting Phase II complete

16. Faivre SJ, et al. ASCO 2007 Sunitinib in patients with unresectable HCC Patients (n=37) sunitinib 50mg daily for 4 weeks, 2 weeks pause Major (≥50%) tumour necrosis: 46% of patients Response (RECIST) –PR: 1 pt (3%) –SD >3 months: 13 pts (35%) –SD >6 months: 8 pts (22%) Grade 3–4 toxicities: thrombocytopenia (43%) neutropenia (24%) CNS symptoms (24%) asthenia (22%) haemorrhage (14%) Grade 5 toxicity (bleeding, drowsiness, hepatic encephalopathy and renal failure) Grade 1–2 skin toxicity frequently reported Dose reductions: 27% of patients

17. 38 pts erlotinib 150mg daily Median OS: 13 months PFS: 3 months Grade 3–4 Aes: 61% of patients (skin rash [13%], diarrhoea [8%] and fatigue [8%]) Erlotinib in patients with advanced HCC Philip PA. J Clin Oncol 2005;23:6657–63 100 80 60 40 20 0 036912151821242730 Follow-up (months) Patients (%) OS PFS

18. Summary Several targeted agents, either alone or in combination with other therapies, have shown promising efficacy and tolerability in phase II trials of patients with advanced HCC Randomised, phase III trials, with sorafenib as an active comparator, will be required to optimise targeted therapy of HCC in the future Sorafenib standard treatment in advanced HCC (BCLC stage C) and well preserved liver function (Child A). Prolongs TTP and survival (Phase III study)

19. Studies with other targeted therapeutic agents in advanced HCC Thalidomide Cetuximab (Erbitux; EGFR-Ak) Bevacizumab (Avastin; VEGF-AK) Bevacizumab + Erlotinib Bevacizumab + Capecitabine Perifosine (Akt- Inhibitor) Erlotinib (Terceva; EGFR Thyrosinkinase-Inhibitor) Gefitinib (Iressa; EGFR Thyrosinkinase-Inhibitor) Lapatinib (Tyverb; EGFR Thyrosinkinase-Inhibitor) 32 pts cetuximab 400 mg / m 2 loading dose + 250 mg / m 2 i.v. weekly 27 pts evaluable for tumour response –SD ≥8 weeks: 12 pts (44.4%) Median time to progression (TTP): 8 weeks –median TTP in pts with SD ≥8 weeks: 22.5 weeks No treatment-related severe AEs noted