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TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA

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

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TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA

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

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

  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 PBC cryptogenic Anti-HCV + hemochromatosis Anti-HCV+ 94 38% HBsAg+ 28 11% ALCOHOLIC 86 35% HEMOCHROMATOSIS 10 4% PBC 2 1% CRYPTOGENIC 29 12% alcoholic HBsAg +

  5. BCLC HCC STAGING AND TREATMENT 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 D Terminal Portal Invasion M1,N1 CHILD C,PST >2 STAGE C Advanced Portal Invasion, N1,M1 CHILD A/B PST 1-2 Portal Pressure / Bilirubin Associated Diseases increased normal no yes Sorafenib TACE Resection LTX PEI / RFA Supportive Treatment Survival < 3 mo Palliative Treatment – RCT Median survival (untreated) 5-16 mo Potentially Curative Treatment 5-year survival 50-70%

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

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

  9. 1.00 PlaceboMedian: 34.4 weeks (95% CI: 29.4, 39.4) 0.75 0.50 0.25 0 Patients at riskSorafenib: 299 274 241 205 161 108 67 38 12 0 0 303 276 224 179 126 78 47 25 7 2 0 Placebo: SORAFENIB TREATMENT FOR HCC PHASE III SHARP TRIAL OVERALL SURVIVAL SorafenibMedian: 46.3 weeks(95% CI: 40.9, 57.9) Survival Probability Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88). P=0.00058* Weeks 0 8 16 24 32 40 48 56 64 72 80

  10. 1.00 SorafenibMedian: 24.0 weeks(95% CI: 18.0, 30.0) PlaceboMedian: 12.3 weeks(95% CI: 11.7, 17.1) 0.75 0.50 0.25 0 0 6 12 18 24 30 36 42 48 54 196 126 80 50 28 14 8 2 0 192 101 57 31 12 8 2 1 0 SORAFENIB TREATMENT FOR HCC PHASE III SHARP TRIAL TIME TO PROGRESSION Probability of progression Hazard ratio (S/P): 0.58 . (95% CI: 0.44, 0.74) P=0.000007 Weeks Patients at riskSorafenib: 299 Placebo: 303

  11. SORAFENIB TREATMENT FOR HCC PHASE III SHARP TRIAL Baseline characteristics of patients Characteristics Sorafenib Placebo (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 / 19 27 / 18 Alcohol / other 26 / 26 26 / 29 Child (A / B; %) 95 / 5 98 / 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. SORAFENIB TREATMENT FOR HCC PHASE III SHARP TRIAL Safety events Sorafenib Placebo (n=299) (n=303) Serious adverse events (SAE;%) 52 54 Adverse events (%) all grade 3/4 all grade 3/4 Diarrhea 39 8/- 11 2/- Pain (abdomen) 8 2/- 3 <1/- Weight loss 9 2/- <1 0/- Anorexia 14 <1/- 3 <1/- Nausea 11 <1/- 8 1/- Hand-foot skin reaction 21 8/- 3 <1/- Vomiting 5 1/- 3 <1/- Alopecia 14 0/- 2 0/- Liver dysfunction <1 <1/- 0 0/- Bleeding 7 <1/- 4 <1/<1

  13. Sorafenib plus doxorubicin in patients with advanced HCC OVERALL SURVIVAL 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 OS (% pts) 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Time from randomisation (mo) Abou-Alfa GK. ECCO 2007

  14. BCLC HCC STAGING AND TREATMENT 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 D Terminal Portal Invasion M1,N1 CHILD C,PST >2 STAGE C Advanced Portal Invasion, N1,M1 CHILD A/B PST 1-2 Portal Pressure / Bilirubin Associated Diseases increased normal no yes New Agents TACE Resection LTX PEI / RFA Supportive Treatment Survival < 3 mo Palliative Treatment – RCT Median survival (untreated) 5-16 mo Potentially Curative Treatment 5-year survival 50-70%

  15. Targeted agents in development for HCC Phase II complete

  16. 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 Faivre SJ, et al. ASCO 2007

  17. Erlotinib in patients with advanced HCC • 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%]) 100 80 60 40 20 0 OS PFS Patients (%) 0 3 6 9 12 15 18 21 24 27 30 Follow-up (months) Philip PA. J Clin Oncol 2005;23:6657–63

  18. Summary • Sorafenib standard treatment in advanced HCC (BCLC stage C) and well preserved liver function (Child A). • Prolongs TTP and survival (Phase III study) • 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

  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 / m2 loading dose + 250 mg / m2 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

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