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Sorafenib for Advanced HCC – Current Status and Future Prospects

Sorafenib for Advanced HCC – Current Status and Future Prospects. Prof Dr Markus Peck-Radosavljevic Allgemeines Krankenhaus & Medizinische Universität Wien Vienna, Austria. Liver Cancer Incidence: Sixth Most Common Cancer Worldwide 1.

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Sorafenib for Advanced HCC – Current Status and Future Prospects

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  1. Sorafenib for Advanced HCC – Current Status and Future Prospects Prof Dr Markus Peck-Radosavljevic Allgemeines Krankenhaus & Medizinische Universität Wien Vienna, Austria

  2. Liver Cancer Incidence:Sixth Most Common Cancer Worldwide1 • HCC is the most common primary liver malignancy in adults2 Lung 1,549,121 Breast 1,301,867 Colon/Rectal 1,167,020 Stomach 1,066,543 Prostate 782,647 Liver 711,128 Cervix Uteri 559,094 Esophagus 529,283 Leukemia 330,963 Bladder 314,256 Ovary 230,555 Corpus Uteri 226,787 Oral Cavity 200,774 Non-Hodgkin's Lymphoma 196,298 0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000 1. Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008. 2. Perz JF, et al. J Hepatol. 2006;45:529-538.

  3. BCLC Staging System HCC Early Stage IntermediateStage Advanced Stage End Stage Surgical Treatment Local Ablation TACE Sorafenib (30%) Potentially Curative Treatments 5-y Survival: 40%-70% (50%-60%) Randomized Trials Median Survival If Untreated: 6-16 mo (10%) BSC Survival <3 mo TACE = transarterial chemoembolization; BSC = best supportive care. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.

  4. Targeted agents in development for HCC *Status as of September 2008 http://clinicaltrials.gov/. Accessed September, 2008; Llovet JM, Bruix J. J Hepatol 2008;48:S20–S37.

  5. RAS MEK ERK Sorafenib Targets Tumor Cell Proliferation and Angiogenesis Tumor Cell Endothelial Cell or Pericyte Paracrine stimulation HGF PDGF-b VEGF Autocrineloop PDGFR-b VEGFR-2 Apoptosis RAS RAF Mcl-1 RAF Sorafenib Mitochondria Sorafenib MEK Mitochondria Angiogenesis: Differentiation HIF ERK HGF Proliferation Apoptosis PDGF Migration VEGF Tubule formation Nucleus Nucleus Proliferation Survival HGF = hepatocyte growth factor. Avila MA, et al. Oncogene. 2006;25:3866-3884; Liu L, et al. Cancer Res. 2006;66:11851-11858; Semela D, et al. J Hepatol. 2004;41:864-880; Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109.

  6. Phase III SHARP and Asia-Pacific studies SHARP1 Asia-Pacific2 • Eligibility • Advanced HCC, ECOG PS 0–2, Child-Pugh A, no prior systemic therapy • Stratification • MVS and/or EHS, ECOG PS (0 vs. 1–2), geographic region RANDOMIZE1:1 RANDOMIZE2:1 n=299 n=303 n=150 n=76 Sorafenib 400 mg bid Placebo Sorafenib 400 mg bid Placebo 1º endpoints: OS, TTSP 2º endpoints: TTP, DCR, safety Endpoints: OS, TTSP, TTP, DCR, safety (no 1º endpoint defined) 1Llovet JM, et al. N Engl J Med 2008;359:378–390; 2Cheng A, et al. Lancet Oncol. 2009; 10; 25-34.

  7. SHARP: Sorafenib increases overall survival compared with placebo 1.00 Sorafenib (n=299) Median OS: 10.7 mo.(95% CI: 9.4–13.3) 0.75 Placebo (n=303) Median OS: 7.9 mo.(95% CI: 6.8–9.1) Survival probability 0.50 HR: 0.69(95% CI: 0.55–0.87)p<0.001* 0.25 *O’Brien-Fleming threshold for statistical significance was p=0.0077 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Months Patients at risk Sorafenib 299 290 270 249 234 213 200 172 140 111 89 68 48 37 24 7 1 0 Placebo 303 295 272 243 217 189 174 143 108 83 69 47 31 23 14 6 3 0 OS = overall survival; HR = hazard ratio. Llovet JM, et al. N Engl J Med 2008;359:378–390.

  8. SHARP: sorafenib delays progression compared with placebo 1.00 HR: 0.5895% CI: 0.45–0.74p<0.001 0.75 Probability of progression 0.50 Sorafenib (n=299) Median TTP: 5.5 mo.(95% CI: 4.1–6.9) Placebo (n=303) Median TTP: 2.8 mo.(95% CI: 2.7–3.9) 0.25 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Patients at risk Sorafenib 299 267 155 101 91 65 37 23 18 10 4 2 0 Placebo 303 275 142 78 62 41 21 11 10 3 1 1 0 TTP = time to tumor progression; HR = hazard ratio. Llovet JM, et al. N Engl J Med 2008;359:378–390.

  9. SHARP: low incidence of grade 3–4 events AEs = adverse events; SAEs = serious adverse events; HFSR = hand-foot skin reaction. Llovet JM, et al. N Engl J Med 2008;359:378–390.

  10. Phase III Asia-Pacific study:overall survival 1.00 Sorafenib (n=150) Median OS: 6.5 mo.95% CI: 5.6–7.6 HR: 0.68(95% CI: 0.50–0.93)p=0.014 0.75 Placebo (n=76) Median OS: 4.2 mo.95% CI: 3.7–5.5 Survival probability 0.50 0.25 0.00 0 2 4 6 8 10 12 14 16 18 20 22 Months Patients at risk Sorafenib 150 134 103 78 53 32 21 15 13 4 1 0 Placebo 76 62 41 26 23 15 9 5 4 1 0 0 Cheng A, et al. Lancet Oncol. 2009; 10: 25-34.

  11. Asia-Pacific PIII Study: Time to Progression 1.00 Sorafenib Median: 2.8 mo (95% CI: 2.6-3.6) 0.75 Placebo Median: 1.4 mo (95% CI: 1.3-1.5) Progression-free probability 0.50 HR (S/P): 0.57 (95% CI: 0.42-0.79)P<0.001 0.25 0 2 4 6 8 10 12 14 16 18 20 22 0 Months Patients at Risk Sorafenib 150 80 38 19 11 8 5 2 1 0 0 0 76 19 10 8 3 0 0 0 0 1 0 0 Placebo Cheng A, et al. Lancet Oncol. 2009; 10: 25-34.

  12. Asia-Pacific Trial1 vs SHARP2:Baseline Patient Characteristics 1. Cheng A, et al. Lancet Oncol 2009; 10: 25-34. 2. Llovet JM, et al. N Engl J Med. 2008 Jul 24;359(4):378-90.

  13. SHARP and Asia Pacific Phase III: Summary • OS, TTP, and PFS hazard ratios were similar in the SHARP and the Asia-Pacific studies, despite more advanced disease in the Asia-Pacific liver cancer study patients • Sorafenib is safe and efficacious in patientswith HCC across geographic regions and across different etiologies

  14. Nexavar in Patients with HCC and Child–Pugh B Liver Dysfunction

  15. Efficacy of Sorafenib in HCCPinter, Peck-Radosavljevic, et al., The Oncologist, in press Child-Pugh * * EASL 2008 * p<0.0001 log rank

  16. Phase II Trial: Maximum Percentage Change in Tumor Size From Baseline* 200 50% 46% 100 Reduction from baseline (%) 0 CP A (n=98) CP B (n=38) -100 CP = Child-Pugh; CP A = CP Class A; CP B = CP Class B. *Reported for each patient. Data on file, Bayer HealthCare.

  17. Nexavar in Combination With Doxorubicin in HCC

  18. Phase II Trial of Doxorubicin ± Sorafenib in HCC: Study Design Period 2* Period 1 Eligibility • Advanced HCC • ECOG PS 0-2 • CP A • No prior systemic therapy • No prior chemoembolization • No history of organ allograft R A N D O M I Z E Doxorubicin60 mg/m2 +sorafenib400 mg bid q3w Sorafenib400 mg bid n=47 Doxorubicin60 mg/m2 +placebo q3w Placebo n=49 1:1 • Primary objective • TTP (independent assessment) • Secondary objectives • ORR, PFS, OS, safety *Sorafenib or placebo continued until withdrawal, PD, or death in Period 2. q3w = once every 3 weeks. Abou-Alfa GK, et al. Eur J Cancer Suppl. 2007;5(4):259. Updated from Abstract 128. Poster and oral presentation at ASCO-GI; Orlando, FL; January 2008.

  19. Phase II Trial of Doxorubicin ± Sorafenib in HCC: Baseline Patient Characteristics *Data for macroscopic vascular invasion not available for 1 patient (2%) in each group. Abou-Alfa GK, et al. Eur J Cancer Suppl. 2007;5(4):259. Updated from abstract 128. Poster and oral presentation at ASCO-GI; Orlando, FL; January 2008.

  20. 1.00 0.75 0.50 0.25 0 Phase II Trial of Doxorubicin ± Sorafenibin HCC: OS Doxorubicin + sorafenibMedian: 13.7 months(95% CI: 10.4-N/E) Doxorubicin + placeboMedian: 6.5 months(95% CI: 4.9-9.5) Censored treatment Probability of Survival HR=0.45P=0.0049 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Months Abou-Alfa GK, et al. Eur J Cancer Suppl. 2007;5(4):259. Updated from abstract 128. Poster and oral presentation at ASCO-GI; Orlando, FL; January 2008.

  21. Phase II Trial of Doxorubicin ± Sorafenib in HCC: AEs With ≥10% Grade 3/4 Incidence Abou-Alfa GK, et al. Eur J Cancer Suppl. 2007;5(4):259. Updated from abstract 128. Poster and oral presentation at ASCO-GI; Orlando, FL; January 2008.

  22. Sorafenib Future Directions

  23. Sorafenib in the Management of Patients With HCC Ph III Adjuvant Adjuvant Ph II TACE Ph II Post-TACE Intermediate Ph II Doxorubicincombination Ph III: SHARP Ph III: Asia-Pacific Advanced/ metastatic Ph II and Ph III Targeted agentcombinations Bayer HealthCare, data on file.

  24. Sorafenib as adjuvant Treatment in the prevention Of Recurrence of hepatocellular carcinoMa STORM) • Phase III, randomized, double-blind, placebo-controlled study of sorafenib as adjuvant treatment of HCC after surgical resection of local ablation • International (Europe, Americas, Asia-Pacific, Japan) • Prior treatment • Resection • RFA • PEI • Eligibility criteria • Child-Pugh • score 5–7 • Intermediate/high risk of recurrence • Randomization • n=1,100 • Stratification • Prior curative treatment • Geographical region • Endpoints • RFS • OS • Biomarkers • Other Sorafenib400 mg bid Placebo RFA = radiofrequency ablation; PEI = percutaneous ethanol injection; RFS: recurrence-free survival.

  25. Sorafenib in patients with advanced HCC after TACE • Phase III, randomized, double-blind, placebo-controlled study of sorafenib as treatment of HCC after TACE • Japan • Prior treatment • TACE • Eligibility criteria • Age >18 • Advanced HCC • Exclusion criteria • Prior systemic chemotherapy • Vital organ failure Sorafenib400 mg bid • Endpoints • Primary • TTP • Secondary • OS • Randomization • n=390 Placebo TACE = transarterial chemoembolization; TTP = time to progression; OS = overall survival. http://clinicaltrials.gov/. Accessed September, 2008.

  26. Sorafenib in patients with advanced HCC undergoing TACE - SPACE • Phase II, randomized, double-blind, placebo-controlled study of sorafenib as treatment of HCC starting before TACE • International, 90 centers • Scheduled TACE (cycles): 1, 3, 7, 13, q6cycles there after • Optional TACE (cycles): 10, 15 • Eligibility criteria • Age >18 • Intermediate HCC • Exclusion criteria • -Prior TACE of target lesion • -Prior systemic chemotherapy • -portal invasion • -hepatofugal flow Sorafenib400 mg bid for 3-7 days Sorafenib400 mg bid • Endpoints • Primary • TTP • Secondary • Untreatable • Progression • Randomization • n=300 TACE Placebo Placebo TACE = transarterial chemoembolization; TTP = time to progression; OS = overall survival.

  27. Tumor extent Liver function Other condition Curable with curative treatment Resectable disease Incurable withcurative treatment Unresectable disease N N Ongoing/approved Proposed Investigator-sponsored studies of sorafenib in HCC* Early stage Advanced stage Surgery/ablation Transplant TACE/TAE HAI Systemic agents Radio- therapy BSC Sorafenib Other agents After surgery/ablation After transplant With TACE/TAE With HAI • Dose escalation • Sub-population • - CP-B • Long-term use • Others 2ndline Targeted agent • Cyto-toxic • Other 2 9 1 4 4 8 * 1 6 1 1 2 3 *Status as of July 2008

  28. HCC BCLC-Classifikation + AlgorithmLlovet et al., J Natl Cancer Inst 2008; 100: 698

  29. SHARP: comparable patient characteristics in sorafenib and placebo groups HBV = hepatitis B virus; HCV = hepatitis C virus. Llovet JM, et al. N Engl J Med 2008;359:378–390.

  30. SHARP: stratification by region and disease status HBV = hepatitis B virus; HCV = hepatitis C virus. Llovet JM, et al. N Engl J Med 2008;359:378–390.

  31. SHARP: response assessment *Independent review by Response Evaluation Criteria in Solid Tumors (RECIST). †DCR = disease control rate (CR+PR+SD ≥28 days). CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; TTSP = time to symptomatic progression; FHSI-8 = Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index-8. Llovet JM, et al. N Engl J Med 2008;359:378–390.

  32. Asia-Pacific PIII Study: Baseline Patient Characteristics BCLC = Barcelona Clinic Liver Cancer. Cheng A, et al. Lancet Oncol. 2009; 10: 25-34.

  33. Asia-Pacific Study: RECIST Response *DCR = CR + PR maintained for 4 weeks + SD documented at least 12 weeks from baseline. Cheng A, et al. J Clin Oncol. 2008;26. Abstract 4509. Updated from oral presentation at ASCO; Chicago, IL; June 2008.

  34. 100 75 50 25 0 Phase II Trial of Doxorubicin ± Sorafenibin HCC: TTP (Independent Assessment) Doxorubicin + sorafenibMedian: 8.6 mo(95% CI: 4.8-12.6) Doxorubicin + placeboMedian: 4.8 mo (95% CI: 2.2-8.0) Censored treatment Progression-free probability (%) HR=0.60* P=0.076 0 2.5 5.0 7.5 10.0 12.5 15.5 Months *Assessed by an independent review committee. Abou-Alfa GK, et al. Eur J Cancer Suppl. 2007;5(4):259. Updated from abstract 128. Poster and oral presentation at ASCO-GI; Orlando, FL; January 2008.

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