Nexavar in advanced HCC: a paradigm shift in clinical practice Tim Greten Hanover Medical School, Germany
Histopathological progression and molecular features of HCC Chronic liver disease Liver cirrhosis HBV HCV Alcohol Aflatoxin B1 Injury Necrosis Hepatocyte proliferative arrest Stellate cell activation Proliferation Extensive scarring (collagen) Abnormal liver nodules Well differentiated Marked genomic instability Loss of p53 Moderate genomic instability Moderately differentiated Poorly differentiated Hepatocellular carcinoma Dysplastic nodule Hyperplastic nodule Farazi PA, DePinho RA. Nat Rev Cancer 2006;6:674 87 2
Mass on surveillance ultrasound in a cirrhotic liver < 1 cm 1-2 cm > 2 cm Repeat US at 3-4 month interval Two dynamic imaging studies One dynamic imaging study Atypical vascular pattern Typical vascular Pattern on dynamic Imaging or AFP > 200 ng/ml Stable over 18-24 months Enlarging Diagnostic of HCC Biopsy Non diagnostic Other diagnosis Return to standard Surveillance protocol (6-12 monthly) Proceed according to lesion size Positive Repeat biopsy or Imaging follow-up Change in size/profile Repeat imaging And/or biopsy Negative Treat as hepatocellular carcinoma 3
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No standard protocol has been established?? What type of chemotherapeutic agent???? What type of embolizing agent???? Repetition of the procedure??? 10
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Chemotherapy for HCC is associated with poor response rates (0 25%) Systemic chemotherapy has not been shown to prolong survival in patients with HCC Thomas MB, Zhu AX. J Clin Oncol 2005;23:2892 9 12
Multiple cellular signalling pathways are implicated in the pathogenesis of cancer Hanahan D, Weinberg RA. Cell 2000;100:57 70 13
Multiple cellular signalling pathways are implicated in the pathogenesis of cancer Hanahan D, Weinberg RA. Cell 2000;100:57 70 14
Multiple cellular signalling pathways are implicated in the pathogenesis of cancer Hanahan D, Weinberg RA. Cell 2000;100:57 70 15
Nexavar targets tumour cell proliferation and angiogenesis, and increases rate of apoptosis Tumour cell Endothelial cell or pericyte (vascular) GFR GF Raf-1 MEK ERK P x P P P Survival Proliferation Ras HIF-1 x Apoptosis HIF-2 Nucleus Mitochondria Paracrine stimulation PDGF VEGF PDGF VEGF X Nexavar PDGFR-b Mitochondria x Apoptosis VEGF-A PDGF-b x P P P x Ras Raf-1 MEK ERK x P P P Nucleus VEGFR-2 VEGF-C x VEGFR-3 Angiogenesis: Differentiation Proliferation Migration Tubule formation Wilhelm SM, et al. Mol Cancer Ther 2008;7:3129 40 16
SHARP: study design Main eligibility criteria Advanced HCC Child Pugh A status ECOG PS 0 2 No prior systemic therapy Stratification Region ECOG PS (0 vs 1 2) Randomisation (1:1) (n=602) Nexavar 400mg b.i.d. (n=299) Placebo (n=303) Primary endpoints OS TTSP Secondary endpoints TTP DCR Safety MVI/EHS (present/absent) *Not eligible for, or had disease progression after surgical or locoregional therapies; Assessed using USA NCI CTCAE version 3.0 MVI = macroscopic vascular invasion EHS = extrahepatic spread Llovet JM, et al. N Engl J Med 2008;359:378 90 17
SHARP: patient baseline demographics Variable, n (%) Nexavar (n=299) Placebo (n=303) Male * 260 (87) 264 (87) Age * mean years ± SD 64.9 ± 11.2 66.3 ± 10.2 Region * Europe and Australasia 263 (88) 263 (87) North America 27 (9) 29 (10) Central and South America 9 (3) 11 (4) Cause of disease * Hepatitis C only 87 (29) 82 (27) Alcohol only 79 (26) 80 (26) Hepatitis B only 56 (19) 55 (18) Unknown 49 (16) 56 (19) Other 28 (9) 29 (10) MVI and/or EHS * Absent 90 (30) 91 (30) Present 209 (70) 212 (70) *No significant difference between arms (p 0.05) MVI = macroscopic vascular invasion; EHS = extrahepatic spread Llovet JM, et al. N Engl J Med 2008;359:378 90 18
SHARP: patient baseline demographics (cont d) Variable, n (%) Nexavar (n=299) Placebo (n=303) ECOG PS * 0 161 (54) 164 (54) 1 114 (38) 117 (39) 2 24 (8) 22 (7) BCLC stage * Stage B (intermediate) 54 (18) 51 (17) Stage C (advanced) 244 (82) 252 (83) Child Pugh status * A 284 (95) 297 (98) B 14 (5) 6 (2) Biochemistry * median(range) Albumin (g/dl) 3.9 (2.7 5.3) 4.0 (2.5 5.1) Total bilirubin (mg/dl) 0.7 (0.1 16.4) 0.7 (0.2 6.1) α-fetoprotein (ng/ml) 44.3 (0 20.8x10 5 ) 99.0 (0 5x10 5 ) *No significant difference between arms (p 0.05) Llovet JM, et al. N Engl J Med 2008;359:378 90 19
SHARP: median overall survival Survival probability 1.00 0.75 0.50 0.25 Nexavar (n=299) = 10.7 months Placebo (n=303) = 7.9 months HR = 0.69 (95% CI: 0.55 0.87) p<0.001 0 0 2 4 6 8 10 12 14 16 18 Time from randomisation (months) Llovet JM, et al. N Engl J Med 2008;359:378 90 20
SHARP: drug-related adverse events* Incidence by grade (%) p-value for between-group Nexavar (n=297) Placebo (n=302) comparison AE* Any 3 4 Any 3 4 Any 3 4 Overall incidence 80 52 Diarrhea 39 8 0 11 2 0 <0.001 <0.001 Fatigue 22 3 1 16 3 <1 0.07 1.00 HFSR 21 8 0 3 <1 0 <0.001 <0.001 Rash/desquamation 16 1 0 11 0 0 0.12 0.12 Anorexia 14 <1 0 3 1 0 <0.001 1.00 Alopecia 14 0 0 2 0 0 <0.001 N/A Nausea 11 <1 0 8 1 0 0.16 0.62 Weight loss 9 2 0 1 0 0 <0.001 0.03 Pruritus 8 0 0 7 <1 0 0.65 1.00 Dry skin 8 0 0 4 0 0 0.04 N/A Pain, abdomen NOS 8 2 0 3 1 0 0.007 0.17 Bleeding 7 1 0 4 1 <1 0.07 1.00 Voice changes 6 0 0 1 0 0 <0.001 N/A Vomiting 5 1 0 3 1 0 0.14 0.68 Hypertension 5 2 0 2 1 0 0.05 0.28 Dermatology, other 5 1 0 1 0 0 <0.001 0.12 *Adverse events, as defined by NCI CTC (version 3.0) that occurred in at least 5% of patients in either study group NOS = not otherwise specified Llovet JM, et al. N Engl J Med 2008;359:378 90 21
SHARP overall survival: exploratory subgroup analysis Subgroup Nexavar benefit Placebo benefit HR (Nexavar / placebo; 95% CI) ECOG PS 0 1 2 0.68 (0.50 0.95) 0.71 (0.52 0.96) EHS No Yes 0.55 (0.39 0.77) 0.85 (0.64 1.14) MVI No Yes 0.74 (0.54 1.00) 0.68 (0.49 0.93) MVI and/or EHS No Yes 0.52 (0.32 0.85) 0.77 (0.60 0.99) 0 0.5 1.0 1.5 HR (95% CI) MVI = macroscopic vascular invasion EHS = extrahepatic spread Llovet JM, et al. N Engl J Med 2008;359:378 90 22
Nexavar prolongs survival in advanced HCC regardless of patient characteristics or extent of disease 16 SHARP exploratory subgroup analyses Nexavar Placebo Median overall survival (months) 14 12 10 8 6 4 2 0 10.7 7.9 HR = 0.69 (95% CI: 0.55 0.87) p<0.001 Overall population 1 n=602 HR=0.79 Prior curative therapy 2 n=158 HR=0.75 HR=0.58 HR=0.76 HR=0.68 HR=0.71 Prior TACE 2 n=176 HCV 3 n=178 Alcoholic cirrhosis 4 n=159 ECOG PS 0 5 n=325 ECOG PS 1 2 5 n=277 HR=0.77 MVI and/or EHS 6 n=421 HR=0.52 No MVI and/or EHS 6 n=181 MVI = macroscopic vascular invasion EHS = extrahepatic spread 1. Llovet JM, et al. N Engl J Med 2008;359:378 90; 2. Galle P et al. EASL 2008, Milan, Italy 3. Bolondi L, et al. ASCO-GI 2008, Orlando, FL, USA; 4. Craxi A, et al. ASCO 2008, Chicago, IL, USA 5. Raoul J, et al. ASCO 2008, Chicago, IL, USA; 6. Sherman M, et al. ASCO 2008, Chicago, IL, USA 23
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Impact of Nexavar on the treatment paradigm of HCC Nexavar is the first systemic therapy shown to extend survival in patients with advanced HCC 1 Based on the results of SHARP, Nexavar has been approved in >60 countries This shift in the treatment of HCC is reflected in updated treatment guidelines and algorithms National Comprehensive Cancer Network (NCCN) guidelines 2 Asian Pacific Association for the Study of the Liver (APASL) consensus statement on HCC 3 Barcelona Clinic Liver Cancer (BCLC) staging and treatment system 4 Spanish liver cancer treatment guidelines (diagnosis and treatment of hepatocellular carcinoma) 5 Nexavar should be considered to be the systemic reference standard in advanced HCC 3 1. Llovet JM, et al. N Engl J Med 2008;359:378 90 2. NCCN Clinical Practice Guidelines in Oncology Hepatobiliary Cancers. v.1.2009 3. Asian Pacific Association for the Study of the Liver. Consensus on HCC, February 2009 4. Llovet JM, et al. J Natl Cancer Inst 2008;100:698 711; 5. Forner A, et al. Med Clin (Barc) 2009. doi:10.1016/j.medcli.2008.11.024 25
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