Presentation on theme: "Disclosures Participated in the following Advisory Boards: Gilead Hoffman La Roche Janssen Merck Vertex Kathy Poldre CAHN 2013."— Presentation transcript:
Disclosures Participated in the following Advisory Boards: Gilead Hoffman La Roche Janssen Merck Vertex Kathy Poldre CAHN 2013
Liver Cancer is the Sixth Most Common Cancer Worldwide 1 HCC is the most common primary liver malignancy in adults 2 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. 196,000 226,000 230,000 200,000 314,000 330,000 529,000 559,000 711,000 782,000 1 million 1.1 million 1.3 million 1.5 million 0200,000400,000600,000800,0001,000,0001,200,0001,400,0001,600,0001,800,000 Non-Hodgkin's Lymphoma Corpus Uteri Ovary Oral Cavity Bladder Leukemia Esophagus Cervix Uteri Liver Prostate Stomach Colon/Rectal Breast Lung
Liver Cancer is the Third Most Common Cause of Cancer-Related Mortality Globally Liver cancer is the third most common cause of cancer-related death 1.3 million 800,000 679,000 602,000 Lung and bronchus StomachLiverColon and rectum Number of estimated deaths Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed August, 2008. 0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000
HCC Risk Factors Are Well Defined and Show Geographical Variation Hepatitis C virus (50-70%) HBV (10-20%) Alcohol (20%) Other (10%) Europe and North America Asia and Africa (excluding Japan) Japan HCV (20%) Hepatitis B virus (70%) Alcohol (10%) Hepatitis C virus (70%) HBV (10-20%) Alcohol (10%) Other (<10%) Adapted from Llovet JM, et al. Lancet. 2003;362:1907-1917. Other (<10%)
AASLD Diagnostic Criteria for HCC Mass on surveillance ultrasound (US) in a cirrhotic liver Stable >18-24 mo Enlarging Return to surveillance every 6-12 mo Proceed according to lesion size Nondiagnostic of HCC Change in size/profile Repeat biopsy or imaging follow-up Repeat imaging and/or biopsy + - Other diagnosis Diagnostic of HCC <1 cm1-2 cm>2 cm One dynamic imaging technique Repeat US every 3-4 mo Coincidental typical vascular pattern Typical vascular pattern with 1 technique Atypical vascular pattern with both techniques Atypical vascular pattern Typical vascular pattern on dynamic imaging or AFP >200 ng/mL Treat as HCC Biopsy Two dynamic imaging studies Adapted from Bruix J and Sherman M. Hepatology. 2005;42(5):1208-1236.
HCC treatment algorithm (BCLC) Liver transplant PEI/RF Curative treatments TACE HCC Single Increased Associated diseases Normal No YesNoYes Terminal stage PST 0-2, Child-Pugh A-B Multinodular, PST 0 Portal invasion, N1, M1 Sorafenib Portal pressure/bilirubin 3 nodules 3 cm Intermediate stage PST > 2, Child-Pugh C Very early stage Single < 2 cm Early stage Single or 3 nodules 3 cm, PST 0 Advanced stage Portal invasion, N1, M1, PST 1-2 PST 0, Child-Pugh A Resection Symptomatic (unless LT) Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. Bruix J, et al. Hepatology. 2005;42:1208-1236.
BCLC Staging System and Treatment Algorithm End Stage Advanced StageIntermediate Stage Very Early Stage Early Stage Surgical Treatment Local Ablation SorafenibTACE HCC ~30% patients ~20% patients TACE = transarterial chemoembolization Adapted from Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. ~30% patients Symptomatic treatment 5-year survival: 40%-70% (treated) ~20% (untreated) Median survival: ~19-20 months (treated) ~16 months (untreated) Median survival: <3 months Median survival: ~10-11 months (treated) ~6-7 months (untreated)
Treatment Options Limited by liver function and characteristics of the malignant lesion i.e. Vascular invasion Solitary vs Multifocal disease Location of lesion(s) – close to vital structures Size of lesion(s) Childs Pugh Score Very early, early, intermediate transplant
Indications Nexavar® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
Sorafenib Targets Tumor Cell Proliferation and Angiogenesis RAS Endothelial Cell or Pericyte Proliferation Migration Angiogenesis: Tubule formation PDGF- VEGF VEGFR-2 PDGFR- Paracrine stimulation Differentiation Mitochondria Apoptosis Tumor Cell PDGF VEGF Proliferation Survival Mitochondria HIF Nucleus Apoptosis ERK RAS MEK RAF Nucleus ERK MEK RAF Mcl-1 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. HGF Autocrine loop Sorafenib HGF = hepatocyte growth factor.
Dosing Continuous daily dosing 400 mg (2 x 200 mg tablets) twice daily No dose adjustments for age, gender, or body weight Can be administered without food or low- moderate fat diet
Sorafenib in Advanced HCC: The SHARP Trial Entry criteria – Advanced HCC Not eligible for or failed surgical or locoregional therapies – Child-Pugh class A disease – At least 1 untreated target lesion – Exclusions Previous chemotherapy Previous molecularly targeted therapy Llovet JM, et al. N Engl J Med. 2008;359:378-390.
SHARP Trial: Baseline Characteristics CharacteristicSorafenib (n = 299) Placebo (n = 303) Median age, yrs 64.966.3 Male, % 87 BCLC stage, % B (intermediate) 1817 C (advanced) 8283 Vascular invasion, % 70 Llovet JM, et al. N Engl J Med. 2008;359:378-390.
The SHARP Trial: Drug-Related AEs AEs (%)Sorafenib (N = 297)Placebo (N = 302)P Value Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any Grade Grade 3 or 4 IGI Events Anorexia14< 10310<.0011.0 Diarrhea39801120<.001 Voice changes600100<.001NA Hypertension520210.05.28 Liver dysfunction< 1 0000.50 Abdominal pain not otherwise specified 820310.007.17 Bleeding71041< 1.071.00
The SHARP Trial: Drug-Related AEs AEs (%)Sorafenib (N = 297)Placebo (N = 302)P Value Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any Grade Grade 3 or 4 Overall incidence 8052 Constitutional symptoms Weight Loss 920100<0.0011.0 Dermatologic events Alopecia 1400100<0.001NA Dry skin 8004000.4NA Hand-foot skin reaction 21803<10<0.001 Other 510100<0.0010.12
Grading of Hand-Foot Syndrome Grade Symptom 1 Minimal skin changes or dermatitis (eg, erythema) without pain 2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function 3Skin changes with pain, interfering with function Common Terminology Criteria for Adverse Events, Version 3.0. Available at: http://ctep.cancer.gov. Accessed October 13, 2008.
Dose modification recommendations Temporary interruption and /or dose reduction of management of AEs Reduced to 400 mg once daily If necessary, single 400 mg dose every other day
Strategies for Managing AEs Hand-foot syndrome - Lanolin containing creams and lotions – Avoid tight footwear, protect feet – May require dose reduction Diarrhea – Antidiarrheal agents –Immodium -Carbohydrates : rice, potatoes - bulk forming agent - Separate solids from fluids Hypertension – Start or adjust antihypertensives
SHARP: Exploratory Subgroup Survival Analysis Favors NexavarFavors Placebo HR (95% CI) for Survival 0.51.01.50.0 ECOG PS 1 & 2 No macroscopic vascular invasion Macroscopic vascular invasion No macroscopic VI/extrahepatic spread Macroscopic VI and/or extrahepatic spread Extrahepatic spread No extrahepatic spread ECOG PS 0 Llovet JM, et al. J Clin Oncol. 2007;25(suppl 18):LBA1. Updated from oral presentation.
Case Study Mr. H: 79 yr old, 6 children HBV 2009- Hong Kong fatigue, hematuria, wt loss Investigations: benign prostatic hypertrophy - mass in the liver CT Oct 2009 : 9 cm x 12 cm mass Seg 6 & 7 - another lesion 8.8 cm Seg 7 - suspicious lymph node
Mr. H (contd) Would think about treatment – TACE March 17, 2010 – started on Sorafenib, 200 mg bid to assess tolerability March 25, 2010 – mod-severe hand/foot syn. drug stopped x 1wk, restarted 200 mg OD April 29, 2010 – dose 400mg OD
Mr. H (contd) May 26, 10 – loss of appetite -hand/foot continues (blisters) June 21 10 – hand/foot continues -desquamating rash on heals - CT scan – stable ; will put up with the discomfort for the benefit Aug 19 10 – off for a few weeks waiting EAP reapproval. Restarts on full dose
Mr. H. (contd) Sept 2010 – present - 83 years old - tolerating drug well - good response to Sorafenib stable disease with no evidence of progression - good liver function, Childs Pugh A, PS 1
Mr. H (contd) CT Oct 13, 2009 Seg 6/7 lesion – 12.8 cm x 8.9 cm Seg 7 – 8.8 cm CT Jan 2, 2013 Seg 6/7 – 9.1 cm x 6.7 cm Seg 7 – 4.9 cm
CT Scans October 13, 2009 January 2, 2013
Sorafenib is the Systemic Treatment Standard in HCC Sorafenib is the first and only drug ever proven to extend overall survival in patients with HCC Two randomized phase III studies demonstrate that sorafenib prolongs overall survival and time to progression in both Western and Asian patient populations Sorafenib prolongs overall survival irrespective of patient characteristics or extent of disease Sorafenib is safe and manageable in patients with HCC – Drug-related adverse events are generally mild-to-moderate, predictable and manageable