Current Concepts in the Treatment of HCC

Transcription

1 Falk Symposium 167 Current Concepts in the Treatment of HCC Peter R. Galle I. Medical Department Johannes Gutenberg-University Mainz Germany

2 Liver cancer: sixth most common cancer worldwide Most common cancers 1 Lung Breast Colon/rectal Stomach Prostate Liver Cervix uteri Oesophagus Non-Hodgkin lymphoma Bladder Ovary Corpus uteri Oral cavity Other Liver cancer is the third most common cause of cancer-related death 1 HCC is the most common primary liver malignancy in adults 2 1. Parkin DM, et al. CA Cancer J Clin 2005;55: Pons-Renedo F, Llovet JM. Med Gen Med 2003;5:11

3 Incidence of liver cancer worldwide: regional variation Eastern Asia Middle Africa Eastern Africa South-Eastern Asia World Western Africa Southern Europe Caribbean Southern Africa Western Europe Eastern Europe Northern America Central America Western Asia Northern Africa Australia/New Zealand South America Northern Europe South Central Asia Region Incidence of liver cancer in different regions of the world (2002) *Age standardised Incidence rate per 100,000 population* Males Females GLOBOCAN 2002 database. Available at

4 Risk factors for HCC worldwide, by geographical region (2000) Risk factors associated with development of HCC Hepatitis C 20% 50 70% 70% 70% Asia/Africa* Europe/N America Japan All Hepatitis B 10 20% 10 20% Alcohol Other 10 20% 10% Cases (%) *Excluding Japan Llovet JM, et al. Lancet 2003;362:

5 Incidence of HCC is increasing in economically developed countries Year Incidence /100,000 Year Incidence /100,000 Australia 1 (men) France* 2 (men) Japan UK USA *Primary liver cancer 1. Law MG, et al. Med J Aus 2000;173: Benhamiche AM, et al. J Hepatol 1998; 29: Yoshizawa H, et al. Oncology 2002;62: El Serag HB, et al. Ann Intern Med 2003;139:817 23

6 Molecular Clock of Hepatitis C Virus Infection Effective population size of HCV infections Japan (Genotype 1b) years USA (Genotype 1a) Tanaka et al., PNAS 2002

7 HCC - in 90% with Cirrhosis Liver cirrhosis = precancerous lesion HCC

8 Poor prognosis for patients with advanced HCC 70 80% of patients with intermediate/ advanced disease at diagnosis 1 OS among 102 patients randomised to no treatment in two RCTs 2 OS (%) 2 Disease stage 1 year 2 years 3 years Intermediate Advanced OS = overall survival RCT = randomised controlled trial 1. Llovet JM. J Gastroenterology 2005;40: Llovet JM. Hepatology 1999;29:62 7

9 Treatment for early HCC: surgical resection Surgical resection: survival in retrospective studies Authors, year n 1-year survival (%) 5-year survival (%) Fong et al, Llovet et al, Takayama et al, 2000 * Wayne et al, *Randomised study of resection adjuvant therapy Llovet JM. J Gastroenterol 2005;40:225 35

10 Resection in HCC - Survival Survival (%) % 50% 25% Best candidates for resection Solitary HCC Child-Pugh A Absence portal hypertension Normal bilirubin No portal hypertension (n= 35) Portal hypertension and normal bilirubin (n=15) Portal hypertension and Bilirubin >1 mg/dl (n=27) months Llovet et al. Hepatology, 1999

11 Perioperative Lethality after partial Hepatectomy in Patients with Cirrhosis Child A % > 60% with Decompensation Child B % Child C % Garrison 1984 Mansour 1997

12 Intrahepatic Recurrence after HCC Resection in Patients with Cirrhosis % Interval (ys) Belghiti J et al Chen MF et al Koike Y et al Yamamoto J et al Metachrone HCC in Cirrhosis

13 HCC: local Therapy Technique Percutaneous Ethanol Injection (PEI) Radio Frequency Thermo Ablation (RFTA) Indication: Child A/B Patients with 1 nodule < 5 cm, or max. 3 nodules < 3 cm Goal: complete Tumor Necrosis in curative intention

14 Treatment for early HCC: percutaneous ablation Percutaneous ethanol injection: survival in retrospective studies Authors, year Disease characteristics n 1-year survival (%) 5-year survival (%) Livraghi et al, 1995 Child Pugh A, HCC 5cm Child Pugh B, HCC 5cm Arii et al, 2000 Stage I HCC <2cm Stage I HCC 2 5cm Stage II HCC <2cm Stage II HCC 2 5cm Llovet JM. J Gastroenterol 2005;40:225 35

15 Treatment for early HCC: percutaneous ablation (cont d) Radiofrequency ablation: single-arm studies and a randomised trial Authors, year Trial design n 1-year survival (%) 5-year survival (%) Rossi et al, 1996 Single arm Buscarini et al, 2001 Single arm Lencioni et al, 2003 RCT: Radiofrequency ND vs Percutaneous ethanol ND ND = not described Llovet JM. J Gastroenterol 2005;40:225 35

16 PEI vs. Resection in HCC with Cirrhosis Yamamoto et al. Hepatology 2001; 34:707-13

17 HCC HCC - Coeliacography

18 Transarterial Chemoembolisation (TACE) Llovet et al.; Lancet 2002; 359:

19 Two-year survival with chemoembolisation or embolisation versus supportive care for unresectable HCC Study Number of patients Odds ratio (95% CI) in random effects model Lin et al, GETCH, Bruix et al, Pelletier et al, Lo et al, Llovet et al, Overall 503 p= Heterogeneity p=0.14 Favours treatment Favours control Adapted from Llovet JM, et al. Lancet 2003;362: Copyright 2003, reproduced with permission from Elsevier

20 Survival after LTX 01/ /2002 (%) Total Log Rank test p = Cirrhosis : Cancers : 4608 Acute hepatic failure : p Log Rank : Acute Hepatic Failure vs Cirrhosis : Cancers vs Cirrhosis : Acute Hepatic Failure vs Cancers : (Wilcoxon test) Yrs

21 HCC - Selection criteria for LTX IN Milano criteria 8.5 cm 5 cm Single Multiple 3 nodules 3 cm OUT > 8.5 cm HCC > 3 nodules > 3 cm

22 Treatment for early HCC: liver transplantation Liver transplantation: survival in retrospective studies Authors, year n 1-year survival (%) 5-year survival (%) Mazzaferro et al, Bismuth et al, Llovet et al, Jonas et al, Llovet JM. J Gastroenterol 2005;40:225 35

23 Systemic Chemotherapy - Summary Response rates 0-20% (Doxorubicin) no survival benefit significant side effects Simonetti et al. Ann Oncol 1997 Nowak et al. EJO 2004 Schwartz et al. Anti-Cancer Drugs 2004 Multi-Drug Resistance (MDR1 gene) Huang et al. J Natl. Cancer Inst HCC

24 HCC: a complex pathogenesis The pathogenesis of HCC is multifactorial 1 5 Cirrhosis/fibrosis Infection (e.g. hepatitis virus) Toxins (e.g. alcohol, aflatoxins) Mutation/deletion/amplification of genes 1 4 Mitogenic oncogenes Tumour suppressor genes Chronic liver damage Hepatocyte regeneration Cirrhosis Genetic alterations I N F L A M M A T I O N HCC 1. Marotta F, et al. Clin Ter 2004;155:187 93; 2. Thorgeirsson S, Grisham JW. Nat Genet 2002;31: Wiesenauer CA, et al. J Am Coll Surg 2004;198: Wang XW, et al. Toxicology 2002;181: Feitelson MA, et al. Surg Clin N Am 2004;84:339 54

25 Key Concepts in Oncogenesis Oncogenic transformation -growth stimulation -apoptosis inhibition Primary event Escape from senescence Angiogenesis Secondary events Invasion and metastasis

26 Potential Therapeutic Pathways Apoptotic stimulus Oncogenic transformation Growth pathway Survival pathway Secondary events Anti-angiogenesis Anti-invasive Anti-metastatic

27 Targeting molecular signalling pathways The inhibition of signalling pathways that play an important role in the development of HCC may provide a promising treatment strategy for HCC These pathways include: Wnt/ -catenin PI3K/Akt mammalian target of rapamycin (mtor) Raf/MEK/ERK growth factor-mediated angiogenic pathways

28 Angiogenesis and HCC In HCC, a net excess of pro-angiogenic factors are secreted, including vascular endothelial growth factor (VEGF) platelet derived-growth factor (PDGF) placental growth factor transforming growth factors and basic fibroblast growth factor epidermal growth factor (EGF) hepatocyte growth factor angiopoietins interleukin (IL)-4, IL-8 Semela D, Dufour JFl. J Hepatol 2004;41:864 80

29 Serum VEGF levels predict prognosis Cumulative survival (%) VEGF >240pg/mL n=80; p<0.007 VEGF <240pg/mL Months after chemoembolisation Median overall survival 19.2 months for VEGF <240pg/ml 6.8 months for VEGF >240pg/ml Poon RT, et al. Oncol Rep 2004;11:

30 Agents that target the VEGF signalling pathway Thalidomide anti-inflammatory and anti-angiogenic agent that downregulates production of VEGF, TNF- and COX-2 Bevacizumab monoclonal antibody targeting VEGF Sunitinib receptor tyrosine kinase inhibitor of VEGF-receptor (VEGFR) and PDGF-receptor (PDGFR) Sorafenib multi-kinase inhibitor of VEGFR, PDGFR and Raf kinase

31 Sorafenib inhibits proliferation and angiogenesis Tumour cell proliferation Tumour angiogenesis Paracrine stimulation PDGF- VEGF KIT/Flt-3/ RET Raf Ras Apoptosis PDGFR- Ras Raf VEGFR-2 MEK ERK EGF PDGF Apoptosis MEK ERK Nucleus VEGF Proliferation Nucleus Angiogenesis Survival Sorafenib Wilhelm SM, et al. Cancer Res 2004;64:

32 Sorafenib inhibits tumour growth and Raf/MEK/ERK signalling in the PLC/PRF/5 HCC xenograft model 750 Tumour growth inhibition Untreated Vehicle Sorafenib 10mg/kg Sorafenib 30mg/kg Mean tumour weight (mg) Days after implant perk 1/2 Total ERK 1/2 Raf/MEK/ERK pathway inhibition perk levels measured in tumours from individual mice MEK DMSO Sorafenib (µm) inhibitor Liu L, et al. Cancer Res 2006;66:

33 Sorafenib: phase I data in advanced tumours Objective responses* Evaluable patients* (n) PR (n) SD (n) PD (n) Median TTP (days) 7 days on/7 days off mg b.i.d days on/7 days off 50mg every 5 days 800mg b.i.d days on/7 days off 50mg every 4 days 800mg b.i.d Continuous dosing 50mg q.d. 800mg b.i.d Overall (40.4%) *136/173 patients were evaluable for antitumour activity across the four phase I studies; In a patient with renal cell carcinoma In a patient with HCC q.d. = once daily PD = progressive disease 1. Clark JW, et al. Clin Cancer Res 2005;11: Awada A, et al. Br J Cancer 2005;92: Moore M, et al. Ann Oncol 2005;16: Strumberg D, et al. J Clin Oncol 2005;23:965 72

34 Sorafenib in HCC Phase II study in advanced HCC 137 patients with advanced HCC 1 TTP 5.5 Month OS 9.2 Month Survival Distribution Function Survival Distribution Function HCC Time (days from start of study treatment) 0 n = 106 Child A Time (days from start of study treatment) 1. Abou-Alfa GK et al. J Clin Oncol 2006;24:

35 Phase III Trial of Sorafenib in HCC (SHARP): Study Design Eligibility Advanced HCC ECOG PS 0-2 Child-Pugh Class A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS (0 vs 1/2) Geographic region R A N D O M I Z E 1:1 n=299 n=303 Sorafenib 400 mg bid Placebo Primary end points: OS, TTSP (assessed by FHSI-8) Secondary end points: TTP (independent assessment) FHSI-8 = Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index-8. SHARP = Sorafenib HCC Assessment Randomized Protocol; OS = overall survival; TTSP = time to symptomatic progression; TTP = time to progression. Llovet JM, et al. NEJM 2008

36 Phase III SHARP Trial Overall survival (Intention-to-treat) Survival Probability Patients at risk Sorafenib: 299 Placebo: 303 Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88). P= * Sorafenib Median: 46.3 weeks (10.7 mo) (95% CI: 40.9, 57.9) Placebo Median: 34.4 weeks (7.9 mo) (95% CI: 29.4, 39.4) *O Brien-Fleming threshold for statistical significance was P= Weeks

37 Phase III SHARP Trial Time to Progression (Independent central review) 1.00 Probability of progression Sorafenib Median: 24.0 weeks (5.5 mo) (95% CI: 18.0, 30.0) Placebo Median: 12.3 weeks (2.8 mo) (95% CI: 11.7, 17.1) 0 Hazard ratio (S/P): 0.58 (95% CI: 0.44, 0.74) P= Weeks Patients at risk Sorafenib: 299 Placebo:

38 SHARP: Maximum Percentage Change in Tumor Size From Baseline Change in target lesion from baseline (%) Placebo 27% 51% Sorafenib *Reported for each individual.

39 The problem of Radiologic Assessment - What Does RECIST Tell us? 10x6 cm 11x7 cm Baseline : AFP weeks : AFP 36

40 Phase III SHARP Trial Response assessment (RECIST; Independent review) Time to Symptom Progression (FSHI8-TSP)* Sorafenib N=299 Placebo N=303 Overall response Complete response (CR) 0 0 Partial response (PR) 7 (2.3%) 2 (0.7%) Stable disease (SD) 211 (71%) 204 (67%) Progressive disease (PD) 54 (18%) 73 (24%) Progression-free rate at 4 mo 62% 42% Duration of treatment (median; weeks) * FSHI8-TSP: No significant differences between treatment groups (P=0.77)

41 SHARP: Adverse Events Patients (%) Treatment-related SAEs Drug-related SAEs Sorafenib (n=299) Placebo (n=302) 54 9 Grade Drug-Related AEs Any 3 / 4 Any 3 / 4 Diarrhea 39 8 / / 0 HFSR 21 8 / 0 3 <1 / 0 Anorexia 14 <1 / 0 3 <1 / 0 Alopecia 14 0 / / 0 Nausea 11 <1 / / 0 Weight loss 9 2 / 0 <1 0 / 0 Pain (abdomen) 8 2 / 0 3 <1 / 0 Bleeding 7 <1 / 0 4 <1 / <1 Vomiting 5 1 / 0 3 <1 / 0 Liver dysfunction <1 <1 / / 0 Llovet JM, et al. J Clin Oncol. 2007;25(suppl 18):LBA1. Updated from oral presentation at ASCO; Chicago, IL; June 2007.

42 Hand-Foot Skin Reaction Maculopapular rash Facial rash Body rash *Incidence reported from the SHARP trial; data on file, BayerHealthCare. Photos courtesy of Elizabeth Manchen, RN, MS, OCN.

43 Hand-Foot Skin Reaction by Grade Grade 1 Incidence: 8%* Grade 3 Incidence: 8%* Grade 2 Incidence: 6%* *Incidence reported from the SHARP trial; data on file, BayerHealthCare. Photos courtesy of Elizabeth Manchen, RN, MS, OCN.

44 Sorafenib in patients with HCC In a phase II trial, sorafenib 400mg b.i.d. demonstrated efficacy in patients with advanced HCC (n=137) 1 PR or minor response (MR) in 8% of patients, SD for 16 weeks in 34% of patients median independently assessed TTP of 5.5 months median investigator-assessed OS of 9.2 months grade 3 4 toxicities included fatigue, diarrhoea and HFSR In a phase III trial (SHARP) sorafenib 400mg b.i.d. significantly prolonged OS versus placebo in patients with advanced HCC (n=602) months with sorafenib versus 7.9 months with placebo (p=0.0006) the most frequent grade 3 4 adverse events were diarrhoea, HFSR, fatigue and bleeding Sorafenib is the first systemic therapy to show a survival advantage over placebo in patients with advanced HCC SHARP = Sorafenib HCC Assessment Randomized Protocol 1. Abou-Alfa GK, et al. J Clin Oncol Llovet JM, et al. NEJM 2008

45 BCLC Treatment Overview: Linking Staging to Treatment HCC Early Stage Intermediate Stage 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. Adapted from Bruix J and Sherman M. Hepatology. 2005;42: ; Llovet JM, et al. Lancet. 2003;362:

46 Confirmation from the Asia-Pacific phase III study

47 Study Schema Eligibility Advanced HCC ECOG 0-2 Child-Pugh A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS Geographic region R A N D O M I Z E 2:1 n=150 n=76 Sorafenib 400 mg bid Placebo End points: Overall survival, time to symptomatic progression (FSHI8-TSP), time to progression, response (RECIST), and safety No primary end point defined Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 30-June 3, 2008; Chicago, IL.

48 Overall Survival Survival Probability HR (S/P): % CI: P=0.014 Months Sorafenib Median: 6.5 months (95% CI: ) Placebo Median: 4.2 months (95% CI: ) Placebo Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 30-June 3, 2008; Chicago, IL.

49 Phase II Trial of Doxorubicin Sorafenib in HCC: Study Design Eligibility Advanced HCC ECOG PS 0-2 Child-Pugh Class A No prior systemic therapy No prior chemoembolization No history of organ allograft R A N D O M I Z E 1:1 n=47 n=49 Period 1 Period 2* Doxorubicin 60 mg/m 2 + sorafenib 400 mg bid q3w Doxorubicin 60 mg/m 2 + placebo q3w Sorafenib 400 mg bid Placebo 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 three 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.

50 Overall survival Survival probability Hazard ratio (sorafenib/doxorubicin): 0.45 (95% Cl: ) p= Sorafenib + doxorubicin (n=47) Median: 13.7 months (95% Cl: 10.4 NA) Placebo + doxrubicin (n=49) Median: 6.5 months (95% Cl: ) Months From randomisation Definitive analysis (data from March 2007 cut-off, 50 events) NA = value can not be estimated due to censored data

51 Targeted agents in development for HCC: overview Agent Anti-angiogenic targets Antiproliferative targets VEGF VEGFR PDGFR EGFR Raf mtor Bevacizumab Brivanib Cediranib Erlotinib Gefitinib Lapatinib RAD001 Sorafenib* Sunitinib* Thalidomide TSU-68 Developmental status Phase II ongoing Phase II recruiting Phase II recruiting Phase II complete Phase II complete Phase II ongoing Phase I/II recruiting Phase III complete Phase II ongoing Phase III recruiting Phase I/II recruiting *Sunitinib and sorafenib also have antiproliferative effects through multi-tyrosine kinase inhibition Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm Insight, MedTrack