New drugs for Hepatocellular Carcinoma Jordi Bruix Head, BCLC Group, Liver Unit Hospital Clínic, University of Barcelona BCLC Staging and Treatment Strategy HCC Stage 0 Stage D Stage A - C PST 0, Child-Pugh A PST >2, Child-Pugh C PST 0-2, Child-Pugh A-B Very early stage (0) Early stage ( A) Intermediate stage ( B) Advanced stage (C) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Multinodular, PS 0 Portal invasion, N1,M1, PS 1-2 Single Terminal stage (D) 3 nodules <3cm Portal pressure/ bilirubin Associated diseases Increased Normal No Resection Liver Transplantation (CLT / LDLT) Curative Treatments (30%) 50% - 75% at 5 years Portal invasion, N1,M1 No Yes PEI/RF Chemoembolization Yes ? Non-curative treatments (50%) 3 year survival 10-40% Sympt. Treat. (20%) Sem Liv Dis 1999 to JNCI 2008 Treatment of advanced HCC Phase II/III studies with systemic treatments Treatments Studies N Objective response Systemic chemotherapy Doxorubicin as single agent Doxorubicin combination (PIAF) Cisplatin Epirubicin Mitoxantrone 5-FU,Paclitaxel, iridotecan, gemcitabine Phase II/III Phase II/III Phase II Phase II Phase II Phase II/III >1000 144 48 62 118 .... 10-18% 26% 10% 11% 16% <10% Anti-androgen Interferon Tamoxifen Octreotide Seocalcitol Phase III Phase III Phase III Phase III Phase III 376 60 >1000 60 746 <10% <10% < 5% <5% <5% The hepatocarcinogenic process Signalling pathways: molecular targets for new therapies. Wnt pathway EGFR pathway Raf/MAPK pathway Akt pathway Jat/Stat pathway Hanahan. Cell 2000. Molecular targeted therapies in HCC Growth factors receptor pathway Erlotinib Targets and agents GROWTH FACTORS (EGF, VEGF, PDGF…) IGF-1 / IGF-2 Bevacizumab Cetuximab Sorafenib RAS RAF Gefitinib EGFR VEGF R PDGF R IGFRI PIP2 p85 PI3K Sorafenib PTEN p110 PIP3 CELL SURVIVAL CELL CYCLE MEK Rapamycin mTOR PROLIFERATION p70S6 Translation (5´ TOP) Ab: Cetuximab VEGF TKI: Sorafenib Ab: Bevacizumab Akt TSC ERK IGFBP3 EGFR: TKI: Erlotinib, Lapatinib 4E-BP1 TRANSLATION (Cap-Dependent) RAF TKI: Sorafenib mTOR Rapamycin Proteasome inhibitors Bortezomib Targeted agents in development for HCC: overview Anti-angiogenic targets Agent Bevacizumab VEGF VEGFR PDGFR Antiproliferative targets EGFR Raf mTOR ● Developmental status Phase II ongoing Brivanib ● Phase II recruiting Cediranib ● Phase II recruiting Erlotinib ● Phase II complete Gefitinib ● Phase II complete Cetuximab ● Phase II complete Lapatinib ● Phase II ongoing ● RAD001 Sorafenib* ● ● Sunitinib* ● ● Thalidomide TSU-68 ● ● Phase I/II recruiting Phase III complete Phase II ongoing Phase III recruiting ● *Sorafenib and sunitinib also have antiproliferative effects through multi-tyrosine kinase inhibition ● Phase I/II recruiting Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm Insight, MedTrack Molecular targeted therapies for EGFR pathway Erlotinib: Phase II studies in HCC Erlotinib (n=38) • Characteristics of patients: Child A/B: 27/11 PST 0/1-2: 10/28 EGFR-1+ in 88% • Treatment : 150 mg/d • Outcomes: Response rate: 3 PR, 50% SD (3.8 mo) Toxicity (G3-4): 8 pts. Median TTP: 3.2 mo Median survival: 13 mo Philip et al. J Clin Oncol 2005 Erlotinib plus bevacizumab in patients with unresectable advanced HCC • Patients (n=29) received bevacizumab 10mg/kg every 14 days plus erlotinib 150mg orally daily • RR (RECIST) in 27 - CR: one patient (4%) – PR: five patients (19%) – SD at ≥16 weeks: nine patients (33%) – SD at 8 weeks: five patients (19%) • Grade 3–4 toxicities transaminase elevation (1), hyperkalaemia (1), acne (1), diarrhoea (2), proteinuria (2), gastrointestinal bleeding (3), fatigue (4), and hypertension (5). • Median Survival 19.5 months. (2009 MS 15months) Thomas MB, et al. ASCO 2007, JCO 2009 Erlotinib plus bevacizumab in patients with unresectable advanced HCC • Patients (n=29) received bevacizumab 10mg/kg every 14 days plus erlotinib 150mg orally daily • RR (RECIST) in 27 - CR: one patient (4%) – PR: five patients (19%) – SD at ≥16 weeks: nine patients (33%) – SD at 8 weeks: five patients (19%) • Grade 3–4 toxicities transaminase elevation (1), hyperkalaemia (1), acne (1), diarrhoea (2), proteinuria (2), gastrointestinal bleeding (3), fatigue (4), and hypertension (5). • Median Survival 19.5 months. (2009 MS 15months) Thomas MB, et al. ASCO 2007, JCO 2009 Molecular targeted therapies for VEGF Bevacizumab (5-10 mg/Kg /2 weeks) in HCC: Phase II (n=46) Characteristics of patients Age Gender (M/F) Child-Pugh (A/B) CLIP (0-4) ECOG (0/1/2) Tumor stage Adverse events (grade 3-4) Transient ischemic accident : Arterial hypertension: Hepatic arterial thrombosis: Hemoperitoneum Gastrointestinal bleeding: 21-81 38/8 34/12 2/19/15/8/1 19/23/2 ? 1 7 1 1 5 (1 death) Baseline 16 weeks after Clinical Outcomes Response rate 1CR, 5 PR Median PFS: 6.9 months Median survival: 12.4 months ASCO 2005, JCO 2008 Molecular targeted therapies for VEGF Bevacizumab (5-10 mg/Kg /2 weeks) in HCC: Phase II (n=46) Characteristics of patients Age Gender (M/F) Child-Pugh (A/B) CLIP (0-4) ECOG (0/1/2) Tumor stage Adverse events (grade 3-4) Transient ischemic accident : Arterial hypertension: Hepatic arterial thrombosis: Hemoperitoneum Gastrointestinal bleeding: 21-81 38/8 34/12 2/19/15/8/1 19/23/2 ? 1 7 1 1 5 (1 death) Baseline 16 weeks after Clinical Outcomes Response rate 1CR, 5 PR Median PFS: 6.9 months Median survival: 12.4 months ASCO 2005, JCO 2008 Sunitinib in patients with unresectable HCC • Patients (n=37) received sunitinib 50mg daily for 4 weeks of every 6-week treatment cycle. • Major (≥50%) tumour necrosis was noted in 46% of patients • Response (RECIST) – partial response (PR): one patient (3%) – stable disease (SD) >3 months: 13 patients (35%) – SD >6 months: eight patients (22%) • Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and haemorrhage (14%) – four patients experienced grade 5 toxicity (bleeding, drowsiness, hepatic encephalopathy and renal failure) RECIST = Response Evaluation Criteria In Solid Tumors; CNS = central nervous system Faivre SJ, et al. ASCO 2007, Chicago, IL, USA Molecular targeted therapies: anti-VEGF Hypoxia PDGF EGF IGF-1 IL-8 bFGF VEGF release Binding and activation of VEGF receptor COX-2 Nitric oxide Oncogenes P– P– –P –P Survival Proliferation Migration ANGIOGENESIS Permeability Rationale • VEGF overexpression in HCC • VEGF known mitogen for hepatocytes • VEGFR expression variable Poon R, Br J Surg, 2004 Treatment of advanced HCC Phase II: sorafenib as a primary treatment of HCC (n=137) Characteristics of the study – Sorafenib 400mg bid in 28-day cycles in 137 patients with advanced HCC. – Characteristics: 48% HCV+, TNM Stage III/IV (31%/66%), Child A:72% – Response WHO: PR: 3 (2.2%), MR: 8 (5.8%), stable disease >4m 33.6% Overall survival: 9.2 mo 1.00 1.00 0.75 0.75 Survival Distribution Function Survival Distribution Function Time-to-progression (TTP): 5.5 mo 0.50 0.25 0.50 0.25 0 0 0 100 200 300 Time (days from start of study treatment) 400 500 0 100 200 300 400 500 600 700 800 Time (days from start of study treatment) Abou-Alfa G et al, JCO 2006 Sorafenib improves survival in hepatocellular carcinoma: Phase III randomized, placebo-controlled trial (SHARP) PIs: JM Llovet and J Bruix, S Ricci, V Mazzaferro, P Hilgard, J-L Raoul, S Zeuzem, A Santoro, MS Shan, M Moscovici, Dimitris Voliotis, A Forner, M Schwartz for the SHARP Investigators Study Group Child-Pugh A : to avoid liver deaths of Child-Pugh B patients obscuring outcome to capture the impact on HCC progression (competing risk) * Macroscopic vascular invasion (portal vein) and/or extrahepatic spread * ECOG PS * Geographical region Randomisation N=602 Stratification: Sorafenib (n=299) 400mg po bid continuous dosing Placebo (n=303) 2 tablets po bid continuous dosing Llovet et al, NEJM 2008 Phase III SHARP trial Overall survival (intention-to-treat) Survival probability 1.00 Sorafenib Median: 10.7 mo (95% CI: 9.4, 13.3) 0.75 Placebo Median: 7.9 mo (95% CI: 6.8, 9.1) 0.50 0.25 Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.87). P<0.001* 0 0 Patients at risk Sorafenib: 299 Placebo: 303 8 16 24 32 40 48 56 64 72 274 276 241 224 205 179 161 126 108 78 67 47 38 25 12 7 0 2 *O’Brien-Fleming threshold for statistical significance was P=0.0077. 80 Weeks 0 0 Llovet et al, NEJM 2008 Phase III SHARP trial Time to progression (independent central review) Probability of progression 1.00 0.75 Sorafenib Median: 5.5 mo (95% CI: 4.1, 6.9) 0.50 Placebo Median: 2.8 mo (95% CI:2.7, 3.9) 0.25 0 Hazard ratio (S/P): 0.58 (95% CI: 0.45, 0.74) P<0.001 0 Patients at risk Sorafenib: 299 Placebo: 303 6 12 18 24 30 36 42 48 196 192 126 101 80 57 50 31 28 12 14 8 8 2 2 1 54 Weeks 0 0 Llovet et al, NEJM 2008 Phase III SHARP trial Exploratory subgroup survival analysis Sorafenib benefit Placebo benefit ECOG PS 0 ECOG PS 1 & 2 No extrahepatic spread Extrahepatic spread No macroscopic vascular invasion Macroscopic vascular invasion No macroscopic VI/extrahepatic spread Macroscopic VI and/or extrahepatic spread 0.0 0.5 1.0 1.5 Hazard Ratio (95%CI) Llovet et al, NEJM 2008 Usual comments about SHARP • SHARP is just informative for HCV European HCC • There is no attempt for biomarker assessment • 3 months survival improvement is marginal • Unknown efficacy in Child-Pugh B Asian-Pacific sorafenib study 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 area R A N D O M I Z E n=150 n=76 Sorafenib 400 mg bid Placebo 2:1 End points: – Overall survival, time to symptomatic progression (FSHI8-TSP), time to progression, response (RECIST), and safety – No primary end point defined Cheng, et al. ASCO 2008 Asian-Pacific sorafenib study Overall survival Survival probability 1.00 Sorafenib Median: 6.5 months (95% CI: 5.6, 7.6) 0.75 Placebo Median: 4.2 months (95% CI: 3.7, 5.5) 0.50 0.25 HR (S/P): 0.68 95% CI: 0.50, 0.93 P=0.014 0 0 Patients at Risk Sorafenib 150 Placebo 76 2 4 6 8 10 12 14 16 18 20 22 Months 134 62 103 41 78 26 53 23 32 15 21 9 15 5 13 4 4 1 1 0 0 0 Cheng, et al. ASCO 2008 Asian-Pacific sorafenib study Time to progression Progression-free probability 1.00 Sorafenib Median: 2.8 months (95% CI: 2.6, 3.6) 0.75 Placebo Median: 1.4 months (95% CI: 1.3, 1.5) 0.50 HR (S/P): 0.57 95% CI: 0.42, 0.79 P<0.001 0.25 0 0 Patients at risk Sorafenib 150 Placebo 76 2 4 6 8 10 12 14 16 18 20 22 Months 80 19 38 10 19 8 11 3 8 0 5 0 2 0 1 0 0 0 0 0 0 0 Adapted from Cheng, et al. ASCO 2008 BCLC Staging and Treatment Strategy HCC Stage 0 Stage D Stage A - C PST 0, Child-Pugh A PST >2, Child-Pugh C PST 0-2, Child-Pugh A-B Very early stage (0) Early stage ( A) Intermediate stage ( B) Advanced stage (C) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Multinodular, PS 0 Portal invasion, N1,M1, PS 1-2 Single Terminal stage (D) 3 nodules <3cm Portal pressure/ bilirubin Associated diseases Increased Normal No Resection Liver Transplantation (CLT / LDLT) Portal invasion, N1,M1 Yes PEI/RF Chemoembolization No Yes Sorafenib Sharp Asia 10.7 months 6.5 months Usual comments about SHARP • SHARP is just informative for HCV European HCC • There is no attempt for biomarker assessment • 3 months survival improvement is marginal • Unknown efficacy in Child-Pugh B Predictors of Survival All patients (univariate analysis) c-Kit Low c-Kit Median OS = 8.8 months (n=245) 0.75 High c-Kit Median OS = 10.4 months (n=244) 0.50 0.25 HR = 0.775 (95% CI: 0.620,0.970) P=0.026 0 1.00 Low HGF Median OS = 10.8 months (n=366) 0.75 High HGF Median OS = 6.0 months (n=122) 0.50 0.25 HR = 1.780 (95% CI: 1.390,2.280) P<0.001 0 0 2 4 6 8 10 12 14 16 18 20 22 Time (Months) Survival Probability 1.00 Survival Probability 1.00 Survival Probability VEGF HGF Low VEGF Median OS = 10.6 months (n=368) 0.75 High VEGF Median OS = 6.2 months (n=122) 0.50 0.25 HR = 1.530 (95% CI: 1.191,1.965) P<0.001 0 0 2 4 6 8 10 12 14 16 18 20 22 Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 Time (Months) • High c-KIT levels and low HGF and VEGF levels correlated with longer OS in the univariate analysis. Llovet et al AASLD 2008 Baseline plasma c-KIT and Sorafenib Prediction of survival Patients with High* Baseline c-KIT Patients with Low* Baseline c-KIT 1.00 Survival Probability Sorafenib Median OS = 9.4 months 0.75 Placebo Median OS = 7.4 months 0.50 0.25 0 HR = 0.90 (95% CI: 0.66, 1.22) (n=245) 0 2 4 6 Survival Probability 1.00 Sorafenib Median OS = 14.1 months Placebo 0.75 Median OS = 8.7 months 0.50 0.25 8 10 12 14 16 18 20 22 mo 0 HR = 0.58 (95% CI: 0.41, 0.81) (n=244) 0 2 4 6 8 10 12 14 16 18 20 22 • Patients with high c-KIT showed a trend of better survival benefit from sorafenib (interaction P-value=0.081). Llovet et al AASLD 2008 Baseline plasma c-KIT and Sorafenib Prediction of time to progression Patients with High* Baseline c-KIT Patients with Low* Baseline c-KIT 1.00 HR = 0.80 (95% CI: 0.55, 1.17) (n=245) 0.75 0.50 Sorafenib 0.25 Median TTP = 4.1 mo Placebo Progression Probability Progression Probability 1.00 HR = 0.45 (95% CI: 0.30, 0.66) (n=244) 0.75 0.50 Sorafenib Median TTP = 6.7 mo 0.25 Placebo Median TTP = 2.8 mo Median TTP = 3.9 mo 0.00 0.00 0 2 4 6 8 Time (Months) 10 12 0 2 4 6 8 10 12 Time (Months) • Patients with high c-KIT showed a better time to progression with sorafenib (interaction P-value=0.05). Llovet et al AASLD 2008 Baseline plasma HGF and Sorafenib Effect Patients with Low Baseline HGF Sorafenib Median OS = 12.4 months 0.75 Placebo Median OS = 9.8 months 0.50 0.25 0 HR = 0.69 (95% CI: 0.53, 0.90) (n=366) 1.00 Sorafenib Survival Probability Survival Probability 1.00 Median OS = 6.3 months 2 4 6 8 10 12 14 16 18 20 22 Time (Months) Placebo 0.75 Median OS = 5.3 months 0.50 0.25 0 0 Patients with High Baseline HGF HR = 1.10 (95% CI: 0.72, 1.67) (n=122) 0 2 4 6 8 10 12 14 16 18 20 22 Time (Months) • Patients with low HGF showed a trend of better survival benefit from sorafenib (interaction P-value=0.073), but not with TTP (p=0.3) Llovet et al AASLD 2008 Usual comments about SHARP • SHARP is just informative for HCV + European HCC • There is no attempt for biomarker assessment • 3 months survival improvement is marginal • Unknown efficacy in Child-Pugh B Impact of molecular agents in cancer outcomes Endpoint, absolute gain HR (95% CI) Survival (3 m) 0.69 (0.55–0.87) Hepatocellular carcinoma (advanced) Sorafenib (n=299) vs placebo (n=303)1 Colorectal (metastatic) IFL+ bevacizumab (n=402) vs IFL (n=411) 2 Survival (4.7 m) 0.66 (NA) Cetuximab (n=287) vs BSCare (n=285) 3 Survival (1.5 m) 0.77 (0.64–0.92) Lung cancer Paclitax. + carbo + vs – bevacizumab (n=434 vs n=444) 4 Erlotinib (n=488) vs placebo (n=243) 5 Survival (2 m) 0.79 (0.69–0.93) Survival (2 m) 0.79 (0.58–0.85) Breast cancer (Advanced (HER2+) Chemotherapy + vs – trastuzumab (n=235 vs n=234) 6 TTP 0.51 (0.39–0.59) Paclitaxel + vs – bevacizumab (n=347 vs n=326) 7 PFS 0.60 (0.51–0.70) 1. Llovet et al NEJM 2008, 2. Hurwitz et al NEJM 2004, 3. Jonkers et al NEJM 2007, 4. Sandler et al NEJM 2006, 5. Shepherd et al NEJM 2005, 6. Slamon et al NEJM 200 7. Miller et al. NEJM 2007 Llovet and Bruix, Hepatology 2008 Usual comments about SHARP • SHARP is just informative for HCV European HCC • There is no attempt for biomarker assessment • 3 months survival improvement is marginal • Unknown efficacy in Child-Pugh B Sorafenib in HCC. Phase I PK: Ctrough,ss (mg/L) Non-HCC vs HCC, Non-Japanese vs Japanese; and CPA vs CPB 20 18 16 14 12 10 8 6 4 2 0 Non-Japanese with advanced solid tumors Japanese with advanced solid tumors Non-Japanese with HCC (CPA) Japanese with HCC (CPA) Non-Japanese with HCC (CPB) Japanese with HCC (CPB) Advanced Solid Tumor Patients HCC Patients (CPA) HCC Patients (CPB) • PK equivalent irrespective of ethnicity or Child-Pugh status ss = steady state Data on file. Bayer HealthCare Sorafenib for HCC and Child-Pugh B patients • Child-Pugh B includes a wide range of profile and outcome • Impact on tumor biology is not modulated by liver function • PK, Safety and AEs in Child-Pugh B are the same • Child-Pugh B 7 can be safely treated. • RCT vs placebo unlikely BCLC Staging and Treatment Strategy HCC Stage 0 Stage D Stage A - C PST 0, Child-Pugh A PST >2, Child-Pugh C PST 0-2, Child-Pugh A-B Very early stage (0) Early stage ( A) Intermediate stage ( B) Advanced stage (C) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Multinodular, PS 0 Portal invasion, N1,M1, PS 1-2 Single Terminal stage (D) 3 nodules <3cm Portal pressure/ bilirubin Associated diseases Increased Normal No Resection Liver Transplantation (CLT / LDLT) Curative Treatments (30%) 50% - 75% at 5 years Portal invasion, N1,M1 No Yes PEI/RF Chemoembolization Yes Sorafenib Non-curative treatments (50%) 3 year survival 10-40% Sympt. Treat. (20%) Sem Liv Dis 1999 to JNCI 2008 Future prospects for Sorafenib Impact of sorafenib results • Effective first-line option for advanced HCC available should be standard first line therapy • Proves the hope of molecular targeted therapy in HCC new agents to be investigated in second line/failures • Opens the path to multipathway blockade • Evaluation in the adjuvant setting (surgery, ablation, TACE) Critical issues in combination therapy • Selection of best partner for sorafenib • Optimal dosage for efficacy and safety Underlying cirrhosis: variceal bleeding, renal failure, ascites, encephaloptahy, HBV/HCV flares • How to define efficacy: RR by RECIST (No meaning), TTP? • Transition from phase 1 into phase 2. RCT phase 2. • Target population Llovet et al, JNCI 2008 Impact of sorafenib results • Effective first-line option for advanced HCC available • Proves the hope of molecular targeted therapy in HCC • Opens the path to multipathway blockade • Evaluation in the adjuvant setting (surgery, ablation, TACE) Design: double-blind RCT RFS Resection RFA PEI Sorafenib 400mg bid 8 weeks randomise 1:1 Stratify: - prior curative tx - geographical region - CP status Placebo TTR OS Biomarkers • Significant OS benefit in phase III gives rationale to go into adjuvant setting • Prospective, randomized, double-blind, placebo-controlled, company sponsored phase III study • Primary endpoint: recurrence-free survival • Patients: n=1100 (randomised) • Global trial, significant number of patients from China • FPFV: August 2008 Clinicaltrials.gov TACE for HCC Sorafenib as coadjuvant Trial in the pipeline – SPACE (2009): Target population: Child-Pugh A Technique: DCBeads End-point: TTP, Survival BCLC Staging and Treatment Strategy HCC Stage 0 Stage D Stage A - C PST 0, Child-Pugh A PST >2, Child-Pugh C PST 0-2, Child-Pugh A-B Very early stage (0) Early stage ( A) Intermediate stage ( B) Advanced stage (C) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Multinodular, PS 0 Portal invasion, N1,M1, PS 1-2 Single 3 nodules <3cm Portal pressure/ bilirubin Normal Portal invasion, N1,M1 Associated diseases Increased No Resection Liver Transplantation (CLT / LDLT) STORM Adjuvant trial No Yes PEI/RF Chemoembolization SPACE Adjuvant trial Yes Sorafenib Combination trial Terminal stage (D) Barcelona-Clínic Liver Cancer (BCLC) Group Liver Unit: J. Bruix, JM. Llovet, A. Forner, M. Reig,, C Rodriguez Radiology: C. Brú, R. Vilana, Ll. Bianchi, C. Ayuso, J. Rimola,, X. Montañá, I. Real, M. Burrel Surgery : J. Fuster Pathology : M. Solé Oncology: J. Maurel Nurse: A. Godoy Laboratory: L. Boix A. Villanueva V. Tovar C. Alsinet L. Cabellos JM. Lopez J. Peix H. Cornellà Ad .support N. Perez D. Segarra Oct. 2008