1 / 42

New treatment approaches in Hepatocellular Carcinoma

New treatment approaches in Hepatocellular Carcinoma. Dr. Francesco Caponigro Istituto Tumori Napoli. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the fifth most prevalent cancer worldwide with > 80% of patients presenting with advanced disease.

neka
Télécharger la présentation

New treatment approaches in Hepatocellular Carcinoma

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. New treatment approachesin Hepatocellular Carcinoma Dr. Francesco Caponigro Istituto Tumori Napoli

  2. F. Caponigro - Istituto Tumori Napoli Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the fifth most prevalent cancer worldwide with > 80% of patients presenting with advanced disease. Late diagnosis and the frequent coexistence of cirrhosis result in a poor prognosis for patients with HCC Drug-resistance genes such as multidrug resistance-1 are common in liver cells, causing HCC tumors to be inherently chemoresistant

  3. Phase II/III Studies of Systemic Treatments in Advanced HCC F. Caponigro - Istituto Tumori Napoli

  4. The turning-point in the management of advanced HCC Sorafenib (BAY 43-9006, Nexavar): a multikinase inhibitor with activity against Raf, VEGFR-2, VEGFR-3, PDGFR, c-Kit F. Caponigro - Istituto Tumori Napoli

  5. Signaling pathways in HCC 1. EGFR 2. 3. VEGF 5. 4. F. Caponigro - Istituto Tumori Napoli Villanueva A et al, Semin Liver Dis 2007

  6. SORAFENIBFarmacokinetics F. Caponigro - Istituto Tumori Napoli Low absorption T1/2: 24-36 h Steady state: after 7 days Time of assumption:1-2 hoursbefore or after meals Elimination: mainly asglucuronate

  7. SORAFENIBSafety Data F. Caponigro - Istituto Tumori Napoli • Sorafenib is well tolerated and grade 3-4 adverse events have been reported in 30% of cases in phase I studies. • The main side effects are: • Skin rash • Hand and foot syndrome • Diarrhea - nausea • Fatigue • Hypertension

  8. SORAFENIB Clinical studies in HCC Phase II Study of Sorafenib in non resectable HCC Abou-Alfa GK, et al. J Clin Oncol 2006 F. Caponigro - Istituto Tumori Napoli

  9. SORAFENIB Clinical studies in HCC • Phase II Study of Sorafenib in non resectable HCC • 3/137 pts (2.2%) partial response • 8/137 pts (5.8%) minor response • 46/137 (33.6%) long-term stable disease (> 16 weeks) • Time to progression (TTP) 4.2 months • Overall survival 9.2 months Grade ¾ toxicity: fatigue (9.5%), diarrhea (8.0%) hand and foot syndrome (5.1%) Abou-Alfa GK, et al. J Clin Oncol 2006 F. Caponigro - Istituto Tumori Napoli

  10. SORAFENIB Clinical studies in HCC Abou-Alfa GK, et al. J Clin Oncol 2006 Pre-treatment pERK was correlated to TTP Although Sorafenib activity was really modest, both the manageable toxicity profile and the peculiarity of its mechanism of action support further trials F. Caponigro - Istituto Tumori Napoli

  11. Phase III SHARP TrialStudy Design Sorafenib 400 mg p.o.,b.i.d. continuous dosing R A N D O M I Z E • Stratifyby: • Macroscopicvascular • invasion (portal vein) and/or extrahepatic spread • ECOG PS • Geographic region (n = 299) Placebo 2 tablets p.o. b.i.d. continuous dosing (n = 303) F. Caponigro - Istituto Tumori Napoli Primary endpoints: overall survival, time to symptomatic progression (FHSI8-TSP) Secondary endpoint: time to progression (independent review)

  12. Phase III SHARP TrialBaseline characteristics of patients F. Caponigro - Istituto Tumori Napoli Llovet JM et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain.

  13. Phase III SHARP TrialBaseline characteristics of patients Llovet JM et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain. Llovet JM and Bruix J, BCLC Group, Semin Liver Dis. 1999.

  14. Phase III SHARP Trial Efficacy (Intent-to-Treat Population) F. Caponigro - Istituto Tumori Napoli

  15. 1.00 SorafenibMedian: 46.3 weeks (10.7 mo)(95% CI: 40.9, 57.9) 0.75 PlaceboMedian: 34.4 weeks (7.9 mo)(95% CI: 29.4, 39.4) 0.50 0.25 0 Patients at riskSorafenib: 299 274 241 205 161 108 67 38 12 0 0 303 276 224 179 126 78 47 25 7 2 0 Placebo: Phase III SHARP TrialOverall survival (Intention-to-treat) Survival Probability Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.87) P=0.00058* Weeks 0 8 16 24 32 40 48 56 64 72 80 *O’Brien-Fleming threshold for statistical significance was P=0.0077 Llovet JM et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain F. Caponigro - Istituto Tumori Napoli

  16. 1.00 0.75 SorafenibMedian: 24.0 weeks (5.5 mo) (95% CI: 18.0, 30.0) 0.50 PlaceboMedian: 12.3 weeks (2.8 mo)(95% CI: 11.7, 17.1) 0.25 0 0 6 12 18 24 30 36 42 48 54 196 126 80 50 28 14 8 2 0 192 101 57 31 12 8 2 1 0 Phase III SHARP TrialTime to progression (Independent central review) Probability of Progression Hazard ratio (S/P): 0.58 (95% CI: 0.45, 0.74)P=0.000007 Weeks Patients at riskSorafenib: 299 303 Placebo: F. Caponigro - Istituto Tumori Napoli Llovet JM et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain.

  17. Phase III SHARP TrialExploratory subgroup survival analysis 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/extrahepatic spread 0.0 0.5 1.0 1.5 Sorafenib benefit Placebo benefit Hazard Ratio (95% CI) F. Caponigro - Istituto Tumori Napoli Llovet JM et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain.

  18. Phase III SHARP TrialAdverse Events (1/2) F. Caponigro - Istituto Tumori Napoli

  19. Phase III SHARP TrialAdverse Events (2/2) * Less than 1 % of patients also experienced grade 4 bleeding F. Caponigro - Istituto Tumori Napoli

  20. Phase III SHARP TrialConclusions F. Caponigro - Istituto Tumori Napoli • Sorafenib prolonged median overall survival compared to placebo in patients with advanced HCC: • Median overall survival: 10.7 months vs. 7.9 months • Hazard ratio 0.69; P = .00058 • 44% increase in median overall survival • Sorafenib prolonged median time to progression compared to placebo in patients with advanced HCC: • Median time to progression: 5.5 months vs. 2.8 months • Hazard ratio 0.58; P = .000007 • 73% prolongation in median time to progression • Sorafenib was tolerable, with manageable side effects • Sorafenib is the first systemic therapy to prolong survival in patients with HCC

  21. Phase II randomizedstudy of Sorafenib + Doxorubicin versus Doxorubicin + Placebo in HCC • PRIMARY ENDPOINT • Time to Progression (TTP) • SECONDARY ENDPOINT • Overall Survival (OS) • Time To Symptom Progression (TTSP) • Quality of life (QoL) Randomization 1:1 Sorafenib + Dox • ~ 90 pts with advanced HCC • ECOG PS: 0,1,2 Placebo + Dox F. Caponigro - Istituto Tumori Napoli Abou-Alfa GK et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain

  22. Demographics (n=96) F. Caponigro - Istituto Tumori Napoli Abou-Alfa GK et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain. DXR=Doxorubicin

  23. Results Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 50 events, PFS: 70 events) Abou-Alfa GK et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain. F. Caponigro - Istituto Tumori Napoli

  24. Toxicities NCI-CTC (version 3); NCI-CTC=National Cancer Institute–Common Toxicity Criteria Abou-Alfa GK et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain. F. Caponigro - Istituto Tumori Napoli

  25. Conclusions F. Caponigro - Istituto Tumori Napoli This randomized phase II study of Doxorubicin plus Sorafenib and Doxorubicin plus placebo, showed encouraging TTP and OS outcome for the Doxorubicin plus Sorafenib This trial supports the growing body of evidence of the activity of Sorafenib in HCC Any synergistic role between Sorafenib plus doxorubicin in HCC needs to be further defined Abou-Alfa GK et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain.

  26. A Phase II Study of Sorafenib Plus Tegafur/Uracil for the Treatment of Advanced or Metastatic Hepatocellular Carcinoma • Rationale NCT00464919 Ongoing trial Tegafur/uracil, which has potential anti-HCC activity (ORR 0-18% ~, in phase II studies) and interesting anti-angiogenesis activity (in several preclinical models), is an ideal candidate drug to improve the efficacy of sorafenib in HCC • Inclusion criteria • Unresectable and/or metastatic HCC • PS 0-2 ECOG • No metastatic brain tumors • Prior systemic treatment for HCC • Primaryend-pointPFS • Secondaryend-pointsToxicity, ORR, SDR, OS F. Caponigro - Istituto Tumori Napoli

  27. Beyond Sorafenib NEW POTENTIAL TARGETED THERAPIES IN HCC F. Caponigro - Istituto Tumori Napoli

  28. Signaling pathways in HCC 1. EGFR 2. 3. VEGF 5. 4. F. Caponigro - Istituto Tumori Napoli Villanueva A et al, Semin Liver Dis 2007

  29. 1. EGFR pathway EGFR is overexpressed in HCC and is associated with increased cell proliferation and reduced apoptosis F. Caponigro - Istituto Tumori Napoli Schmidt CM et al, Biochem Biophys Res Commun 1997 Ito Y et al, Br J Cancer 2001

  30. Inhibition of EGFR by gefitinib induces growth inhibition, apoptosis and cell cycle arrest in human HCC cell lines A In HepG2 cells, Gefitinib causes: • time- and dose-dependent growth inhibition • dose-dependent accumulation in the G0/G1-phase of the cell cycle. • dose-dependently induced caspase-3 activation C B F. Caponigro - Istituto Tumori Napoli Hopfner M et al, J Hepatol 2004

  31. Phase II Study of Erlotinib in Patients With Advanced Hepatocellular Cancer (N = 38) • Patients with unresectable or metastatic HCC • 47% of patients received prior chemotherapy • Erlotinib given continuously at of 150 mg/day orally • Primary end-point: proportion of patients progression-free at 6 months PFS at 6 months: 32% (CI 95%, 18 to 49) Median OS = 13 months F. Caponigro - Istituto Tumori Napoli Philip et al, JCO 2005

  32. Erlotinib in Combination With Docetaxel in Advanced Hepatocellular and Biliary Tract Carcinomas NCT00532441 Phase II ongoing study • Inclusion criteria • HCC or biliary tract carcinomas, not amenable to curative resection or transplantation • ≤ 2 prior chemotherapy regimens • PS  2 ECOG • Child-Pugh A cirrhosis • Primary end-point • Treatment protocol • Erlotinib: 150 mg p.o., days 2-7, 9-14, 16-28 q28 • Docetaxel: 30 mg/m2 iv d 1, 8, 15 q28 • PFS rate at 16 weeks • Secondary end-points • ORR; d RR; disease control; OS • Safety and toxicity • Correlation of response with biomarkers F. Caponigro - Istituto Tumori Napoli

  33. 2. The mTOR pathway Key regulator of cell proliferation • Bjornsti MA et al, Nat Rev Cancer 2004 • Sahin F et al, Clin Cancer Res 2004 • Semela D et al, • J Hepatol 2007 Rapamycininhibits HCC growthin vivo tumor-bearing control animal

  34. NCT00516165 Ongoing study • Inclusion criteria • Unresectable of metastatic HCC • 0-2 prior systemic therapy for HCC • PS  2 ECOG RAD001 (Everolimus) is an oral kinase inhibitor that blocks the mTOR, a key component of PI3K/AKT pathway • Primary end-points • To determine the maximum tolerated dose of RAD001 • To determine PFS rate at 24 weeks F. Caponigro - Istituto Tumori Napoli

  35. 3. The Wnt pathway In the absence of ligand, -catenin is degraded through ubiquitin-proteasome systems after phosphorylation by the APC/AXIN/GSK3b complex. Upon Wnt ligand stimulation, -catenin accumulates in the cytosol and translocates into the nucleus. Intranuclear b-catenin leads to modifications in expression of numerous genes related to cell proliferation, cell cycling, apoptosis, and differentiation (Survivin, c-myc, Cyclin D1, etc). Moreover, mutations of components of the Wnt pathway (-catenin, AXIN 1, AXIN 2) have been described in HCC Nuclear -catenin accumulation, a hallmark of the activeted Wnt signaling, has been observed in 33-67% of HCC. Breuhahn K et al, Oncogene 2006 Miyoshi Y et al, cancer Res 1998 Lee HC et al, Front Biosci 2006 F. Caponigro - Istituto Tumori Napoli

  36. 4. VEGF Pathway (angiogenesis) HCCs are highly vascularized tumors and increased levels of VEGF and microvessel density (MVD) have been observed. High VEGF expression has been associated with inferior survival Microvessels stained by anti-CD34 in a tumor section of HCC, with almost no staining in the adjacent non-tumorous liver DFS after hepatic resection in pts with HCC ≤5 cm stratified into low and high MVD by CD34 immunostaining (P=0.002) Poon RT et al, J Clin Oncol 2002 F. Caponigro - Istituto Tumori Napoli Chao Y et al, Ann Surg Oncol 2003 Yamaguchi R et al, Hepatology 1998

  37. Phase II Trial of Bevacizumab in HCC * Including 1 death F. Caponigro - Istituto Tumori Napoli ASCO Chicago 2007

  38. Phase II Study of Gemcitabine and Oxaliplatin in Combination With Bevacizumab in Patients With Advanced Hepatocellular Carcinoma • 33 pts, PS 0-1, with unresectable or metastatic HCC were enrolled • Treatment Protocol: Bevacizumab 10 mg/kg d1 q14 Gemcitabine 100 mg/mq (10 mg/mq/min) d2, d16 q28 Oxaliplatin 85 mg/mq d2, d16 q28 Median OS = 9.6 months (95% CI, 8.0 to NA) Median PFS = 5.3 months (95% CI, 3.7 to 8.7) ORR = 20% SD = 27% of pts The most common treatment-related G3-G4 toxicities included leukopenia/neutropenia, transient elevation of aminotransferases, hypertension, and fatigue. GEMOX-B could be safely administered and had moderate antitumor activity for patients with advanced HCC F. Caponigro - Istituto Tumori Napoli Zhu AX et al, J ClinOncol 2006

  39. Bevacizumab and Erlotinib in Inoperable and Metastatic Hepatocellular Carcinoma NCT00287222 Phase II ongoingstudy • Primary endpointproportion of subjects that remain free of progression at the 27th week following the onset of treatment F. Caponigro - Istituto Tumori Napoli

  40. General Conclusions (1/2) A majority of HCC patients (>80%) presents with advanced disease and is inelegible for surgical or locoregional therapies At this moment, there is not effective systemic chemotherapy for HCC Understanding the molecular pathway of HCC is crucial to the development of novel therapies The relevant molecular signaling in HCC are: EGFR, VEGFR, AKT/mTOR, Raf/MEK/ERK pathways F. Caponigro - Istituto Tumori Napoli

  41. General Conclusions (2/2) Sorafenib, inhibiting both cell growth and angiogenesis, is the first agent to improve survival of patients with advanced HCC. This effect establishes Sorafenib as first-line treatment for these pts The next steps include testing Sorafenib earlier in the disease and eventually in combination with other targeted therapies (Bevacizumab, Erlotinib, Sunitinib have all been tested for liver cancer in phase II studies) Until now, experimental therapies for HCC have been compared with placebo. Many patients are reluctant to join clinical trials if they have a 50% chance of receiving a sugar pill. Participation in trials may now increase, with Sorafenib replacing placebo as the standard control F. Caponigro - Istituto Tumori Napoli

  42. Thanks for your attention Any Questions? F. Caponigro - Istituto Tumori Napoli

More Related