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Session 2.2: Kaubisch

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Andreas Kaubisch

Andreas Kaubisch

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Session 2.2: Kaubisch Session 2.2: Kaubisch Presentation Transcript

  • Medical Management of Hepatocellular Cancer- Novel Agents Andreas Kaubisch, MD Medical Oncology Montefiore Medical Center Albert Einstein College of Medicine May 2010
  • Staging of Liver Cancer - 2 Diseases Anatomic: AJCC: TNM Clinical: (Combine liver function + Tumor characteristics) Okuda CLIP Clinical: (Focus on Liver Function) Child- Pugh Model for End-Stage Liver Disease (MELD)
  • Treatment Options
    • (Potentially) Curative Treatments
    • - Surgery
    • - Transplantation
    • - Ablation (RFA)
    • - Radiation
    • Palliative Treatments
    • - Loco- Regional Therapies
          • Ablation (RFA, EA, Cryo, Electroporation)
          • Arterial Embolization +/- Chemo (TACE) or Y-90 beads (SIRT)
          • Radiation
    • - Systemic Treatments
          • Hormonal (Tamoxifen, Octreotide)
          • Cytotoxic Chemotherapy
          • Biologic/ Targeted Rx
          • Immunotherapy
  • Treatment Options- BCLC Algorithm Figure 5. Barcelona-Clínic Liver Cancer staging classification and treatment schedule PST=performance status test. N=nodules. M=metastases. PEI=percutaneous ethanol injection. * Cadaveric liver transplantation or living donor liver transplantation. Modified from 54 and 40 with permission from The American Association for the Study of Liver Disease. Llovet, Burroghs, Bruix; Lancet 2003; 362: 1907
  • Treatment Options- Early Stage Figure 5. Barcelona-Clínic Liver Cancer staging classification and treatment schedule PST=performance status test. N=nodules. M=metastases. PEI=percutaneous ethanol injection. * Cadaveric liver transplantation or living donor liver transplantation. Modified from 54 and 40 with permission from The American Association for the Study of Liver Disease. Llovet, Burroghs, Bruix; Lancet 2003; 362: 1907 <----------
  • Treatment Options- Advanced Stage Figure 5. Barcelona-Clínic Liver Cancer staging classification and treatment schedule PST=performance status test. N=nodules. M=metastases. PEI=percutaneous ethanol injection. * Cadaveric liver transplantation or living donor liver transplantation. Modified from 54 and 40 with permission from The American Association for the Study of Liver Disease. Llovet, Burroghs, Bruix; Lancet 2003; 362: 1907 <---------- --->
  • Treatment Options- Local and Systemic Rx Figure 5. Barcelona-Clínic Liver Cancer staging classification and treatment schedule PST=performance status test. N=nodules. M=metastases. PEI=percutaneous ethanol injection. * Cadaveric liver transplantation or living donor liver transplantation. Modified from 54 and 40 with permission from The American Association for the Study of Liver Disease. Llovet, Burroghs, Bruix; Lancet 2003; 362: 1907 <---------- --->
  • Arterial Embolization +/- Chemotherapy (TACE) Llovet, Bruix, Hepatology 2003; 37: 429-442 Meta- Analysis of Randomized Trials • TACE improved 2 year survival vs control: odds ratio: 0.53 (.32-.89), P=0.017 • Benefit with use of Cisplatin and Doxorubicin • NO survival benefit with embolization alone • Response rate: 35% (16 %- 61%) • Optimal patients for TACE: well preserved liver function, multi- nodular HCC, no vascular invasion
  • Systemic Treatment for Unresectable Liver Cancer - Hormonal - Cytotoxic Chemotherapy - Biologic or “Targeted” Agents
  • Hormonal Rx of HCC Simonetti et al. 1997, Ann Oncol 8: 117-136 Tamoxifen: One clinical study suggests benefit, several others do not- considered largely ineffective Octreotide: One clinical study suggests benefit, several others do not- considered largely ineffective Thalidomide (? Mechanism) Multiple trials with at best minimal efficacy (Revlimid more potent)
  • Chemotherapy for HCC (Recent Trials- Phase III) Lopez et al, Alimet Pharm Ther 23: 1535- modified Several large clinical trials fail to demonstrate significant benefit of one treatment over another 10.7/ 7.9 P=.00058 2.3 299/ 301 Sorafenib vs Placebo Llovet Proc ASCO 2007 6/ 6 339 T138067 vs Doxorubicin Posey ASCO 2005 5/ 7.5 446 Nolatrexed vs Doxorubicicn Porta ASCO 2006 9.6/ 9.2 80/ 80 <10/ <10 747 Seocalcitol vs Placebo Beaugrand 2000 J Hepatol 8.7/ 6.8 39/ 30 20.9/ 10.5 94/94 PIAF vs Doxorubicin Yeo 2005 JNCI MS (mo) 1 Yr S (%) RR(%) N Rx Study
  • RP Massive HCC
  • Molecular Classification of HCC
    • • Immunohistochemistry
    • • Mutation analysis
    • • Expression Profiles
    • • Epigenetic Alterations
    • • Micro RNA patterns
    • • Others
  • Sanger Institute- Cosmic Database Reported Mutations in HCC Other Genes with mutations in HCC: APC (2), BRAF (1), BRCA2 (1), CSF1R (3), EGFR (2), ERBB2 (2), MET (3), NRAS (10), RB1 (3), SMAD4 (2), SMO (1), TCF1 (8), TP53 (6) http://www. sanger .ac. uk / perl /genetics/CGP/cosmic?action= byhist &s=4& hn =carcinoma& sn =liver& sh = hepatocellular _carcinoma (COSMIC Database) 4 % KRAS 6 % PIK3CA 5 % PTEN 14 % CDKN2A 17 % CTNNB1 Percent Mutated Gene Name
  • Molecular Classification of HCC- Expression Profiles Molecular Classification and Novel Targets in Hepatocellular Carcinoma: Recent Advancements   Yujin Hoshida, Sara Toffanin, Anja Lachenmayer, Augusto Villanueva, Beatriz Minguez, Josep M. Llovet
  • Regulatory Control- Micro RNAs Fig. 1  Schematic representation of pathways affected by miRNAs deregulated in human hepatocellular carcinoma . Receptor tyrosine kinase (here indicated HGF/MET axis solely), RAS and PI3K pathways affected by the down-regulated (downward green arrow) miR-1, miR-199a*, Let-7 and the up-regulated (upward red arrow) miR-21 may lead to cell growth, survival, motility, invasion and metastasis. The cell cycle progression is mainly affected by the miR-221 (and miR-222, not indicated) up-regulation, which can repress the CDK inhibitors CDKN1 B/p27 and CDKN1 C/p57. MicroRNA involvement in hepatocellular carcinoma, Gramantieri , Francesca Fornari , Elisa Callegari, Silvia Sabbioni , Giovanni Lanza , Carlo M. Croce , Luigi Bolondi , Massimo Negrini; J Cell Mol Med 2008
  • Molecular Targeted Drugs for Hepatocellular Carcinoma Phase III Clinical Trials Molecular Classification and Novel Targets in Hepatocellular Carcinoma: Recent Advancements   Yujin Hoshida, Sara Toffanin, Anja Lachenmayer, Augusto Villanueva, Beatriz Minguez, Josep M. Llovet VEGFR, PDGFR, CKIT Sunitinib (Sutent) BRAF, VEGFR, PDGFR Sorafenib (Nexavar) mTOR Rapamycin FGF, VEGF PI-88 VEGFR, PDGFR Linifanib EGFR Erlotinib (Tarceva) VEGFR2, FGFR Brivanib
  • Molecular Targeted Drugs for HCC- Phase II Clinical Trials ? Revlimid VEGF ZD-6474 EGFR, Her2, VEGFR2 XL-647 MET, RET, VEFGR2 XL-184 VEGF, FGF, PDGF TSU-68 mTOR RAD-001 (Temsirolimus) Bcl-2 Oblimersen TRAIL Mapatumumab Survivin LY-2181308 Fab'2 Fragment Licartin Kinesin spindle protein Ispinesib IGFR1 IMC-A12 VEGF, FGF, SCF E-7080 BCR/ABL Dasatinib PD-1/2 CT-011 26S proteasome Bortezomib IGFR1 BIIB-022 VEGF, PDGF, FGF BIBF-1120 MEK1/2 AZD-6244 VEGF AZD-2171 IGF-1R AVE-1642 Angiopoietin 1/2 AMG-386
  • Bio/ Targeted Agents: VEGF ++ 9.5 37 5.6 5 137 Sorafenib (Nexavar) Abou-Alfa 10.7/ 7.9 5.5/ 2.8 2.3 299/ 301 Sorafenib (Nexavar) Llovet (Ph3) Proc ASCO 2007 11.6 4.1 4 26 Sunitinib (Sutent) Zhu ASCO 2007 - - 6.5 7 28 Bevacizumab (Avastin) Schwartz - - - 22 29 Erlotinib- Bev Thomas 9.6 48 5.3 20 33 GemOx-Bev Zhu MS (mo) 6 Mo PFS PFS/ TTP RR(%) N Rx Study
  • SHARP Trial: Sorafenib vs Placebo
    • International, randomized Phase III Study
    • Eligible:
      • Biopsy proven HCC
      • Advanced HCC (not operable or OLT candidate)
      • Measurable disease
      • ECOG 0-2
      • Child- Pugh A class
      • No previous Rx
    • N= 600, half received sorafenib, half placebo
    • Trial stopped early because sorafenib arm showed survival benefit
    C 21 H 16 ClF 3 N 4 O 3 . C 7 H 8 SO 3
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  • Abou-Alfa, G. K. et al. J Clin Oncol; 24:4293-4300 2006 Fig 1. A representative example of baseline and serial follow-up scans demonstrating tumor necrosis in a hepatocellular carcinoma patient
  •  
  • HFS- Soraf 2
  • HFS Soraf 3
  • Molecular Targeted Drugs for HCC- Multi- kinase Inhibitors Sunitinib (Sutent); Targets: VEGFR, PDGFR, CKIT Small Molecule Multi- kinase inhibitor Side Effects: Fatigue, Diarrhea, Anorexia, Vomiting, HTN Phase II: 30- 40% of patients have period of cancer control Phase III: Sunitinib vs sorafenib, failed; sunitinib with more side effects without additional efficacy- trial closed early for lack of benefit Brivanib , Targets: VEGF, FGFR Small Molecule Multi- kinase inhibitor Phase II: Second line- after sorafenib 58% stable disease, 43% AFP drop > 50% Phase III: ongoing trials Brivanib vs BSC, TACE +/- Brivanib
  • Summary- Challenges
    • Sorafenib first systemic agent with proven efficacy in Rx of HCC- future studies
    • Modalities and techniques (Surgery/ Loco- regional/ systemic/ RT) need to combined and integrated rationally
    • Drug glut
    • Increasing number of targets
  • HCC Clinical Trials @ Montefiore/ Einstein
    • Pfizer A6181170 Phase III HCC study: Sunitinib Malate Versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma- closed to accrual, more toxicity with sunitinib
    • Lenalidomide (Revlimid) phase II study for advanced HCC (Safran- Brown), for patients who have received sorafenib
    • Bristol Phase III: Brivanib (VEGFR, FGFR) vs placebo after TACE, Can Brivanib prevent or delay recurrence after TACE?
    • NY Consortium 8233 Phs. II Trial of Temsirolimus (mTor) & Bevacizumab (VEGF).
  • Proposed Standards for Future Clinical Trials in HCC J Natl Cancer Inst. 2008 May 21;100(10):698-711. Epub 2008 May 13.   Sorafenib vs drug**     Sorafenib vs Sorafenib +drug (Sorafenib) Drug vs placebo TACE vs drug or device** BCLC C- Advance stage           (Chemoembolization-TACE) - TACE vs TACE + drug BCLC B-Intermediate stage           (Resection, Transplantation Local ablation) - Adjuvant: drug vs placebo BCLC 0 or A –Early stages       2nd line treatment* 1st line treatment (standard of care)   Testing novel drugs HCC subclass
  • Clinical and Translational Reasearch Opprtunities in Liver Cancer at AECOM/ Monte 1) Tissue Banking- Molecular Profiling ; large patient population will lead quickly to meaningful tissue bank (identification of prognostic or treatment guiding biomarkers?) 2) Therapeutic trials A) Enhancements to Local treatments: TACE + novel agents, TACE + RT?, TACE + RFA as standard local Rx B) Can local ablative techniques (TACE, RFA, HIFU, RT etc) generate auto- immunizing antigens, perhaps with in vivo dendritic cell stimulation? C) Can moderate doses of 2 separate local therapies result in better cancer control with an improved therapeutic index? (eg SIRT and drug- eluting beads) D) Rational combinations of biologic agents (eg mTor/ EGFR inhibition) E) How can we enhance the efficacy of radiation in the treatment of HCC 3) All of the above with correlative science to enhance our understanding of the biology of liver cancer
  • &quot;You know, medicine is not an exact science, but we are learning all the time. Why, just fifty years ago, they thought a disease like your daughter's was caused by demonic possession or witchcraft . But nowadays we know that Isabelle is suffering from an imbalance of bodily humors , perhaps caused by a toad or a small dwarf living in her stomach.“ SNL, Theodoric of York, Medieval Barber (Steve Martin)
  •  
  • Hepatocellular Cancer
    • Revlimid for advanced HCC (Safran)
    • Open at Brown, at PRC/IRB @ Monte
    • Objectives: RR, TTP, OS, toxicities
    • lenalidomide 25 mg po days 1-21 then 7 days off in 28-day cycles
    • Prior sorafenib required, no biopsy needed
    • At Brown both AFP responses and radiographic responses noted
  • HCC- Phase III Brivanib vs placebo after TACE
    • Hypothesis: Brivanib after TACE will prolong OS
    • Objective: compare OS
    • N- 870, multinational phase III
    • Clinically or histologically documented HCC
    • Sites have to commit to standard approach to TACE
  • Brivanib (BMS 540215)
    • Oral TKI- inhibits VEGF and FGF (fibroblast growth factor)
    • FGF is hypoxia induced, and can rescue tumors from VEGF inhibition (Cancer Cell 2005; 8: 299-309)
    • Xenograft evidence of efficacy against HCC (reduced VEGFR-2 phosphorylation, decreased microvessel density, growth inhibition) CCR 2008, 14:6146-53
    • Biomarkers: Tie-1, collagen rec IV alpha1, angiotensin like receptor-1, vasc endoth-cadherin 5
    • PK: good brain penetration, oral bio- availability 22-88% (dissolution reta limited), human clearance anticipated to be low, VD large
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  •  
  • Radiation for HCC
    • Phase I study of stereotactic radiotherapy for unresectable hepatobiliary cancer and liver metastases.
    • 2007 ASCO   Abstract No: 4590   L. A. Dawson
    • 6 fraction stereotactic RT (SRT)
    • Patients: HCC, Cholangio, Colon mets, LFT’s < 6x, Plat > 80K, Child-Pugh A, > 800 cc uninvolved liver, KPS >= 60
    • Dose escalation according to risk of liver toxicity (5%, 10%, 20%)
    • Stratification according to volume of irradiated liver
    • N- 82, (38 LM, 32 HCC, 10 CC)
    • 17 (53%) had portal vein thrombosis
    • Median dose 40Gy in 6 fractions
    • Tox: LFT’s, Platelets, N, Fatigue, 8 pts with decline of Child score (6 POD)
    • 1 tumor- duodenal fistula
    • RR (in- field): 60% (LM 57 %, CC 50%, HCC 67 %), 14% CR, 46% PR
    • 12 Mo local control rate 78%
    • MS: LM: 16.6, CC: 13.1, HCC: 11
  •  
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  • RP Massive HCC
  • Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid Tumors Dirk Strumberg et al JCO , Vol 23, 2005: pp. 965-972
    • Sorafenib is an oral multi-kinase inhibitor that targets kinases involved in tumour cell proliferation and angiogenesis, including RAF kinase, VEGFR-2, VEGFR-3, PDGFR-B, KIT, and FLT-3
    • Phase I
    • N- 45
    • MTD: 400 mg po bid
    • Tox: diarrhea (55%), pancreatitis (n=3), Bili (n=3), mild stomatitis (n=5), HFSyndrome (23%), Rash (26%), alopecia (n=2), fatigue (n=4),
    • Response: 1 patient with HCC
  • Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma Abou-Alfa et al, Journal of Clinical Oncology , Vol 24, No 26, 2006: pp. 4293-4300
    • Multicenter Phase II
    • N= 137 patients, Child- Pugh A or B
    • PR: 2.2%, MR: 5.8%, SD: 33.6%
    • TTP: 4.2 mos
    • med OS: 9.2 mos
    • pERK levels correlated with TTP, 18 gene panel distinguished progressors from non- progressors
  • HFS of sorafenib-1
  •  
  • miRNA signatures associated with hepatocellular carcinoma (HCC) metastasis and survival    Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Zanetti KA, Ye QH, Qin LX, Croce CM, Tang ZY, Wang XW. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 2008; 47: 897–907. mirR-148a mirR-126 mirR-124b-2 mirR-124a-2 miR-122 miR-1-2 3p21 Down Let-7g 17q25 Mir-338mir-657 Up Yes miR-338 6p21 Up Yes miR-219-1 9p21 Up miR-207 22q11 Up miR-185 Chromosome miRNA Cluster Expression in HCC Survival- associated miRNA Metastasis- associated miRNA
  • Biologic Agents- Erb/ EGFR 9.6 1.4 0 30 Cetuximab Zhu 2007 Cancer 110: 581 - - 1.8 12* 17* Lapatinib Ramanathan - - - 22 29 Erlotinib- Bev Thomas 9.6 48 5.3 20 33 GemOx-Bev Zhu 13 32 3.2 9 38 Erlotinib Philip MS (mo) 6 Mo PFS PFS/ TTP RR(%) N Rx Study