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Session 2.2: Kaubisch
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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) 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 Llovet, Bruix, Hepatology 2003; 37: 429-442
    • Systemic Treatment for Unresectable Liver Cancer - Hormonal - Cytotoxic Chemotherapy - Biologic or “Targeted” Agents
    • Hormonal Rx of HCC 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) Simonetti et al. 1997, Ann Oncol 8: 117-136
    • Chemotherapy for HCC (Recent Trials- Phase III) Study Rx N RR(%) 1 Yr S MS (mo) (%) Yeo PIAF vs Doxorubicin 94/94 20.9/ 10.5 39/ 30 8.7/ 6.8 2005 JNCI Beaugrand Seocalcitol vs 747 <10/ <10 80/ 80 9.6/ 9.2 2000 J Hepatol Placebo Porta Nolatrexed vs 446 5/ 7.5 ASCO 2006 Doxorubicicn Posey T138067 vs 339 6/ 6 ASCO 2005 Doxorubicin Llovet Sorafenib vs Placebo 299/ 2.3 10.7/ 7.9 Proc ASCO 2007 301 P=.00058 Several large clinical trials fail to demonstrate significant benefit of one treatment over another Lopez et al, Alimet Pharm Ther 23: 1535- modified
    • 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 Gene Name Percent Mutated CTNNB1 17 % CDKN2A 14 % PTEN 5% PIK3CA 6% KRAS 4% 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)
    • 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. Llove
    • 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 Brivanib VEGFR2, FGFR Erlotinib (Tarceva) EGFR Linifanib VEGFR, PDGFR PI-88 FGF, VEGF Rapamycin mTOR Sorafenib (Nexavar) BRAF, VEGFR, PDGFR Sunitinib (Sutent) VEGFR, PDGFR, CKIT Molecular Classification and Novel Targets in Hepatocellular Carcinoma: Recent Advancements Yujin Hoshida, Sara Toffanin, Anja Lachenmayer, Augusto Villanueva, Beatriz Minguez, Josep M. Llovet
    • Molecular Targeted Drugs for HCC- Phase II Clinical Trials AMG-386 Angiopoietin 1/2 AVE-1642 IGF-1R AZD-2171 VEGF AZD-6244 MEK1/2 BIBF-1120 VEGF, PDGF, FGF BIIB-022 IGFR1 Bortezomib 26S proteasome CT-011 PD-1/2 Dasatinib BCR/ABL E-7080 VEGF, FGF, SCF IMC-A12 IGFR1 Ispinesib Kinesin spindle protein Licartin Fab'2 Fragment LY-2181308 Survivin Mapatumumab TRAIL Oblimersen Bcl-2 RAD-001 (Temsirolimus) mTOR TSU-68 VEGF, FGF, PDGF XL-184 MET, RET, VEFGR2 XL-647 EGFR, Her2, VEGFR2 ZD-6474 VEGF Revlimid ?
    • Bio/ Targeted Agents: VEGF ++ Study Rx N RR(%) PFS/ 6 Mo MS TTP PFS (mo) Schwartz Bevacizumab 28 7 6.5 - - (Avastin) Zhu Sunitinib (Sutent) 26 4 4.1 11.6 ASCO 2007 Abou-Alfa Sorafenib 137 5 5.6 37 9.5 (Nexavar) Llovet (Ph3) Sorafenib 299/ 2.3 5.5/ 10.7/ Proc ASCO 2007 (Nexavar) 301 2.8 7.9 Zhu GemOx-Bev 33 20 5.3 48 9.6 Thomas Erlotinib- Bev 29 22 - - -
    • SHARP Trial: Sorafenib vs Placebo  International, randomized Phase III Study  Eligible:  Biopsy proven HCC  Advanced HCC (not operable or OLT candidate) C21H16ClF3N4O3.C7H8SO3  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
    • Fig 1. A representative example of baseline and serial follow-up scans demonstrating tumor necrosis in a hepatocellular carcinoma patient Abou-Alfa, G. K. et al. J Clin Oncol; 24:4293-4300 2006 C rci n o e oc p i oc y c fa rAyO i ga C h n llo t ©t i m ny Si e l o g
    • 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 HCC subclass Testing novel drugs (standard of care) 1st line treatment 2nd line treatment* BCLC 0 or A –Early stages Adjuvant: drug vs placebo - (Resection, Transplantation Local ablation) BCLC B-Intermediate stage TACE vs TACE + drug - (Chemoembolization-TACE) BCLC C- Advance stage TACE vs drug or device** Drug vs placebo (Sorafenib) Sorafenib vs Sorafenib +drug Sorafenib vs drug** J Natl Cancer Inst. 2008 May 21;100(10):698-711. Epub 2008 May 13.
    • 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
    • "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
    • 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
    • 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 Metastasis- Survival- associated Expression in miRNA Cluster Chromosome associated miRNA miRNA HCC miR-185 Up 22q11 miR-207 Up 9p21 miR-219-1 Yes Up 6p21 miR-338 Yes Up Mir-338mir-657 17q25 Let-7g Down 3p21 miR-1-2 miR-122 mirR-124a-2 mirR-124b-2 mirR-126 mirR-148a 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 micr
    • Biologic Agents- Erb/ EGFR Study Rx N RR(%) PFS/ 6 Mo MS TTP PFS (mo) Ramanathan Lapatinib 17* 12* 1.8 - - Philip Erlotinib 38 9 3.2 32 13 Zhu 2007 Cetuximab 30 0 1.4 9.6 Cancer 110: 581 Zhu GemOx-Bev 33 20 5.3 48 9.6 Thomas Erlotinib- 29 22 - - - Bev