Andreas Kaubisch

1. Medical Management of Hepatocellular
Cancer- Novel Agents
Andreas Kaubisch, MD
Medical Oncology
Montefiore Medical Center
Albert Einstein College of Medicine
May 2010

2. 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)

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. Systemic Treatment for
Unresectable Liver Cancer
- Hormonal
- Cytotoxic Chemotherapy
- Biologic or “Targeted” Agents

10. 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

11. 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

12. RP Massive HCC

13. Molecular Classification of HCC
• Immunohistochemistry
• Mutation analysis
• Expression Profiles
• Epigenetic Alterations
• Micro RNA patterns
• Others

14. 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)

15. 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

16. 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

17. 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

18. 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 ?

19. 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 - - -

20. 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

23. 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
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p i oc
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25. HFS- Soraf 2

26. HFS Soraf 3

27. 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

28. 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

29. 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).

30. 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.

31. 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

32. "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)

34. 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

35. 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

36. 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

39. 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

42. RP Massive HCC

43. 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

44. 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

45. HFS of sorafenib-1

47. 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

48. 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