clinicaloptions.com/oncology Multidisciplinary Approaches to a Growing Clinical Challenge By Heba El-Zawahry M.D. Prof. Medical Oncology Head of Medical Oncology Department National Cancer Institute, Cairo University Role of Molecular Targeted Therapy in HCC
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clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
By
Heba El-Zawahry M.D.Prof. Medical OncologyHead of Medical Oncology DepartmentNational Cancer Institute, Cairo University
Role of Molecular Targeted Therapy in HCC
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical ChallengeMalignant Transformation
Multistep (pathogenesis of HCC)
Potential TargetsOxidative stress and
inflammationViral oncogenes Carcinogens
Growth factors Telomere shortening
Cancer stem cells
Loss of cell cycle checkpoints
Antiapoptosis Angiogenesis
Normal liver
Liver cirrhosis
Hepatitis CHepatitis B
EthanolNASH
Epigenetic alterationsGenetic alterations
HCC[2]
Dysplastic nodules[1]
1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
Prognostic factors in HCC: dismal prognosis
Prognosis of HCC and treatment options are determined by
– A natomical extent of tumor (stage)
– B iological aggressiveness (grade)
– C irrhosis severity and functional status
– D isease extension; through staging workup include multiphase CT/MRI of abdomen, chest CT, and bone scan
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
Anatomic Staging : TNM
Goodman J, et al. Arch Surg. 2005;140:459-464.
Stage TNMI Single tumor < 2 cmII 1 tumor 2-5 cm or 2 or 3 tumors, largest < 3 cmIII 1 tumor > 5 cm or 2 or 3 tumors, largest > 3 cm
IV4 or more intrahepatic tumors or vascular invasion or
extrahepatic metastasis
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
Survival by HCC Tumor Stage
Survival of HCC is strongly related to stage at diagnosis
Earlier detection of HCC could improve outcome
Stravitz RT, et al. Am J Med. 2008;121:119-126.
II
III
IV
I
0
0.2
0.6
0.4
0.8
1.0
0 1 2 3 4 5Yrs
Surv
ival
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical ChallengeChild-Pugh Classification of Severity of Liver
Cirrhosis and functions
Pugh RN, et al. Br J Surg. 1973;60:646-649. Lucey MR, et al. Liver Transpl Surg. 1997;3:628-637.
arm) and ↓ Ang2 and ↓ VEGF (placebo arm) associated with ↑ OS in multivariate analyses
– sVEGFR2, sVEGFR3, Ras, EGF, FGF, IGF2 were not prognostic
None predicted benefit– Trend towards improved OS in
subset with baseline ↑ sc-Kit in SOR arm over placebo
1. Abou-Alfa GK, et al. J Clin Oncol. 2006;24:4293-4300. 2. Llovet JM, et al. N Engl J Med. 2008;359:378-390. 3. Llovet JM, et al. Clin Cancer Res. 2012;18:2290-2300.
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical ChallengeLight Trial multicenter multinational randomized clinical trial for
the use of linifenib vs sorafenib in advanced HCC
900 HCC (A/B)
Randomized between sorafenib 400mg bid vs linifenib 400mg bid for 28days to be continued
Evaluation after 4 months
RECIST response
Radiological response
Interim report March 2013
Non inferiority result for Linifenib
Diarrhea and neutropenia were more in Sorafenib arm
DFP was superior in Sorafenib arm bur NS
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
Egyptian National trial for Sorafenib vs Sorafenib and UFT for systemic treatment of advanced HCC
Egyptian Trial include 5 big centers
Aimed for 715 advanced HCC
Randomized between Sorafenib vs Sorafenib and UFT as first line of treatment for HCC
Started November 2011 still ongoing
Recruitment of more than 100 cases up till now
Still interim analysis not yet
The advantage of this study is to evaluate the response of HCC following HCV in one genotype with some basic biological marker that may identify a target to HCC following this genotype
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
Beyond Sorafenib: New Agents in HCC
Agent Molecular Targets Phase Response,
%Median OS,
MosMedian TTP,
MosMedian PFS,
MosSafety:
Grade 3-4 AEs, %
Doxorubicin ± sorafenib[1] II PR: 4.0 13.7 6.4 6.0
Fatigue (6)Hand–foot skin
reaction(6.4)
Sunitinib[2]
VEGFR, PDGFR,
FLT3, KIT, RET
III CR+PR: <7 7.9 4.1 3.6Significant toxicities;
discontinued
Brivanib[3] VEGFR, FGFR II ORR: 4.3 9.8 1.8 2.0
HTN (7.3)Diarrhea (6.5)
Headache (4.3)
Linifanib (ABT-869)[4]
VEGFR, PDGFR II ORR: 6.8 9.7 3.7 NR HTN (18)
Fatigue (14)
Cabozantinib (XL184)[5]
c-MET, VEGFR2 II PR: 9.0 NR NR 4.2
Hand-foot syndrome (15)
Diarrhea(9)TP (9)
Tivantinib(ARQ197)[6] c-MET II NR MET high: 7.2 MET high: 2.9 MET high: 2.4 Neutropenic
sepsis (4.2)
1. Abou-Alfa GK, et al. JAMA. 2010;304:2154-2160. 2. Cheng A, et al. ASCO 2011. Abstract 4000. 3. Finn RS, et al. Clin Cancer Res. 2012;18:2090-2098. 4. Toh H, et al. ASCO 2010. Abstract 4038. 5. Cohn AL, et al. ASCO GI. 2012. Abstract 261. 6. Rimassa, L, et al. ASCO 2012. Abstract 4006.
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical ChallengeMolecular classification of HCC
HCC genomic-based classification In a meta-analysis of 603 HCC patients
– 3 HCC subtypes were observed: S1–S3
– Distinguished by molecular phenotype, tumor size, cellular differentiation, and AFP levels
S1 S2 S3
Molecular pathways
TGF-βWnt MYC
AKT
Retained hepatocyte-like phenotypeE2F1 , p53
IFN
Published subclasses
Poor survival Good survival
Proliferation CTNNB1
Late TGF-β EpCAM (+)
Clinical phenotype
Moderately/poorly differentiated Well differentiated
Large tumor Smaller tumor
AFP Hoshida Y, et al. Cancer Res. 2009;69:7385–92.
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
Tivantinib (ARQ 197): Target MET in HCC
Ongoing efforts to study hepatocarcinogenesis have identified an important role for c-MET signaling in the promotion of tumor growth, angiogenesis, and metastasis. – Only known receptor for hepatocyte growth factor
– Correlated with poor prognosis
c-MET inhibitors fhave been evaluated in many phase I tilas for or more rational clinical trial design.
Tivantinib is a selective oral MET inhibitor
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical ChallengeTivantinib vs Placebo in Previously Treated
Unresectable HCC
Multicenter, randomized phase II trial
Primary endpoint: TTP Stratification: MET status, HBV vs HCV, and duration of previous therapy Crossover on PD
Rimassa L, et al. ASCO 2012. Abstract 4006.
Patients with unresectable HCC following failure of
1 systemic therapy, ECOG PS < 2
(N = 107)Placebo PO BID
(n = 36)
Tivantinib 360 mg PO BID(n = 38)
Tivantinib 240 mg PO BID(n = 33)
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical ChallengeTivantinib vs Placebo in Previously Treated
Unresectable HCC
MET level predictive of tivantinib benefit: TTP and OS similar with tivantinib vs placebo among patients with low MET expression
ITT
Rimassa L, et al. ASCO 2012. Abstract 4006.
MET Diagnostic High Population
Prop
ortio
n of
Pat
ient
s Pr
ogre
ssio
n Fr
ee
1.0
0.8
0.6
0.4
0
0.2
Wks to Tumor Progression0 10 20 30 40 50 60
Median TTP6.9 wks6.0 wks
TivantinibPlacebo
Patients7136
Events4630
HR: 0.64 (90% CI: 0.43-0.94;log-rank P = .04)
Prop
ortio
n of
Pat
ient
sSu
rviv
ing
1.0
0.8
0.6
0.4
0
0.2
Wks From Date of Randomization0 5 10 15 20 25
Median TTP6.6 wks6.2 wks
TivantinibPlacebo
Patients7138
Events5630
HR: 0.90 (90% CI: 0.57-1.40;log-rank P = .63)
Prop
ortio
n of
Pat
ient
s Pr
ogre
ssio
n Fr
ee
1.0
0.8
0.6
0.4
0
0.2
Wks to Tumor Progression0 10 20 30 40
Median TTP11.7 wks6.1 wks
TivantinibPlacebo
Patients2215
Events1413
HR: 0.43 (95% CI: 0.19-0.97;log-rank P = .03)
Prop
ortio
n of
Pat
ient
sSu
rviv
ing
1.0
0.8
0.6
0.4
0
0.2
Mos From Date of Randomization0 5 10 15 20
Median TTP7.2 wks3.8 wks
TivantinibPlacebo
Patients2215
Events1715
HR: 0.38 (90% CI: 0.18-0.81;log-rank P = .01)
clinicaloptions.com/oncologyMultidisciplinary Approaches to a Growing Clinical Challenge
• Imaging every 3–6 months for 2 years, then every 6–12 months
• AFP, if initially elevated, every 3–6 months for 2 years, then every 6–12 months
Options:• Sorafenib
(Child–Pugh class A [category 1] or B)c, d, e, f
• Chemotherapy + RT only in the context of a clinical trial• Clinical trial• Locoregional therapya
• RT (conformal or stereotactic)v (category 2B)• Supportive care• Systemic or intra-arterial chemotherapy in clinical trial
Options:• Sorafenib
(Child–Pugh class A [category 1] or B) c, d, e, f
• Clinical trial• Locoregional therapya
• RT (conformal or stereotactic)g (category 2B)
• Sorafenib(Child–Pugh class A [category 1] or B) c, d, e, f