Monotematica AISF 2013
Personalizzazione della Cura in Epatologia
Pisa, 17-19 Ottobre 2013
Epatocarcinoma: terapia medica
Dott. Angelo Sangiovanni
U.O. Gastroenterologia 1
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Università di Milano
Milano
Dott. Angelo Sangiovanni
Epatocarcinoma: Terapia Medica
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi
conflitto d’interesse in relazione a questa presentazione
e
che la presentazione contiene discussione di farmaci in
studio o ad uso off-label: sorafenib, brivanib, linifanib,
sunitinib, everolimus, tivantinib, ramucirumab, ADI-PEG,
lenvantinib, regorafenib, cabozantinib, pexa-vec,
tremelimumb, nivolumag, AMG 386
HCC Management Patterns from the HCC BRIDGE Study
Park et al, ASCO 2012
Challenges in the Development of Drug Therapy for HCC
• Advanced stage at presentation
• Relative resistance to cytotoxic chemotherapy
• Liver dysfunction
Poor drug metabolism
Altered plasma-binding proteins
Altered drug distribution volumes
Competing cause of morbidity and mortality
• Diverse underlying etiologies of liver dysfunction among patients
• Difficulty in quantifying tumor response
• Multiple staging systems
Giglia et al, Cancer Control 2010;17:120-9
Molecular Targeted Therapies in HCC
Giglia et al, Cancer Control 2010;17:120-9
Levels of Evidence in the Assessment of Benefits in
the Treatment of “Advanced” HCC
Systemic treatment
Benefit
Evidence
Sorafenib
Increased survival
1iA
Hormonal compounds
Tamoxifen
Antiandrogen
Seocalcitiol
No survival benefit
1iA
Systemic chemotherapy
No survival benefit
1iiA
Interferon
No survival benefit
1iiA
Forner et al, Lancet 2012;379:1245-55
EASL: BCLC Staging System and Treatment Strategy
HCC
Stage 0
Stage A-C
Stage D
PST 0, child-Pugh A
PST 0-2, child-Pugh A-B
PST >2, child-Pugh C
Very early stage (0)
Early stage (A)
Intermediate stage (B)
Advanced stage (C)
Single <2cm,
Carcinoma in situ
Single or 3 nodules ≤ 3 cm
PS 0
Multinodular
PS 0
Portal invasion
N1, M1, PS 1-2
Single
3 nodules ≤ 3cm
Terminal stage (D)
Portal pressure/bilirubin
Increased
Normal
Resection
Associated diseases
No
Liver transpl.
(CLT/LDLT)
Yes
RF/PEI
Curative treatment (30-40%)
Median OS > 60 mo; 5-yr survival: 40-70%
TACE
Target: 20%
OS:20 mo (45-14)
Sorafenib
Best supportive care
Target: 40%
OS: 11 mo (6-14)
Target: 10%
OS: < 3 mo
EASL–EORTC CPG: Management of Hepatocellular Carcinoma, J Hepatol. 2012;56:908-43
First-line Treatment with Sorafenib of Newly Diagnosed
Consecutive Patients with Hpatocellular Carcinoma
Tumor Stage
Number of patients
Single center study1
(No.= 383)
Multicenter study2
(No.= 490)
BCLC 0 & A
0/258 (0%)
4/294 (2%)
BCLC B
3/68 (4%)
2/116 (2%)
BCLC C
27/57 (47%)
48/80 (60%)
1. Sangiovanni A, uunpublished data; 2 Borzio M, Future Oncol. 2013;9:283-294
Survival Outcomes for Subgroups of Patients Enrolled
in the SHARP Trial
Bruix J et al, J Hepatol 2012;57:821-9
Incidence of Drug-related Adverse Events
with Sorafenib Therapy
Kaneko et al, Hepatology Research 2012;42:523-42
Adherence to Sorafenib Therapy: RCT vs Field Practice
SHARP1
SOFIA2
Treatment duration, months
5.3
3.8
Mean sorafenib daily dose, mg
710
696
Discontinuation due to AEs
38%
45%
Dose reductions due to AEs
26%
54%
Dose interruptions due to AEs
44%
56%
Outcomes
1Llovet JM
et al N Engl J Med 2008
2Iavarone M
et al Hepatology 2011
Overall Survival According to the Prevalent Dose of
Sorafenib in the SOFIA Study (296 Patients)
219 patients
Predictors of mortality
HR (95% CI)
- 97 (40%) discontinued without
previous dose reduction
ECOG Performance Status
1.9 (1.5 – 2.5)
Macroscopic vascular invasion
1.9 (1.4 – 2.6)
- 122 with half dose for <70% of
the treatment period
Extrahepatic spread
1.4 (1.1 – 1.9)
Early radiological progression
1.4 (1.1 – 2.1)
Full dosing
Iavarone M et al. Hepatology 2011;54:2055-63
1.8 (1.4-2.4)
77 patients with half dose
for ≥70% of the treatment
period
Cost-effectiveness Analyses of Sorafenib Therapy for HCC
Treatment Strategies
Best supportive care
BCLC B+C
BCLC B
BCLC C
Costs in 2012
euros
QALY
ICER/QALY base-case
analysis (2012 euros)
4,142
-
-
Full dose
16,081
0.16
69,344
Dose-adjusted
19,944
0.44
34,534
Full dose
24,224
0.32
57,385
Dose-adjusted
26,914
0.38
54,881
Full dose
14,841
0.16
65,551
Dose-adjusted
16,625
0.44
27,916
Willingness to pay for 1 ICER/Quality = 34,000€
Cammà et al, Hepatology. 2013;57:1046-54
Usefulness of Alpha-fetoprotein Response in Patients Treated
with Sorafenib for Advanced Hepatocellular Carcinoma
Personeni et al J Hepatol 2012;57:101-7
Diarrhea Is a Positive Outcome Predictor for Sorafenib Treatment of
Advanced Hepatocellular Carcinoma
Koschny Oncology 2013;84:6–13
Dermatological AEs Within The First 60 Days of Sorafenib
Treatment Are Associated with Better OS
Prospective study of 147 BCLC B/C 2008–2011. Treatment duration = 6.7 months
Overall survival
p=0.016
TTP (months)
DAE60: 8.1 mo
(IC95%: 1.6–14.5)
no DAE60: 3.9 mo
(IC95%: 2.08–5.7)
M. Reig et al. EASL 2013 Amsterdam, Abstract #267
Probability of survival
Probability of progression
Time to tumor progression
p=0.009
p<0.001
Survival (months)
DAE60: 18.2 mo
(IC95%: 11.9–24.4)
no DAE60: 10.1 mo
(IC95%: 10.1–13.0)
Sorafenib Exposure Decreases Over Time in Patients
with Hepatocellular Carcinoma
Decrease of sorafenib dose-normalized AUC over time in 15 patients with HCC
Arrondeau et al, Invest New Drugs 2012;30:2046–2049
VEGF and VEGFR Polymorphisms in the Prediction of
Clinical Outcome in 142 Advanced HCC Receiving Sorafenib
OS
p value
(months)
VEGF-A rs125468
for C 15.0
for T
9.4
for G
14.2
for A
1.7
VEGFR2 rs1870377 for A
29.6
for T
11.9
VEGF-C rs7664413 for C
14.7
for T
5.6
VEGF-A rs10434
0.025
Multivariate Analysis
TTP
p value
Hazard Ratio
(months)
OS
TTP
n.a.
n.a.
0.0076
4.1
0.0076
1.2
0.0096
19.9
0.0271
3.0
0.0007
13.4
0.0125
2.0
Faloppi et al, poster 2013 ASCO Gastrointestinal Cancers Symposium
0.65
0.61
Post-progression Survival of Patients with Advanced HCC
Rationale for Second Line Trial Design
Multivariate Cox analysis of post-progression survival in patients with
radiologic tumor progression under sorafenib treatment
Reig M et al, Hepatology, in press
Post-progression Survival of Patients with Advanced HCC
Rationale for Second Line Trial Design
BCLCp C1: Patients BCLC-C under sorafenib treatment with progression due to growth of existing nodules or new intra-hepatic sites.
BCLCp C2: Patients BCLC-C under sorafenib treatment with progression due to new extra-hepatic lesion and/or vascular invasion.
Reig M et al, Hepatology, in press
Tivantinib For Second-line Treatment of Advanced Hepatocellular
Carcinoma: A Randomised, Placebo-controlled Phase 2 Study
Santoro et al, Lancet Oncology 2013;14:55-63
Tivantinib (ARQ 1971) vs Placebo as Second Line Therapy
for Advanced HCC. A Phase 2 RCT
Improved TTP in c-MET (+)
Santoro et al, Lancet Oncology 2013;14:55-63
Improved OS in c-MET (+)
Advanced HCC: Ongoing Phase III Trials
Sorafenib+erlotinib : 1st line
Primary endpoint not met
Data: ESMO 2012
Everolimus: 2nd line
Q2 2013 (data)
endpoint not met
Brivanib PS: 2nd line
Primary endpoint not met
Data: EASL 2012
Ramucirumab 2nd line
Q4 2013 (data)
Brivanib TA:
with TACE
Q3 2014 (data)
Development
stopped
Brivanib FL: 1st line
Primary endpoint not met
Data: AASLD 2012
Linifanib: 1st Line
Study stopped
Data: ASCO GI 2013
Brivanib PS:
2nd line AP
Q3 2014 (data)
Development
stopped
Sunitinib SUN1170 Primary
endpoint not met
ASCO 2011
2010
Phase 3
ADI-PEG20 2nd line July
2014
2013
2015
Phase 3
Lenvatinib 1st line
Feb 2015
Phase 3
Tivantinib 2nd line
Sept 2015
Phase 3
Regorafenib 2nd line
Oct 2015
2018
2020
Y90 +/- Nexavar (US:STOP-HCC) 2016 data
Y90 vs. Nexavar (EU:SARAH)
2015 data
Y90 vs. Nexavar (Asia: SIRveNIB)
2015 data
Y90 vs. Nexavar (EU: YES-P in pts with PVT)
2015 data
Novel Therapies in Development Presented at ASCO
Annual Meeting 2013
Target/ Mechanism
Trial
Trial Design
Status
Anti-angiogenic mAB
Ramucirumab v. PBO (REACH)
AMG 386 + SOR
R.Ph3, 2°line
Ph2
In follow-up
In follow-up
C-MET inhibition
Cabozantinib v. PBO
Tivantinib v. PBO (Metiv-HCC)
R.Ph3
R.Ph3 (MET-high),
2°line
In development
Enrolling. (TPS 4159)
Chemotherapy + sorafenib
SECOX
SOR ± GEMOX
SOR ± DOX (CALGB 80802)
Ph2
R.Ph2
R.Ph3
Abs. 4117
Abs. 4028
Enrolling
Immune modulation
Nivolumab (anti-PD1)
Pexa-Vec (poxvirus) v. BSC
Tremelimumb (anti-CTLA4)
Ph1
R.Ph2b, Ph2
Ph2
Enrolling. TPS 3111
TPS 4161, abs 4122
Sangro, J.Hepat 2012
Etabolism/other
ADI-PEG 20 v. PBO
R.Ph3
Enrolling
mTOR pathway
Everolimus v. PBO (EVOLVE)
R.Ph3, 2°line
In follow-up*
Multikinase/VEGFR
inhibition
Regorafenib v. PBO
R.Ph3
Enrolling. TPS 4163
mAb= monoclonal antibody; PBO= placebo; SOR= sorafenib; R.Ph= randomized phase
*Update August 7, 2013 - Novartis announced that results of this study did not extend OS compared to placebo in locally advanced or metastatic HCC
after progression on or intolerance to sorafenib
Unmet Needs in HCC
1. Clinical development of drugs
2. Identification and validation of biomarkers
3. Properly designed and powered clinical trials for adjuvant therapy, combo
first line, second line therapy and radioembolization
4. Systematic inclusion of cost-benefit analyses in clinical trials
5. Search for tools to assess quality of life in clinical trials
EASL–EORTC CPG: Management of Hepatocellular Carcinoma, J Hepatol. 2012;56:908-43
RESIDUO
Post-progression Survival of Patients with Advanced HCC.
Rationale For Second Line Trial Design.
Reig et al, Hepatology in press
Comparative Efficacy of Sorafenib Versus BSC in Recurrent
HCC After LT: A Case-control Study
Overal Survival
Sposito et al, J Hepatol 2013;59:59-66
Time to Tumor Progression
Phase III Study of Sorafenib after TACE in Japanese and
Korean Patients with Unresectable HCC
Kudo et al, Eur J Cancer 2011;47:2117-27
Use of Sorafenib in Patients With HCC Before Liver Transplantation: A
Cost-Benefit Analysis While Awaiting Data on Sorafenib Safety
Vitale et al, Hepatology 2010
Cost-Effectiveness of Sorafenib Treatment in Field Practice for
Patients With Hepatocellular Carcinoma
Cammà et al, Hepatology 2013;57:1046-1054
Adjuvant Systemic Drug Therapy And Recurrence Of Hepatocellular
Carcinoma Following Curative Resection
Zhong et al, Drug Discoveries & Therapeutics. 2013; 7(4):164-166.
Phase 2 Study of Regorafenib as a Second Line for
HCC Patients Resistant to Sorafenib
Study patients
36 patients with BCLC-B/C, all Child Pugh A
Drug regimen
160mg x d x 3 wks – 1 wk off
Duration of treatment
15.5 wks (range 2-36)
Outcomes
26 patients reached disease control (1 PR only)
4.2 months TTP; 80% alive at 6 mo.
Adverse events
21 discontinuations (12 AE, 5 drug)
18 HFS (50%), 5 grade ≥ 3
17 fatigue (47%), 6 ≥ grade 2
Bruix et al, European Journal of Cancer 2013 in press
Comparative Efficacy Of Sorafenib Versus Best Supportive Care
in Recurrent Hepatocellular Carcinoma After Liver Transplantation:
A Case-control Study
Patients survival after diagnosis of recurrence (A) or from the time of untreatable progression (B)
Sposito et al, J Hepatol 2013 in press
Usefulness Of Alpha-fetoprotein Response In Patients Treated
With Sorafenib For Advanced Hepatocellular Carcinoma
Personeni et al J Hepatol 2012;57:101-7