Current Standards of Care of Hepatocellular Carcinoma? · Current Standards of Care of...
Transcript of Current Standards of Care of Hepatocellular Carcinoma? · Current Standards of Care of...
Current Standards of Care of Hepatocellular Carcinoma?
Prof. Mohsen Mokhtar M.D
Cairo Univ.
Disclosures
Honoraria Received :
Amgen, Astra Zeneca, Bohrengier, Hikma,Hospira,
GSK, Lilly, Merck, MSD, Novartis, Pfizer,
Pierre Fabre, Roche, Sandoz, Sanofi Avantis
Agenda
Overview of Hepatocellular Carcinoma
Very Early–Stage and Early-Stage HCC: Current Best Practices
Advanced, Incurable HCC: Latest Developments in Treatment
The Many Challenges of HCC
Common malignancy
Fifth most common cancer in men worldwide, second leading cause of cancer death
MOST COMMON IN EGYPT
Complex malignancy
1. Mittal S, et al. J Clin Gastroenterol. 2013;47:S2-S6.
2. Weledji EP, et al. Ann Med Surg (Lond). 2014;3:71-76.
1 pt, 2 diseases
Cirrhosis leads to multifocal hepatocarcinogenesis, high recurrence rates
Portal HTN, thrombocytopenia
Impaired hepatic function
Complicated clinical trial design
While transplant potentially curative, candidacy/access limited
3. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
4. Madkhali AA, et al. Saudi J Gastroenterol. 2015;21:11-17.
AASLD Diagnostic Criteria for HCC
Stable > 18-24 mos
Enlarging
Return to surveillance
every 6-12 mos
Proceed according to lesion size
Nondiagnostic of HCC
Repeat imaging and/or biopsy + -
Other diagnosis
Diagnostic of HCC
Typical vascular pattern
Atypical vascular pattern with both
techniques
Atypical vascular pattern
Typical vascular pattern on dynamic
imaging
Treat as HCC
Biopsy
> 2 cm
1 dynamic imaging technique
< 1 cm
Repeat USevery 3-4 mos
1-2 cm
1 dynamic imaging study
Repeat biopsy or imaging follow-up
Change in size/profile
Mass on surveillance US or high AFP in a cirrhotic liver
Adapted from Bruix J, et al. Hepatology. 2011;53:1020-1022.
Hepatocellular carcinoma: ESMO–ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up†
Ann Oncol. 2012;23(suppl_7):vii41-vii48. doi:10.1093/annonc/mds225
ESMO GUIDELINES FOR HCC
Very Early–Stage and Early-Stage HCC: Current Best
Practices
Multidisciplinary Approach to the Pt With HCC
Palliative careHepatology
Radiology
Medical oncology
Primary care provider
Interventional radiology
Radiation oncology
Nursing
Clinical
research
Surgery Pt
Curative Treatments
Belghiti J, et al. HPB (Oxford). 2005;7:42-49. Bruix J, et al. Hepatology. 2011;53:1020-1022. Feng Q, et al. J
Cancer Res Clin Oncol. 2015;141:1-9. Sapisochin G, et al. at Rev Gastroenterol Hepatol. 2017;14:203-217.
Thuluvath PJ, et al. Liver Transpl. 2009;15:754-762.
Resection Ablation Transplant
▪ Noncirrhotics
– Choice of therapy
▪ Cirrhotics
– Reserved for CTP A
– Avoid R hepatectomy
▪ Best for solitary HCC
▪ < 30% eligible
▪ Effective when < 3 cm
▪ Multiple modalities
– Thermal
– Chemical
– Stereotactic radiation
▪ Minimally invasive
▪ Cures both
▪ MELD exception
– Milan criteria
– Downsizing
▪ Demand > supply
▪ Survival
– 5 yrs: 70%
▪ Survival
– 5 yrs: 40% to 50%
▪ Survival
– 5 yrs: > 70%
▪ Recurrence
– 5 yrs: 70%
▪ Recurrence
– 5 yrs: 70%
▪ Recurrence
– 5 yrs: 15%
Surv
ival (%
)
Mos
Log-rank P = .00001
Survival After Resection for HCC
Of 1265 HCC pts evaluated, only 35 were ideal candidates for resection
Portal hypertension, normal bilirubin
No portal hypertension, normal bilirubin
Portal hypertension, bilirubin ≥ 1 mg/dL
0
20
60
40
80
100
0 24 48 72 9612 36 60 84
Llovet JM, et al. Hepatology. 1999;30:1434-1440.
Liver Embolotherapy Techniques
Kishore S, et al. Curr Oncol Rep. 2017;19:40.
Technique Mechanism Pros Cons
TAE
Ischemic necrosis induced at arteriolar
level via permanent embolic
(eg, small particles)
▪ Low cost, no chemotherapy adverse events▪ Postembolization syndrome may
cause PEs
Conventional TACE
(cTACE)
Intrahepatic chemotherapy with
embolization by ethiodized oil
▪ Strongest evidence supporting benefit from
RCT data
▪ Intraoperator technical variation
(cTACE)
▪ Systemic release of chemotherapy
(cTACE)
▪ Postembolization syndrome
DEB-TACE
Intrahepatic chemotherapy +
embolization with slow-release drug-
eluting beads
▪ More standardized than cTACE, less systemic
release of chemotherapy
▪ More expensive than cTACE
▪ Postembolization syndrome
RadioembolizationRadiation necrosis induced by beta-
emitting Yttrium-90 microspheres
▪ May improve TTP
▪ Fewer sessions required
▪ No postembolization syndrome
▪ May be safer in adv disease with PVT
▪ Radiation segmentectomy may be curative
▪ FLR hypertrophy from radiation lobectomy can
provide tumor control and facilitate resection
▪ Cost: 2-3x more expensive
▪ Requires multidisciplinary
coordination
▪ Nontarget delivery may cause severe
ulceration
▪ Potential biliary toxicity
▪ Radiation-induced liver disease
Palliative TACE Prolongs Survival in Unresectable HCC
40 29 14 4 235 19 7 3 0
0
20
60
40
80
100
Mos Since Randomization
Pro
babili
ty o
f S
urv
ival (%
)
0 12 24 36 48 60
Chemoembolization (n = 40)
Control (n = 35)
Log-rank P < .009
Pts at Risk, n
Llovet J, et al. Lancet. 2002;359:1734-1739. Llovet J, et al. Hepatology. 2003;37:429-442.
Phase III SARAH: SIRT vs Sorafenib in Progressive,
Inoperable HCC After 2x TACE
Selective internal radiation therapy
SIRT comprises yttrium-90 resin microspheres injected into the tumors, delivering up to 40
times more radiation than would be possible using standard radiation therapy.
Because SIRT is directly delivered to the tumor, surrounding healthy tissue is spared
radiation exposure.
Patients with locally advanced or inoperable HCC who did not respond to other treatments
or who had 2 failed rounds of transarterialchemoembolization
SIRT (n=237)
Sorafenib400 mg BID
(n = 222)
Vilgrain V, et al. EASL 2017. Abstract GS-012.
Phase III SARAH: SIRT vs Sorafenib in Progressive,
Inoperable HCC After 2x TACE
Vilgrain V, et al. EASL 2017. Abstract GS-012.
ITT Population
(N = 459)1.0
0.8
0.6
0.4
0.2
0
Pro
babili
ty o
f S
urv
ival
mOS, Mos
8.0
9.9SIRT
Sorafenib
HR: 1.15 (95% CI: 0.94-1.41;
log-rank P = .179)
Mos Since Randomization
480 6 12 18 24 30 36 42
Per Protocol Population
(n = 380)1.0
0.8
0.6
0.4
0.2
0
Pro
babili
ty o
f S
urv
ival
mOS, Mos
9.9
9.9SIRT
Sorafenib
HR: 0.99 (95% CI: 0.79-1.24;
log-rank P = .92)
Mos Since Randomization
480 6 12 18 24 30 36 42
Management of Advanced HCC
Advanced HCC: Challenges
Competing causes of death
Cirrhosis vs HCC
Unreliable hepatic function
Variable metabolism
Inherent drug resistance?
Function of liver
SHARP trial HCC: Sorafenib
Prior to 2007, no therapy was of benefit in advanced
HCC
SHARP trial: CTP A pts with advanced HCC
randomized to sorafenib 400 BID vs placebo
Sorafenib delayed progression and prolonged
survival from 7.9 to 10.7 mos
Led to approval by the FDA in 2007 for palliation of
advanced-stage HCC
It remains the only approved first-line systemic
therapy for HCC
Sorafenib
PlaceboP < .001
Time to Radiologic Progression
Mos Since Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
1.00
0.75
0.50
0.25
0
Pro
babili
ty o
f
Ra
dio
log
ic P
rog
ressio
n
Sorafenib
Placebo
P < .001
OS
Mos Since Randomization
1.00
0.75
0.50
0.25
0
Pro
babili
ty o
f S
urv
ival
0 1 2 3 4 5 6 7 8 9 1011121314151617
Llovet JM, et al. N Engl J Med. 2008;359:378-390.
Desai JR, et al. J Gastrointest Oncol. 2017;8:243-255.
First-line Randomized Phase III
Trials in HCCPhase III Trial Targets Median TTP, Mos Median OS, Mos
Sunitinib vs sorafenib[1] VEGFRs, PDGFRs, c-KIT, FLT3, RET[2]
4.1 vs 3.8HR: 1.13 (95% CI: 0.98-1.31;
P = .8312)
7.9 vs 10.2HR: 1.30 (95% CI: 1.13-1.50;
2-sided P = .0014)
Brivanib vs sorafenib (BRISK-FL)[3] VEGFR2, FGFR[4]
4.2 vs 4.1HR: 1.01 (95% CI: 0.88-1.16;
P = .8532)
9.5 vs 9.9 HR: 1.07 (95% CI: 0.94-1.23;
P = .3116)
Linifanib vs sorafenib[5] VEGFR, PDGFR5.4 vs 4.0
HR: 0.759 (95% CI: 0.643-0.895; P = .001)
9.1 vs 9.8HR: 1.046 (95% CI: 0.896-
1.221; P = NS)
Sorafenib + erlotinibvs sorafenib + placebo[6]
VEGFR1/2/3, PDGFR, Ras, Raf, EGFR[6,7]
3.2 vs 4.0HR: 1.135 (95% CI: 0.944-
1.366; P = .18)
9.5 vs 8.5HR: 0.929 (95% CI: 0.781-
1.106; P = .408)
Doxorubicin + sorafenib vs sorafenib (CALGB 80802)[8]
VEGFR1/2/3, PDGFR, Ras, Raf[7]
4.0 vs 3.9*HR: 0.9 (95% CI: 0.72-1.20;
P = .98)
8.9 vs 10.5HR: 1.06 (95% CI: 0.8-1.4;
P = .24)
Lenvatinib: Mechanism of Action
Multitargeted, PO small molecular
TKI
Potent against VEGFR2 and
VEGFR3
Also targets VEGFR1, FGFR1-3,
PDGFRα, RET, and KIT
VEGFR FGFR
Angiogenesis
X
T202/Y204
S235/S236
T389
T421/S424
RAS
RAF
MEK
ERK1/2
Lenvatinib
PI3K
AKT
mTOR
S6K
S6
P
PP
P
Finn RS, et al. ASCO 2014. Abstract TPS4153. Stjepanovic N, et al. Biologics. 2014;8:129-139.
REFLECT: Study Design
Multicenter, randomized, open-label phase III noninferiority study
Pts with unresectable HCC, no prior systemic therapy, ≥ 1 measurable target lesion, BCLC stage B/C, Child-Pugh A, ECOG PS 0/1, and
adequate organ function(N = 954)
Lenvatinib 8 mg (BW < 60 kg) or 12 mg (BW ≥ 60 kg) QD
(n = 478)
Sorafenib 400 mg BID
(n = 476)
Cheng AL, et al. ASCO 2017. Abstract 4001.
Stratified by region (Asia-Pacific vs Western), MVI and/or EHS (yes vs no), ECOG PS (0 vs 1), and BW (< vs ≥ 60 kg)
▪ Primary endpoint: OS
– Noninferiority margin 1.08; criteria met if upper limit of 2-sided 95% CI for HR < 1.08
▪ Secondary endpoints: PFS, TTP, ORR, QoL, lenvatinib PK
▪ Other endpoints: DCR, CBR, exploratory biomarker analysis
REFLECT: PFS and OS
Cheng AL, et al. ASCO 2017. Abstract 4001.
Pro
bab
ility
of
PFS
Mos
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Median, mos (95% CI)
Lenvatinib: 7.4 (6.9−8.8)
Sorafenib: 3.7 (3.6−4.6)
HR: 0.66 (95% CI: 0.57-0.77)Log-rank test: P < .00001 P
rob
abili
ty o
f O
S
Mos
Median, mos (95% CI)
Lenvatinib: 13.6 (12.1−14.9)
Sorafenib: 12.3 (10.4−13.9)
1.0
0.8
0.6
0.4
0.2
0
HR: 0.92 (95% CI: 0.79-1.06)
0.9
0.7
0.5
0.3
0.1
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Conclusion: lenvatinib noninferior to sorafenib in OS in first-line setting for unresectable HCC
Statistically significant improvements in PFS, TTP, and ORR for lenvatinib vs sorafenib
Second-line Phase III Randomized Trials in HCC
*Difference not statistically tested per prespecified analysis plan.
1. Zhu AX, et al. Lancet Oncol. 2015;16:859-870. 2. Llovet JM, et al. J Clin Onco. 2013;31:3509-
3516. 3. Huynh H, et al. Clin Cancer Res. 2008;14:6146-6153. 4. Zhu AX, et al. JAMA. 2014;312:
57-67. 5. Rimassa L, et al. ASCO 2017. Abstract 4000. 6. Katamaya R, et al. Cancer Res. 2013;
73:3087-3096.
Phase III Trial Target(s) Median TTP, Mos Median OS, Mos
Ramucirumab vs placebo[1] IgG1 Ab to VEGFR2 3.5 vs 2.6
HR: 0.59 (95% CI: 0.49-0.72;
P < .0001)
9.2 vs 7.6
HR 0.87 (95% CI: 0.72-1.05;
P = .14)
Brivanib vs placebo[2] VEGFR2, FGFR[3] 4.2 vs 2.7
HR: 0.56 (95% CI: 0.42-0.76;
P < .001)
9.4 vs 8.2
HR: 0.89 (95% CI: 0.69-1.15;
P = .3307)
Everolimus vs placebo[4] mTOR 3.0 vs 2.6
HR: 0.93 (95% CI: 0.75-1.15;
P = NR*)
7.6 vs 7.3
HR: 1.05 (95% CI: 0.86-1.27;
P = .68)
Tivantinib vs placebo[5] cMet[6] 2.4 vs 3.0
HR: 0.96 (95% CI: 0.74-1.25;
P = .76)
8.4 vs 9.1
HR 0.97 (95% CI 0.75-1.25;
P = .81)
Phase III RESORCE: Second-line Regorafenib vs
Placebo in HCC With Progression
Pts with HCC with documented
radiologic progression on
sorafenib (N = 573)
Until PD, unacceptable
toxicity, or withdrawal
Regorafenib 160 mg PO QD
Days 1-21 of 28-day cycle
+ BSC
(n = 379)
Placebo
Days 1-21 of 28-day cycle
+ BSC
(n = 194)
Randomized 2:1
Stratified by geography (Asia vs other), macrovascular invasion, extrahepatic
disease, ECOG PS (0 vs 1), AFP (< 400 ng/mL vs ≥ 400 ng/mL)
▪ 152 centers in 21 countries in North/South America, Europe, Australia, Asia
Bruix J, et al. Lancet. 2017;389:56-66.
RESORCE: Efficacy
Regorafenib
(n = 379)
Placebo
(n = 194)
mOS, mos 10.6 7.8
(HR: 0.63; 95% CI: 0.50-0.79;
1-sided P < .0001)
Placebo
Pro
ba
bili
ty o
f S
urv
ival (%
) 100
80
60
40
20
00
Mos From Randomization
333 6 12 15 18 21 24 27 309
Regorafenib
Placebo
Regorafenib
Mos From Randomization
Pro
babili
ty o
f P
FS
(%
)
100
80
60
40
20
0330 3 6 12 15 18 21 24 27 309
Regorafenib
(n = 379)
Placebo
(n = 194)
mPFS, mos 3.1 1.5
(HR: 0.46; 95% CI: 0.37-0.56;
1-sided P < .0001)
Bruix J, et al. Lancet. 2017;389:56-66.
*P < .05 vs placebo.
Outcome, %
Modified RECIST RECIST 1.1
Regorafenib
(n = 379)
Placebo
(n = 194)
Regorafenib
(n = 379)
Placebo
(n = 194)
ORR 11* 4 6.6* 2.6
DCR 65* 36 65.7* 34.5
Emerging Drugs for HCC
MET signaling inhibitors
Cabozantinib (second line phase III)
FGFR inhibitors
Pan-FGFR inhibitor (erdafitinib)
Selective FGFR4 inhibitor (FGF401)
TGF-β signaling
Galunisertib
Antiangiogenic and antiproliferative
TKIs
Donafenib (first line phase III under
way: NCT02645981)
Immune checkpoint inhibitors
Cabozantinib versus placebo in patients with
advanced HCC phase 3 CELESTIAL trial. Celestial was a Ph 3 HCC study in analyzing cabozantinib vs placebo in patient post-sorafenib.
The study showed that the overall survival had significantly improved (10.2 mo) vs over placebo (8.0 mo) in HCC patients in the 2L
setting.
Progression free survival (5.2 mo vs 1.9 mos) and objective response rates (4.0% vs. 0.4%) were improved as well.
Six grade 5 adverse events were reported in the cabozantinib arm.
Ghassan K. Abou-Alfa ASCO GI Jan 2018
Ramicirumab in HCC breaking news
REACH-2 phase III trial improves PFS and OS versus placebo as a second-line treatment of patients with HCC
and elevated baseline AFP
4 April 2018
Rationale for Immunotherapy in HCC
HCC is a classical inflammation-induced tumor type
Spontaneous immune responses are frequently
observed
Independent of liver function (no metabolism)
Can be combined with ablative therapies
1.0
0.8
0.6
0.4
0.2
0.0
0 20 40 60
Dis
eas
e-F
ree
Surv
ival
P=0.094
PD-L2 Low
PD-L2 High
Time After Surgery (months)
1.0
0.8
0.6
0.4
0.2
0.0
0 20 40 60
P=0.0047
Dis
eas
e-F
ree
Surv
ival
PD-L1 Low
PD-L1 High
Time After Surgery (months)
Ove
rall
Surv
ival
1.0
0.8
0.6
0.4
0.2
0.0
0 20 40 60
P=0.029
PD-L1 Low
PD-L1 High
Time After Surgery (months)
1.0
0.8
0.6
0.4
0.2
0.0
0 20 40 60
P=0.041Ove
rall
Surv
ival
PD-L2 Low
PD-L2 High
Time After Surgery (months)
PD-L1 expression (observed in ~74% of HCC cases) predicts recurrence/survival in
HCC patients after resection1,2
PD-L1
expression2
PD-L2
expression2
1. Umemoto Y et al. J Gastroenterol. 2015;50(1):65-75; 2. Gao Q et al. Clin Cancer Res. 2009;15(3):971-979.
a Median follow-up calculated from first dose to last known date alive or
death.b Using RECIST v1.1.
ESC, dose-escalation phase; EXP, dose-expansion phase.3
Study Endpoints
Primary
• Safety and tolerability (ESC)
• ORR (EXP)b
Secondary
• ORR (ESC)b
• Disease control rate
• Time to response
• Duration of response
• Overall survival
Other
• Biomarker assessments
Sorafenib
Naive
n = 80
Sorafenib
Experienced
n = 182
Dose Escalation
Nivolumab0.1–10 mg/kg
n = 11
All Patients (N = 262)
Dose Expansion
Nivolumab3 mg/kg
n = 69
Dose Escalation
Nivolumab0.1–10 mg/kg
n = 37
Dose Expansion
Nivolumab3 mg/kg
n = 145
• Median follow-up:a 16.4 months in sorafenib-naive patients
14.3 months in sorafenib-experienced patients (ESC)
14.9 months in sorafenib-experienced patients (EXP)
HCV Infected, HBV Infected, Uninfected
Phase I/II CheckMate 040: Nivolumab in Advanced HCC
El-Khoueiry AB, et al. Lancet. 2017;389:2492-2502.
CheckMate 040 Best Overall Response
8
• 15% of sorafenib progressors and 23% of patients who were intolerant of sorafenib achieved an objective response
• Disease control rates were 54% in sorafenib-naive patients and 55% in all sorafenib-experienced patients
Patients, n (%)
Sorafenib NaiveESC + EXP
n = 80a
Sorafenib ExperiencedESC
n = 37a
Sorafenib ExperiencedEXP
n = 145
Objective response using RECIST v1.1 16 (20) 7 (19) 21 (14)
Complete response 1 (1) 1 (3) 2 (1)
Partial response 15 (19) 6 (16) 19 (13)
Stable disease 25 (31) 12 (32) 60 (41)
Progressive disease 32 (40) 13 (35) 56 (39)
Not evaluable 5 (6) 4 (11) 8 (6)a Two sorafenib-naive patients and 1 sorafenib-experienced (ESC) patient had a best overall response reported as non-CR/non-PD by BICR.
Blinded Independent Central Review
El-Khoueiry AB, et al. Lancet. 2017;389:2492-2502.
CheckMate 040 Overall Survival
9
Sorafenib Naive (ESC + EXP):Median OS (95% CI), mo = 28.6 (16.6–NE)
Sorafenib Experienced (EXP):Median OS (95% CI), mo = 15.6 (13.2–18.9)
Sorafenib Experienced (ESC):Median OS (95% CI), mo = 15.0 (5.0–28.1)
Pro
bab
ilit
y o
f su
rviv
al
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
0.1
0
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MonthsEl-Khoueiry AB, et al. Lancet. 2017;389:2492-2502.
KEYNOTE-224: Pembrolizumab in Patients
with Advanced HCC Previously Treated with Sorafenib. Keynote-224 was a Phase 2 HCC single arm study analyzing pembrolizumab in a patient population post-sorafenib.
Data presented with 8 months follow-up.
Disease control rate was 61.5% , median duration of response was 8.2 mo, median time for response and overall
survival was NR (9.4-NE).
1 treatment related death was reported during the study.
Zhu AX,, et al. ASCO GI January 18-20, 2018; San Francisco, Calif. Abstract 209
Ongoing Immunotherapy Clinical Trials in HCC
TreatmentClinical Trial
Identifier
Planned
EnrollmentTherapy Line
Enrollment
Start Date
Nivolumab (anti–PD-1) vs
sorafenibNCT02576509 726 First 11/2015
Pexastimogene devacirepvec
(Pexa-Vec) + sorafenib vs
sorafenib
NCT02562755 600 First 10/2015
Pembrolizumab (anti–PD-1)
vs BSC NCT02702401 408 Second 5/2016
Durvalumab (anti–PD-L1) +
tremelimumab (anti–CTLA-4)NCT02519348 144 Second 10/2015
How to treat pts with advanced disease?
Third lineFirst line
Sorafenib
Lenvatinib?
Immunotherapy?
Ongoing phase III trial of
nivolumab vs sorafenib
Second line
Regorafenib
Immunotherapy?
Ongoing phase III study
of pembrolizumab vs BSC
Nivolumab ?
RAP UP
Early-stage HCC may be cured with
Thermal ablation
Resection
Liver transplantation
Advanced-stage HCC may be palliated
with
TACE or XRT
Sorafenib
Experimental therapies
Local measures often fail in tumors with
aggressive biology
Application of therapies may be limited by
severity of cirrhosis
Choosing the optimal treatment requires
collaboration of multiple specialties
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