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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