selecting optimal antiangiogenic strategies for patients with hepatocellular carcinoma

Selecting Optimal Antiangiogenic

Strategies for Patients With

Hepatocellular Carcinoma

Thomas A. Abrams, MD

Assistant Professor of Medicine, Harvard Medical School

Senior Physician, Dana-Farber Cancer Institute

ACCREDITATION

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation

Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and i3 Health.

The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Postgraduate Institute for Medicine designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians

should claim only the credit commensurate with the extent of their participation in the activity.

The Postgraduate Institute for Medicine is accredited with distinction as a provider of continuing nursing education by the American

Nurses Credentialing Center’s Commission on Accreditation. This educational activity for 1.0 contact hours is provided by Postgraduate

Institute for Medicine.

INSTRUCTIONS TO RECEIVE CREDIT

In order to receive credit for this activity, participants must:

1. Participate in the live webinar

2. Complete and submit the posttest and activity evaluation via the link provided after the webinar

3. Download or print their Certificate of Credit

UNAPPROVED USE DISCLOSURE

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The

planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the

planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and

warnings.

DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional

development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures,

medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without

evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

COMMERCIAL SUPPORT

This activity is supported by an independent educational grant from Bayer HealthCare Pharmaceuticals Inc.

Disclosures

▶ Dr. Abrams discloses the following commercial

relationships:◼ Consulting/advisory board: Aduro Biotech, Bayer,

Bristol-Myers Squibb, Celgene, Genentech, Kaleido

◼ Research funding: Celgene, Lilly

▶ The PIM planners and managers, Trace Hutchison,

PharmD, Samantha Mattiucci, PharmD, CHCP, Judi

Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz,

MSN, RN, CHCP have nothing to disclose

▶ i3 Health planners and managers have no relevant

financial relationships to disclose

Learning Objectives

▶ Describe the epidemiology of HCC and the etiologic

factors associated with disease development

▶ Review the rationale for angiogenesis inhibitor usage

for the treatment of advanced HCC

▶ Evaluate available HCC staging systems and their role

in treatment planning

▶ Assess data supporting the use of antiangiogenic

agents in first- and second-line treatment of advanced

HCC

HCC = hepatocellular carcinoma.


American Cancer Society, 2015; Pons-Renedo et al, 2003; Jemal et al, 2011.

Worldwide Incidence

1,824,700

1,676,600

1,360,600

1,111,700

951,600

782,500

527,600

385,700

330,400

323,000

319,600

238,700

200,700


Altekruse et al, 2009; Ryerson et al, 2016.

US Incidence

HCC Risk Factors

▶ Cirrhosis: >90% of HCC cases in patients with

antecedent liver cirrhosis (all causes)

▶ Viral hepatitis infection◼ Hepatitis B virus (HBV)

– Can develop in HBV patients without cirrhosis

– Viral load a factor

◼ Hepatitis C virus (HCV): HCV treatment associated with risk

reduction

▶ Obesity, metabolic syndrome: likely through increased

incidence of NAFLD, NASH

NAFLD = non-alcoholic fatty liver disease; NASH = non-alcoholic steatohepatitis.

Chen et al, 2006; Omland et al, 2012; Van der Meer et al, 2012; Welzel et al, 2011.

HCC Risk Factors (cont.)

▶ Male sex: 4 x increase in incidence

▶ Alcoholic cirrhosis

▶ Rare causes◼ Aflatoxin exposure

◼ Hemochromotosis

◼ Porphyria

◼ Alpha-1 antitrypsin deficiency

◼ History of Fontan cardiac surgery

Chen et al, 2006; Omland et al, 2012; Van der Meer et al, 2012; Welzel et al, 2011.

Multistep Malignant Transformation

Tornillo et al, 2002; Verslype et al, 2007.

Potential Targets

Oxidative stress

and inflammation

Viral

oncogenesCarcinogens

Growth factorsTelomere

shortening

Cancer stem

cells

Loss of cell cycle

checkpointsApoptosis Angiogenesis

Normal

Liver

Hepatitis C

Hepatitis B

Ethanol

NASH

Liver

Cirrhosis

Dysplastic

Nodules

Epigenetic

Alterations

Genetic

Alterations

HCC

Comparison of HCC Staging

PT/INR = prothrombin time/international normalized ratio; AFP = alpha-fetoprotein;

TNM-7 = tumor, node, metastasis classification, 7th ed.

Subramaniam et al, 2013.

Parameter Okuda CLIP CUPI TNM7 JIS GRETCH BCLC

Cirrhosis-Related Parameters

Albumin X X X X

Bilirubin X X X X X X

Ascites X X X X X

PT/INR X X X

Encephalopathy X X X

Alkaline phosphatase X X

Tumor-Related Parameters

Tumor extent/stage X X X X X X

Portal vein thrombosis X X X

AFP X X X

Asymptomatic X

Performance status X X

BCLC Staging

BCLC = Barcelona Clinic Liver Cancer; ECOG PS = Eastern Cooperative Oncology Group performance status.

Llovet et al, 1999.

BCLC StageECOG

PS

Tumor Size/Number, Vascular

Involvement, Etc

Child-Pugh

Score

0 Very early 0 Solitary <2 cm nodule A

A Early 0Solitary <5 cm nodule or up to 3

nodules each ≤3 cmA - B

B Intermediate 0 Large/multinodular A - B

C Advanced 1-2Portal venous invasion and/or

extrahepatic spread (N+ or M+)A - B

D Terminal >2 Any of the above C

Treatment Recommendations

According to BCLC Stage

Llovet et al, 2008a.

Case Study: Mr. LT

▶ 58-year-old man with a history of chronic HCV

infection and cirrhosis

▶ Had not seen his PCP in several years

▶ Presents with several months of abdominal

pain, fatigue, and weight loss

▶ PE notable for 5.5-cm mass in the right upper

quadrant, palmar erythema, and spider

angiomata

PCP = primary care provider; PE = physical examination.

Case Study: Mr. LT (cont.)

▶ Routine laboratories notable for AST/ALT 2.5 x ULN,

bilirubin 0.9 mg/dL, albumin 3.3 g/dL, PT/INR WNL,

platelet count 80 x 109/L

▶ MRI scan of the abdomen reveals an 8-cm mass in the

right liver with early washout, tumor thrombus in the

portal vein, and hilar adenopathy

▶ Chest CT scan shows multiple metastatic nodules

throughout the lungs

▶ AFP >100,000 ng/mL

AST/ALT = aspartate transaminase/alanine transaminase; ULN = upper limit of normal;

PT/INR = prothrombin time/international normalized ratio; WNL = within normal limits;

MRI = magnetic resonance imaging; CT = computed tomography; AFP = alpha-fetoprotein


▶ Pop Quiz


▶ What treatment would you recommend for this

patient?

a. Sorafenib

b. Radioembolization

c. Chemoembolization

d. Radiofrequency ablation

e. Liver transplantation

Angiogenesis in HCC

▶ HCC is characterized by an excess of angiogenic

factors produced by:◼ Tumor cells

◼ Vascular endothelial cells

◼ Immune cells

◼ Surrounding tumor microenvironment

▶ VEGF is an important mediator in hepatocarcinogenesis◼ Regulated by oncogenic gene mutations, hormones, and

cytokines

▶ VEGF creates a vascular network of leaky vessels and

abnormal vascular structure and function

Ghouri et al, 2017.

Sorafenib: A Multikinase Inhibitor

Adapted from Wilhelm et al, 2008.

NucleusNucleus

EGF/HGF

Angiogenesis:Differentiation

Proliferation

Migration

Tubule formation

MEK

ERKEGF/HGF

PDGF

VEGF

Proliferation

Survival

RAS

Vascular Cell

Autocrine loopParacrinestimulation

HIF-2

Mitochondria

Mitochondria

Apoptosis

RAS

RAF

MEK

ERK

Apoptosis

RAF

Tumor Cell

PDGFR-b VEGFR-2

Inhibits tumor growth and vascularization through a series of antiangiogenic

and antiproliferative effects

SHARP: Phase III Trial of

Sorafenib in Advanced HCC

OS = overall survival.

Llovet et al, 2008b.

Arm 2 (placebo) N=303

Eligibility▶ Advanced stage HCC▶ ECOG PS ≤2▶ Child-Pugh A▶ No prior treatment▶ Age ≥18 years

Arm 1 (sorafenib) N=299

602 pts randomly assigned

1:1 for 90% power to detect a

40% increase in OS

R

A

N

D

O

M

I

Z

E

Study Design▶ Double blind, placebo-

controlled▶ 121 sites primarily in North

America and Europe▶ Primary end point: OS

SHARP: Baseline Characteristics


SHARP: Baseline Characteristics

(cont.)


SHARP: Overall Survival


SHARP: Overall Survival in

Selected Subgroups


SHARP: Treatment-Emergent AEs

AEs = adverse events.

Kane et al, 2009.

AEs, %Sorafenib (n=297) Placebo (n=302)

Any

GradeGrade 3 Grade 4

Any

GradeGrade 3 Grade 4

Constitutional symptoms

Fatigue 46 9 1 45 12 2

Weight loss 30 2 0 10 1 0

Dermatology/skin

Rash/desquamation 19 1 0 14 0 0

Pruritus 14 <1 0 11 <1 0

Hand-foot skin reaction 21 8 0 3 <1 0

Dry skin 10 0 0 6 0 0

Alopecia 14 0 0 2 0 0

Gastrointestinal

Diarrhea 55 10 <1 25 2 0

Anorexia 29 3 0 18 3 <1

Nausea 24 1 0 11 2 0

Vomiting 15 2 0 11 2 0

Constipation 14 0 0 10 0 0

Hepatic dysfunction 11 2 1 8 2 1

Abdominal pain 31 9 0 26 5 1

Hand-Foot Skin Reaction

▶ General principle is to treat the

hyperkeratosis and skin

inflammation◼ Creams or ointments containing

urea, ammonium lactate, or

salicylic acid

▶ Topical corticosteroids may

help reduce grade 2 or higher

inflammation▶ When grade 3 or intolerable,

treatment should be withheld for

7 days or until symptoms resolve◼ May be restarted at a lower

dose

Lacouture et al, 2008.

SHARP vs Asia-Pacific Study

TTP = time to progression; RR = response rate.

Llovet et al, 2008b; Cheng et al, 2009.

SHARP Asia-Pacific

Randomization Sorafenib vs Placebo Sorafenib vs Placebo

End pointHazard ratio

(95% CI)P value

Hazard ratio

(95% CI)P value

OS10.7 vs 7.9 mo

0.69 (0.55-0.87)<0.001

6.5 vs 4.2 mo

0.68 (0.50-0.93)0.014

TTP5.5 vs 2.8 mo

0.58 (0.45-0.74)<0.001

2.8 vs 1.4 mo

0.57 (0.42-0.79)<0.001

RR 2% vs 1% 3.3% vs 1.3%


▶ Pop Quiz

Case Study 2 (cont.)

▶ Six months post-sorafenib, Mr. LT develops

progressive disease. What would you now

recommend?

a. FOLFOX

b. Liposomal doxorubicin

c. Regorafenib

d. Repeat chemoembolization

Regorafenib in HCC: Rationale

▶ Multikinase inhibitor that differs from sorafenib by the

addition of a lone fluorine atom

▶ Despite similar molecular structure, it differentially

inhibits tyrosine kinases such as VEGFR1, RET, FGFR-

1, and c-KIT

▶ Has metabolites that allow the agent to continue to have

effect despite 1-week washout period

Trojan & Waidmann, 2016.

RESORCE: Phase III Trial of

Regorafenib in Post-Sorafenib HCC

POD = progression of disease.

Bruix et al, 2017.

Placebo (n=194)

Eligibility▶ Advanced stage HCC with

documented POD on sorafenib treatment

▶ ECOG PS 0 or 1▶ BCLC stage B or C▶ Child-Pugh A▶ Age ≥18 years

Regorafenib 160 mg

daily, 3 weeks on/1 week

off (n=379)


2:1 for 90% power to detect a

43% increase in OS

R

A

N

D

O

M

I

Z

E

Study Design▶ Double blind, placebo-

controlled▶ 152 sites in North and

South America, Europe, Australia, and Asia

▶ Primary end point: OS

RESORCE: Baseline Characteristics

Bruix et al, 2017.

Characteristic Regorafenib (n=379) Placebo (n=194)

Male 88% 80%

Age, median years (range) 64 (19-85) 62 (23-83)

Race

White 36% 35%

Asian 41% 40%

Black 2% 1%

Other/not reported 21% 24%

Geographic region Asia 38% 38%

ECOG PS, 0/1 65%/35% 67%/33%

Etiology of HCC

Alcohol abuse 24% 28%

HBV 38% 38%

HCV 21% 21%

NASH 7% 7%

Other 7% 5%

Unknown 17% 16%

RESORCE: Baseline Characteristics

(cont.)

MVI = macrovascular invasion; EHD = extrahepatic disease.

Bruix et al, 2017.

Characteristic Regorafenib (n=379) Placebo (n=194)

BCLC stage, A/B/C 0.3%/14%/86% 0%/11%/89%

Child Pugh class

A 98% 97%

B 1% 3%

MVI 29% 28%

EHD 70% 76%

MVI and/or EHD 80% 84%

AFP ≥400 ng/mL 43% 45%

Cirrhosis present 75% 74%

RESORCE: OS

Bruix et al, 2017.

Regorafenib

N=379

Placebo

N=194

Events 232 (61%) 140 (72%)

Censored 147 (39%) 54 (28%)

Median OS

(95% CI)

10.6 months

(9.1, 12.1)

7.8 months

(6.3, 8.8)

HR 0.62 (95% CI: 0.50, 0.78)

P<0.001 (2-sided)

RESORCE: OS Subgroup Analysis

Bruix et al, 2017.

RESORCE: Treatment-Emergent AEs

HFSR = hand-foot skin reaction.

Bruix et al, 2017.

AEs

Regorafenib

n=374

Placebo

n=193

Any

GradeGr 3 Gr 4

Any

GradeGr 3 Gr 4

HFSR 53% 13% NA 8% 1% NA

Fatigue 41% 9% NA 32% 5% NA

Hypertension 31% 15% <1% 6% 5% 0

Bilirubin increased 29% 10% 1% 18% 8% 3%

AST increased 25% 10% 1% 20% 10% 2%

Ascites 16% 4% 0 16% 6% 0

Anemia 16% 4% 1% 11% 5% 1%

Hypophosphatemia 10% 8% 1% 2% 2% 0

Lipase increased 7% 5% 2% 3% 2% 0

Case Study: Mr. DS

▶ 54-year-old man with advanced HCC in the

setting of chronic HCV

▶ Started on sorafenib 6 weeks ago

▶ After several dose reductions, his

desquamating rash has not improved. Also has

difficult-to-control diarrhea and fatigue

▶ Has decided that he cannot continue on

sorafenib

▶ Not interested in clinical trials

Case Study: Mr. DS (cont.)

▶ Pop Quiz

Case Study: Mr. DS (cont.)

▶ What treatment would you recommend for this

patient?

a. FOLFOX

b. Liposomal doxorubicin

c. Lenvatinib

d. Regorafenib

Lenvatinib: A New Option in HCC

▶ Oral, multitargeted inhibitor of:◼ VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), and

VEGFR3 (FLT4)

◼ FGFR1, 2, 3, and 4

◼ PDGFRα, KIT, and RET

▶ Approved for recurrent or metastatic iodine-refractory

thyroid cancer and in renal cell carcinoma in

combination with everolimus following prior

antiangiogenic therapy

Lenvima® prescribing information, 2017.

REFLECT Phase III: Lenvatinib vs

Sorafenib as First-Line Therapy

NI = noninferiority; PFS = progression-free survival.

Cheng et al, 2017.

Sorafenib

400 mg twice daily

(n=476)

Eligibility▶ Unresectable HCC with no

prior treatment

▶ ECOG PS 0 or 1

▶ BCLC stage B or C

▶ Child-Pugh A

▶ Age ≥18 years

Lenvatinib 8 or 12 mg

daily based on body

weight; 8 mg for <60 kg

(n=478)


1:1 to detect NI in OS

R

A

N

D

O

M

I

Z

E

Study Design▶ Open-label, randomized NI

study▶ Primary end point: OS▶ Secondary end points:

PFS, TTP

REFLECT: Outcomes

ORR = overall response rate.

Cheng et al, 2017.

Outcomes Lenvatinib Sorafenib HR

Median OS, mo

(95% CI)13.6 (12.1-14.9) 12.3 (10.4-13.9) 0.92 (0.79-1.06)

Median PFS, mo

(95% CI)7.4 (6.9-8.8) 3.7 (3.6-4.6) 0.66 (0.57-0.77)

Median TTP, mo

(95% CI)8.9 (7.4-9.2) 3.7 (3.6-5.4) 0.63 (0.53-0.73)

ORR, n (%) 115 (24%) 44 (9%)

REFLECT: Treatment-Emergent AEs

▶ Grade 3 and higher events were more common in the

lenvatinib arm (57% vs 49%)

▶ Most common AEs in the lenvatinib arm:◼ Hypertension (42% overall with 23% grade ≥3)

◼ Diarrhea (39%)

◼ Decreased appetite (34%)

◼ Weight loss (31% with 8% grade ≥3)

◼ Fatigue (30%)

▶ Grade 3 HFSR was more common in the sorafenib arm

(11% vs 3%)

Cheng et al, 2017.

Ramucirumab

▶ Anti-VEGFR2 monoclonal antibody approved for the

treatment of gastric and colon cancers

▶ In the REACH trial, patients were randomly assigned to

ramucirumab vs placebo after progression on sorafenib◼ Although the primary end point of OS was not met,

a prespecified population of patients with baseline

AFP ≥400 ng/mL and Child-Pugh scores of 5 or 6 demonstrated

a significant OS advantage vs placebo

Zhu et al, 2017.

REACH: OS in Child-Pugh 5/6 and

AFP ≥400 ng/mL

Zhu et al, 2017.

Key Takeaways

▶ Sorafenib and regorafenib are the only agents approved for

advanced HCC◼ Both are multikinase inhibitors with prominent antiangiogenic effects

◼ Sorafenib is approved for first-line treatment

◼ Regorafenib is approved for second-line treatment after sorafenib

failure or intolerance

▶ In a head-to-head phase III trial, lenvatinib was shown to be

noninferior to sorafenib and may be considered an alternative to

sorafenib, particularly in patients with intolerance

▶ Important to recognize the class-wide side effects of these agents

(eg, hand-foot skin reaction, hypertension, diarrhea, weight loss)

and employ timely interventions to optimize treatment outcomes

Questions?

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