SYSTEMIC THERAPY

WHAT IS REALISTIC IN THE LMIC SETTING ?

MITESH J. BORAD, M.D.

Director, Liver and Biliary Cancer Research Program

Mayo Clinic Arizona

COLDA 2019Cairo, Egypt

September 6-8, 2019

CONFLICTS OF INTEREST

RESEARCH FUNDING

Boston Biomedical

Mirna

Sunbiopharma

Senhwa

Medimmune

Bioline

Agios

Halozyme

Threshold

Celgene

Toray

Dicerna

Sillajen

Eisai

CONSULTANT

G1 Therapeutics

TD2

Fujifilm

Insys

Novartis

Arqule

Celgene

Inspyr

Halozyme

Exelixis

Taiho

Ionis

EMD Serono

Incyte

ARIAD

Imclone

Adaptimmune

Redhill Biopharma

HEPATOCELLULAR CANCER

1. Most common primary cancer of the liver

2. Common etiologies include hepatitis B/C,

NASH/metabolic syndrome, alcohol and others (e.g.

Wilson’s disease)

3. Global incidence ~782,000 cases

(~554,000 deaths : GLOBOCAN)

GLOBAL DISTRIBUTION OF HEPATITIS B

Schweitzer et al, The Lancet 2015

GLOBAL DISTRIBUTION OF HEPATITIS C

SOURCE: cdc.gov (2015)

Roswall et al, J Prev Public Health 2015

GLOBAL DISTRIBUTION OF ALCOHOL CONSUMPTION

LOW-MIDDLE INCOME COUNTRIES

SOURCE : worldbank.org

LENVATINIB

REGORAFENIB

SORAFENIB

ANTI-ANGIOGENIC TYROSINE KINASE

INHIBITORS USED IN HCC

CABOZANTINIB

VEGFR1, VEGFR2, VEGFR3, RET, PDGFRA, KITRAF1, BRAF

VEGFR2, MET, RET, TIE2, AXL, FLT3, KIT, RON

VEGFR1, VEGFR2, VEGFR3, RET, PDGFRA, KITFGFR1-4

VEGFR1, VEGFR2, VEGFR3, RET, PDGFRB, KITRAF1, BRAF

R

SORAFENIBN=299

PLACEBON=303

SHARP STUDY – SORAFENIB N HCC

ELIGIBILITYAdvanced HCCChild Pugh AECOG 0-2No prior treatmentAge >18 years

DESIGNDouble blind121 sites US/Europe/AsiaPrim End: OS

R

SORAFENIBN=150

PLACEBON=76

ASIA PACIFIC STUDY – SORAFENIB N HCC

ELIGIBILITYAdvanced HCCChild Pugh ANo prior treatmentAge >18 years

DESIGNDouble blindChina, Korea, TaiwanPrim End: OS

SORAFENIB IN HCC

A Phase 3 Trial of Lenvatinib vs Sorafenib

in First-line Treatment of Patients With

Unresectable Hepatocellular Carcinoma

(REFLECT Study)

Ann-Lii Cheng,1 Richard S. Finn,2 Shukui Qin,3 Kwang-Hyub Han,4 Kenji

Ikeda,5 Fabio Piscaglia,6

Ari Baron,7 Joong-Won Park,8 Guohong Han,9 Jacek Jassem,10 Jean

Frederic Blanc,11 Arndt Vogel,12 Dmitry Komov,13 TR Jeffry Evans,14 Carlos

Lopez,15 Corina Dutcus,16 Min Ren,16 Silvija Kraljevic,17 Toshiyuki Tamai,16

Masatoshi Kudo18

Used with permission of Dr. Ann-

Lii Cheng

Study SchemaGlobal, randomized, open-label, phase 3 noninferiority

studyPatients with unresectable HCC (N = 954)

• No prior systemic

therapy for

unresectable HCC

• ≥ 1 Measurable

target lesion per

mRECIST

• BCLC stage B or C

• Child-Pugh A

• ECOG PS ≤ 1

• Adequate organ

function

• Patients with ≥ 50%

liver occupation,

clear bile duct

invasion, or portal

vein invasion at the

main portal vein were

excluded

Stratification• Region:

(Asia-

Pacific or

Western)

• MVI and/or

EHS:

(yes or no)

• ECOG PS:

(0 or 1)

• Body

weight:

(< 60 kg or

≥ 60 kg)

Lenvatinib(n = 478)8 mg (BW <

60 kg) or

12 mg (BW ≥

60 kg)

once daily

Sorafenib(n = 476)

400 mg

twice daily

Primary endpoint:• OS

Secondary endpoints:

• PFS

• TTP

• ORR

• Quality of life

• PK lenvatinib

exposure

parameters

Tumor assessments were performed according to mRECIST by the investigator

Random

izati

on 1

:1

Used with permission of Dr. Ann-

Lii Cheng

Primary Endpoint: Kaplan-Meier

Estimate of OS

Used with permission of Dr. Ann-

Lii Cheng

Secondary Endpoint: Kaplan-Meier Estimate of

PFS by mRECIST

Used with permission of Dr. Ann-

Lii Cheng

Maximum Change in Tumor Size by

mRECISTn, (%) Lenvatinib (n =

478)

Sorafenib (n =

476)

Odds Ratio

(95% CI)

ORR

95% CI

115 (24.1)

20.2−27.9

44 (9.2)

6.6−11.8

3.13

(2.15−4.56)

P < 0.00001CR 6 (1.3) 2 (0.4)

PR 109 (22.8) 42 (8.8)

SD 246 (51.5) 244 (51.3)

Durable SD 167 (34.9) 139 (29.2)

PD 71 (14.9) 147 (30.9)

Unknown/NE 46 (9.6) 41 (8.6)

DCR

95% CI

361 (75.5)

71.7−79.4

288 (60.5)

56.1−64.9

Percentage change in tumor size is truncated at 100% (rectangles). ORR is defined as CR+PR, according to mRECIST; durable SD is

defined as SD lasting ≥ 23 weeks.

CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

CR

(n=6

)

CR

(n=2

)

Used with permission of Dr. Ann-

Lii Cheng

RECIST 1.1 response: 18.8% vs 6.5%

Most Frequent TEAEs (≥ 15%)Adverse event, n (%) Lenvatinib (n = 476) Sorafenib (n = 475)

Any grade Grade 3/4 Any grade Grade 3/4

Hypertension 201 (42) 111 (23) 144 (30) 68 (14)

Diarrhea 184 (39) 20 (4) 220 (46) 20 (4)

Decreased appetite 162 (34) 22 (5) 127 (27) 6 (1)

Decreased weight 147 (31) 36 (8) 106 (22) 14 (3)

Fatigue 141 (30) 18 (4) 119 (25) 17 (4)

Palmar-plantar

erythrodysesthesia 128 (27) 14 (3) 249 (52) 54 (11)

Proteinuria 117 (25) 27 (6) 54 (11) 8 (2)

Dysphonia 113 (24) 1 (0) 57 (12) 0 (0)

Nausea 93 (20) 4 (1) 68 (14) 4 (1)

Decreased platelet count 87 (18) 26 (6) 58 (12) 16 (3)

Abdominal pain 81 (17) 8 (2) 87 (18) 13 (3)

Hypothyroidism 78 (16) 0 (0) 8 (2) 0 (0)

Vomiting 77 (16) 6 (1) 36 (8) 5 (1)

Constipation 76 (16) 3 (1) 52 (11) 0 (0)

Elevated aspartate

aminotransferase 65 (14) 24 (5) 80 (17) 38 (8)

Rash 46 (10) 0 (0) 76 (16) 2 (0)

Alopecia 14 (3) 0 (N/A) 119 (25) 0 (N/A)Used with permission of Dr. Ann-

Lii Cheng

ANTI-ANGIOGENICS IN HCC

TIME

GROWTH

RECIST

PD

NO

THERAPY

ANTI-ANGIOGENIC D/C

ANTI-ANGIOGENIC

CONTINUOUS

Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016

Efficacy and safety of regorafenib versus

placebo in patients with hepatocellular

carcinoma (HCC) progressing on sorafenib:

Results of the international, randomized

phase 3 RESORCE trial

J Bruix, P Merle, A Granito, Y-H Huang, G Bodoky, O Yokosuka,

O Rosmorduc, V Breder, R Gerolami, G Masi, PJ Ross, S Qin,

T Song, J-P Bronowicki, I Ollivier-Hourmand, M Kudo,

M-A LeBerre, A Baumhauer, G Meinhardt, G Han

on behalf of the RESORCE Investigators

Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016

Regorafenib160 mg po once daily

3 weeks on / 1 week off

(4-week cycle)

(n=379)

Placebo(n=194)

• HCC patients with documented

radiological progression during

sorafenib treatment

• Stratified by:

− Geographic region (Asia vs ROW)

− Macrovascular invasion

− Extrahepatic disease

− ECOG PS (0 vs 1)

− AFP (<400 ng/mL vs ≥400 ng/mL)

RESORCE trial designClinicaltrials.gov NCT01774344

N= 573

ROW, rest of the world; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein

R2:1

• 152 centers in 21 countries in North and South America, Europe, Australia, Asia

• All patients received best supportive care

• Treat until progression, unacceptable toxicity, or withdrawal

Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016

Overall survival (OS)Primary endpoint

Pro

ba

bil

ity o

f S

urv

iva

l (%

)

Regorafenib

Placebo

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)

Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016

Subgroup analysis of OS

AFP, alpha-fetoprotein

Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016

Progression-free survival (PFS)

Pro

ba

bilit

y o

f P

rog

res

sio

n-f

ree

Su

rviv

al

(%)

Regorafenib

Placebo

Regorafenib

n=379

Placebo

n=194

Events 291 (77%) 181 (93%)

Censored 88 (23%) 13 (7%)

Median PFS

(95% CI)

3.1 months

(2.8, 4.2)

1.5 months

(1.4, 1.6)

HR 0.46 (95% CI: 0.37, 0.56)

P<0.001 (2-sided)

Based on mRECIST

Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016

Best overall tumor response mRECIST RECIST 1.1

Regorafenib

n=379

Placebo

n=194

Regorafenib

n=379

Placebo

n=194

Response rate10.6% 4.1% 6.6% 2.6%

P=0.01 (2-sided) P=0.04 (2-sided)

Disease control rate65.2% 36.1% 65.7% 34.5%

P<0.001 (2-sided) P<0.001 (2-sided)

Complete response 0.5% 0 0 0

Partial response 10.0% 4.1% 6.6% 2.6%

Stable disease 54.4% 32.0% 58.8% 32.0%

Non CR/Non PD 0.3% 0 0.3% 0

PD 22.7% 55.7% 22.4% 57.2%

Not evaluable 5.0% 4.1% 5.0% 4.6%

Not assessed 7.1% 4.1% 6.9% 3.6%

Clinical progression* 22.7% 20.6% 22.7% 20.6%

*Worsening of ECOG PS≥3 or symptomatic deterioration including increase in liver function tests

PD, progressive disease

Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016

Treatment-emergent grade 3 or 4 adverse events

occurring in at least 5% of patients in either group

Treatment-emergent Drug-related treatment-emergent

Regorafenib

n=374

Placebo

n=193

Regorafenib

n=374

Placebo

n=193

Any

gradeGr 3 Gr 4

Any

gradeGr 3 Gr 4

Any

gradeGr 3 Gr 4

Any

gradeGr 3 Gr 4

HFSR 53% 13% NA 8% 1% NA 52% 13% NA 7% 1% NA

Fatigue 41% 9% NA 32% 5% NA 30% 6% NA 19% 2% NA

Hypertension 31% 15% <1% 6% 5% 0 23% 13% <1% 5% 3% 0

Bilirubin increased 29% 10% 1% 18% 8% 3% 19% 6% <1% 4% 2% 0

AST increased 25% 10% 1% 20% 10% 2% 13% 4% 1% 8% 5% 1%

Ascites 16% 4% 0 16% 6% 0 2% 1% 0 1% 1% 0

Anemia 16% 4% 1% 11% 5% 1% 6% 1% <1% 1% 1% 0

Hypophosphatemia 10% 8% 1% 2% 2% 0 6% 4% 1% 1% 1% 0

Lipase increased 7% 5% 2% 3% 2% 0 5% 4% <1% 2% 1% 0

AST, aspartate aminotransferase; HFSR, hand-foot skin reaction; NA, not applicable

NCI-CTCAE v4.03

COST EFFECTIVENESS - REGORAFENIB

SHLOMAI ET AL, PLOS ONE 2018

COST EFFECTIVENESS - REGORAFENIB

SHLOMAI ET AL, PLOS ONE 2018

COST EFFECTIVENESS - CABOZANTINIB

SOTO-PEREZ-DE-CELIS ET AL, JNCCN 2019

OTHER OPTIONS : FOLFOX ?

QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013

FOLFOX IN HEPATCELLULAR CANCER

QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013

FOLFOX IN HEPATCELLULAR CANCER

QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013

FOLFOX IN HEPATCELLULAR CANCER

QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013

COST EFFECTIVENESS – FOLFOX VS SORAFENIB

ZHANG ET AL, DIGESTIVE AND LIVER DISEASE 2016

ANTI-VIRAL RX ANTI-VIRAL RX

ANTI-VIRAL HEP B THERAPY IN ADVANCED

HCC PATIENTS ?

ZHANG ET AL, JOURNAL OF GASTRO AND HEPATOLOGY 2016

PFS: 6.0 vs. 4.5 mth OS: 12.2 vs. 8.0 mth

ANTI-VIRAL HEP B THERAPY IN ADVANCED

HCC PATIENTS ?

ZHANG ET AL, JOURNAL OF GASTRO AND HEPATOLOGY 2016

Sangro et al, J Hepatology 2013

Sangro et al, J Hepatology 2013

▪Total evaluable patients (n=17)

▪Complete response (n=0; 0%)

▪Partial response (n=3; 17.6%) [Duration of response 3.6, 6.9 and 15.2 mths]

▪Stable disease (n=10; 58.8%)

▪Alpha-fetoprotein evaluable patient (n=11)

▪Alpha-fetoprotein response (>50% decrease): n=4 (36%)

▪Median time to tumor progression (TTP): 6.48 mth (95% CI: 3.95-9.14 mth)

▪Median overall survival (OS): 8.2 mth (95% CI: 4.64-21.34 mth)

EFFICACY

Sangro et al, J Hepatology 2013

NIVOLUMAB IN HEPATOCELLULAR CANCER

El-Khoueiry et al, Lancet 2017

NIVOLUMAB IN HEPATOCELLULAR CANCER

El-Khoueiry et al, Lancet 2017

NIVOLUMAB IN HEPATOCELLULAR CANCER

NIVOLUMAB IN HEPATOCELLULAR CANCER

El-Khoueiry et al, Lancet 2017

NIVOLUMAB IN HEPATOCELLULAR CANCER

PEMBROLIZUMAB IN HCC

Zhu et al, Lancet Onc 2018

N =104

RESPONSE RATE = 17%

200 MG IV Q3W

PEMBROLIZUMAB IN HCC

Zhu et al, Lancet Onc 2018

PFS =4.9 MTHS

OS = 12.9 MTHS

ATEZOLIZUMAB + BEVACIZUMAB IN HCC

Stein et al, ASCO 2018

Stein et al, ASCO 2018

ATEZOLIZUMAB + BEVACIZUMAB IN HCC

UPDATED RESPONSE RATE 32%, PFS = 14.9 MONTHS

ATEZOLIZUMAB + BEVACIZUMAB IN HCC

Stein et al, ASCO 2018

NIVOLUMAB240 MG Q2WK

SORAFENIB400 mg BID

RANDOMIZATION 1:1

N=1723

CHECKMATE 459 – NIVOLUMAB IN HCC

(1st LINE)

PRIMARY END POINT : OVERALL SURVIVAL

OVERALL SURVIVAL: HR = 0.85 [95% CI: 0.72-1.02]; P = 0.0752

PEMBROLIZUMAB200 MG Q3WK

BEST SUPPORTIVE CARE

RANDOMIZATION 2:1

N=278

N=135

KEYNOTE 240 – PEMBROLIZUMAB IN HCC

(2nd LINE)

PRIMARY END POINT : OVERALL SURVIVAL

▪ OS PROLONGED BUT FAILED TO MEET PRE-SPECIFIED SIGNIFICANCE 13.9 VS 10.6 MOS (HR: 0.781; 95% CI: 0.611-0.998; P = .0238)

▪ FAILED TO REACH PRE-SPECIFIED LEVEL OF STATISTICAL SIGNIFICANCE (P = .0174)

CONCLUSIONS

▪ ANTI-ANGIOGENICS ARE EFFICACIOUS IN THE FIRST (SORAFENIB/LENVATINIB/FOLFOX) AND SECOND+ LINE SETTINGS (REGORAFENIB/CABOZANTINIB/RAMUCIRUMAB) IN ADVANCED HCC

▪ ONLY FOLFOX ACHIEVED COST-EFFECTIVENESS IN A LMIC SETTING

▪ ANTI-VIRAL THERAPY FOR HEPATITIS B MAY HELP IN ADVANCED HCC PATIENTS AND IS COST-EFFECTIVE IN LMIC SETTING

▪ IMMUNE THERAPIES ARE PROMISING IN ADVANCED HCC AND COST-EFFECTIVENESS IN LMIC SETTING NEEDS TO BE DETERMINED