Update on Medical Treatment for Advanced Hepatocellular ... · TKI-IO combo early phase? OPTIMIS OS...

Update on Medical Treatment for

Advanced Hepatocellular Carcinoma

Dr Thomas Yau

Clinical Associate Professor

Principle Investigator in State Key laboratory for Liver

Disease

MD(HK),MBBS(HK), MRCP (UK), FRCP(London)

FHKCP (Med Onc), FHKAM( Medicine)

Honorary Consultant in Queen Mary Hospital,

Grantham Hospital and Kwong Wah Hospital

The University of Hong Kong

Disclosures

Thomas Yau, MD, FRCP, has disclosed that he has

received research or consulting fees from

Bristol Myers-Squibb, Eisai, Merck, Bayer, Novartis, EMD Sereon,

Exelixis, Ipsen, Abbvie, Pfizer, Sirtex, Sillajen, New B Innovation,

Sirtex, OrigiMed, Taiho

What We need to know in treating HCC

• Staging patients is important

– physiologic and anatomic

– Liver reserve is the key

• The only curative approach is surgery (resection or transplant), and perhaps RFA

– Most patients are not candidates for above

• Chemoemblization (TACE) can improve survival

– In selected patients

• Eventually most patients will require systemic treatment if they live long enough

• Systemic therapy

– Cytotoxic chemotherapy little impact on this disease

– Sorafenib is improves survival for patients with advanced HCC

&……

Challenges in Management of HCC

One patient with two diseases

A highly malignant tumor

High propensity for venous invasion

Rapid growth (tumor volume doubling time 3 months)

Associated cirrhosis (80%)

Impaired liver function

Multicentric hepatocarcinogenesis

5

What we know about treating

HCC? Tu

mor

Bur

den

Death

Time

Resection RFA

TACE TACE TACE

Sorafenib

Unresectable HCCResectable

HCC

Clinical trials

Liver function

EHS

TACE, transcatheter arterial chemoembolization.

SOURCE: Llovet JM, et al. J Natl Cancer Inst 2008;100:698–711. Verslype C, et al. Ann Oncol 2012;23(Supp 7):vii41–8.

2L nivolumab

Milestone trials in uHCC

2007

1L sorafenib

SHARP/AP-SHARP RCT

better than placeboGIDEON OS

2017

1L lenvatinib

P3 REFLECT RCTNon-inferior to sorafenib

TACE

2002

Llovet J et al., 2002Lo C et al., 2002Better than placebo

P1/2 CHECKMATE 040single-arm

2L cabozantinib

2018

1L nivolumabP3 CHECKMATE 459 (vs sorafenib)

2L pembrolizumabP3 KEYNOTE-240 placebo controlled?

TKI-IO combo early phase?

OPTIMIS OS for TACE-

systemic therapy

1L nivolumab

2L regorafenIb

2016

P3 RESORCE RCTbetter than placebo

P1/2 CHECKMATE 040single-arm

P3 CELESTIAL non-inferior to placeboNon-inferior to placebo

2L pembrolizumab

P2 KEYNOTE 224single-arm

1L sunitinib

1L brivinib

1L linifanib

1L erlotinib

2L brivinib

2L everolimus

2L ramucirumab

Key systemic therapy trials in uHCC

7

Settings

Design Trial name Presentation Publicatio

n

FDA/ EMA approval

1st line 1. Sorafenib vs placebo

2. Sorafenib vs placebo

3. Sorafenib vs Sunitinib*

4. Sorafenib vs Brivanib*

5. Sorafenib vs Linifanib*

6. Sorafenib +/- HAIC*

7. Lenvatinib vs Sorafenib#

8. Nivolumab (single arm)

9. Nivolumab vs Sorfenib

10. Durvalumab vs

Druvalumab/

tremelimumab combo

vs Sorafenib

SHAPR

AP-SHARP

SUN1170

BRISK-FL

LiGHT

SILIUS

REFLECT

Checkmate 040

CheckMate 459

HIMALAYA

ASCO 2007

ASCO 2011

AASLD 2012

ASCO-GI 2013

EASL 2016

ASCO2017

ASCO2016

Ongoing

Start Soon

NEJM 2008

Lancet-O

2009

JCO 2013

JCO 2013

JCO 2015

Lancet 2017

Y

Y

2nd Line 1. Brivanib vs Placebo*

2. Everolimus vs Placebo*

3. Ramucirumab vs

Placebo*

4. S-1 vs Placebo*

5. Regorafenib vs Placebo

6. Tivantinib vs Placebo*

7. Nivolumab (single arm)

8. Ramucirumab vs

Placebo

9. Cabozantinib vs Placebo

BRISK-PS

EVOLVE-1

REACH

S-CUBE

RESORCE JET-HCC/ METIV-

HCC

Checkmate 040

REACH-2

CELESTIAL

KEYNOTE-224

EASL 2012

ASCO-GI 2014

ESMO 2014

ASCO 2015

WCGI 2016

ASCO2017

ASCO2017

Ongoing ASCO-GI

2018

ASCO-GI 2018

Ongoing

JCO 2013

JAMA 2014

Lancet-O

2015

Lancet 2017

Lancet 2017

Y

Y (FDA

accelerated)

* RCT Halted or Negative results Positive result

Sorafenib: Targets Tumor Cell Proliferation & Angiogenesis

Wilhelm S et al. Cancer Res. 2004;64:7099-7109.

RAS

Vascular cell

Angiogenesis:

PDGF-

βVEG

F

VEGFR-2PDGFR-β

Paracrine stimulation

Mitochondria

Apoptosis

Tumor cell

PDGFVEGF

EGF/HGF

ProliferationSurvival

Mitochondria

EGF/HGF

HIF-2

Nucleus

Autocrine loop

Apoptosis

ERK

RAS

MEK

RAF

Nucleus

ERK

MEK

Sorafenib

RAF

DifferentiationProliferationMigrationTubule formation

MetMab

• Raf/MEK/ERK signaling pathway is implicated in liver

tumorigenesis

• Sorafenib is an inhibitor of Raf, VEGFR, and other kinases

Phase III SHARP and AP trialsSorafenib vs placebo in advanced HCC

Su

rviv

al

pro

ba

bil

ity

1.00

0.75

0.50

0.25

Time (months)

0 4 6 8 10 12 14 162

0.00

Sorafenib (n=299)

Median OS: 10.7 months

Placebo (n=303)


18

HR=0.69

Su

rviv

al

pro

ba

bil

ity

1.00

0.75

0.50

0.25

Time (months)

0 4 8 12 22

0.00

Sorafenib (n=150)


Placebo (n=76)


2 6 10 14 16 18 20

HR=0.68

SHARP1 Asia-Pacific2

HR, hazard ratio; OS, overall survival; SHARP, Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol.

1. Llovet JM et al. N Engl J Med 2008;359:378–90; 2. Cheng A et al. Lancet Oncol 2009;10:25–34.

Summary of Failed Phase III Trials for HCC

Agent MOA Patient Population Trial Design Results Comments

Brivanib[1-3]

(BRISK-FL,

BRISK-PS,

BRISK-TA)

VEGF and

FGF inhibitor

• BRISK-FL: 1L

unresectable; CP A

• BRISK-PS: 2L after

sorafenib; CP A/B7

• BRISK-TA: adjuvant

after 1st TACE; CP

A/B

• 1L: briv vs

sorafenib

(N=1150)

• 2L: briv vs

BSC(N=395)

• Adjuvant: briv vs

placebo (N= 870)

• 1L: mOS=9.5 vs 9.9 mo

(HR 1.06 [95.8% CI: 0.93–

1.22])

• 2L: mOS=9.4 vs 8.2 mo

(HR 0.89, P=0.3307)

• Adjuvant: mOS=26.4 vs

26.1 mo

(HR 0.9, P=0.528)

• Did not improve

survival over

sorafenib in 1L

• Did not meet primary

endpoint (OS) in 2L or

as adjuvant

Linifanib[4]

(LIGHT)

VEGFR and

PDGFR

inhibitor

• 1L unresectable/

metastatic HCC

• CP A

Linifanib vs sorafenib

(N=1035)

mOS=9.1 vs 9.8 mo

(HR 1.046 [95% CI: 0.896–

1.221])

• OS inferior to

sorafenib

• Safety results favored

sorafenib

Sunitinib [5,6]

(SUN)

VEGFR,

PDGFR,

FLT3R, KIT,

and RET

inhibitor

• 1L advanced liver

cancer

• CP A

Sunitinib vs sorafenib

(N=1074)

mOS=7.9 vs 10.2 mo

(HR 1.3, one-sided

P=0.9990)

• OS inferior to

sorafenib

• Associated with more

frequent and severe

toxicities

Orantinib[7]

VEGFR2,

FGFR2, and

PDGFR

inhibitor

Unresectable HCCTACE + orantinib vs

placebo (N=889)mOS=NA

• Did not meet primary

endpoint (OS)

Multiple multikinase inhibitors have failed to show survival benefit akin to sorafenib in HCC pts

1L, first-line; 2L, second-line; BSC, best supporti ve care; CI, confidence interval; CP, Child-Pugh; CR, complete response; FG F, fibroblast growth factor; FGFR2, FGF receptor 2; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; m, median; NA, not available; OS , overall survival; PDGFR, platelet-derived growth factor receptor; TAC E, transcatheter arterial chemoembolization; TKI, tyrosine kinase in hibitor; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2.

1. Johnson PJ et al. J Clin Oncol. 2013;31(28):3517-3524. 2. Llovet JM et al. J Clin Oncol. 2013;31(28):3509-3516. 3. Kudo M et al. Hepatology. 2014;60(5):1697-1707. 4. Cainap C et al. J Clin Oncol. 2015;33(2):172-179. 5. Cheng AL et al. J Clin Oncol. 2013;31(32):4067-4075. 6. Clinicaltrials.gov. NCT00 699374. 7. Healio. Orantinib Ph3 termination. Available at: http://www .healio.com/hematology-oncology/gastrointestinal-cancer/news/online/%7B98d 87e56-a37b-462f-a7ac-17a361e432e3%7D/taiho-pharmaceutical-to-terminate-p hase-3-trial-of-orantinib-tace-for-hepatocellular-carcinoma. Accessed January 28, 2015.

Study Schema

Presented By Ann-Lii Cheng at 2017ASCO Annual Meeting

Primary Endpoint: Kaplan-Meier Estimate of OS


Secondary Endpoint: Kaplan-Meier Estimate of PFS by mRECIST


Most Frequent TEAEs ( ≥ 15%)


CheckMate-459 (CA209-459)

• CheckMate-459 Study Design1,2

1. ClinicalTrials.gov. NCT02576509. https://clinicaltrials.gov/ct2/show/NCT02576509; 2. Sangro B, et al. Poster presentation at ASCO 2016. TPS4147.

15

Start Date: November 2015

Estimated Study Completion Date: June 2019

Estimated Primary Completion Date: October 2018

Status: recruiting

Study Sponsor: Bristol-Myers Squibb

Nivolumab30 min IV Q2W

Sorafenib PO BID

Eligibility Criteria

Advanced HCC

Systemic therapy naive

Locoregional therapy for HCC

completed ≥ 4 weeks prior to

baseline scan

Child-Pugh class A

ECOG PS 0 or 1

• Tumor imaging assessments

• On-treatment safety assessments

• Viral biomarkers (HBV, HCV)

Until

unacceptable

toxicity

or

disease

progression

Objectives

Primary: OS

Secondary: ORR, PFS,

PD-L1 expression/

efficacy

R

N = 726

RESORCE study

Regorafenib(n=379)

Placebo(n=194)

Advanced HCCDiscontinued radiological progression during sorafenib

Child-Pugh A ECOG-PS 0 or 1

R

Bruix J, et al. Lancet2017

2:1

5 Stratification factors

•Geographic region (Asia vs ROW)

•Macrovascular invasion

•Extrahepatic disease

•ECOG PS (0 vs 1)

•AFP (<400 ng/mL vs ≥400 ng/mL)

N =573

152 centers in 21 countries in North and South America, Europe, Australia, and AsiaAll patients received BSCTreat until progression, unacceptable toxicity, or withdrawal

Primary endpoint: OS

Sorafenib vs Regorafenib: Key Molecular

Difference

H3C

HN

N

OO

O

HN

HN

CF3

CI

H3C

HN

N

OO

OCI

CF3

HN

HN

F

Regorafenib

Sorafenib

Slide credit

RESORCE: Pt Criteria

• HCC confirmed by histologic or cytologic analysis or diagnosed by

noninvasive assessment per AASLD criteria in pts with confirmed cirrhosis

• BCLC stage B or C pts who could not benefit from resection, local ablation,

or chemoembolization

• Documented radiological progression while receiving sorafenib

• Randomization within 10 wks after the last sorafenib dose

• Tolerability of previous sorafenib, defined as receiving sorafenib

≥ 400 mg/day for at least 20 of the last 28 days of treatment

• ECOG PS 0/1 Child-Pugh A liver function

Bruix J, et al. Lancet. 2017;389:56-66.

Characteristic, %Regorafenib

(n = 379)

Placebo

(n = 194)

Asian 41 40

ECOG status 0/1 65 / 35 67 / 33

BCLC stage A/B/C < 1 / 14 / 86 0 / 11 / 89

Child-Pugh class A/B 98/1 97/3

MVI 29 28

EHD 70 76

MVI and/or EHD 80 84

AFP ≥ 400 ng/mL 43 45

Duration of sorafenib

treatment, Median, months7.8 (4.2–14.5) 7.8 (4.4–14.7)

Cirrhosis present

(investigator assessed)75 74

Bruix J, et al. Lancet. 2017;389:56-66; Bruix J. et al. 2017 WCGI, O-009

Phase III RESORCE study – Baseline characteristics

Regorafenib(n=379)

Placebo(n=194)

47 28

1-yr survival rate, %

Regorafenib (n=379)

Placebo (n=194)

Updated analysis (January 13, 2017)P

roba

bilit

y of

Sur

viva

l (%

)

100

12

Months from randomization

36 4824

908070605040302010

00

Number at risk379194

16852

5312

91

00Placebo

Regorafenib

*updated analysis; primary analysis conducted @29 February, 2016 had median OS of 10.6m and 7.8m for regorafenib and placebo respectively; HR: 0.63 (95% CI, 0.50-0.79); P<0.0001

HR, hazard ratio.Bruix J, et al. Presented at the ESMO 2017; Barcelona, Spain.

Regorafenib(n=379)

Placebo(n=194)

Median OS 10.7 months(9.1, 12.2)

7.9 months(6.4, 9.0)

HR: 0.61 (95% CI, 0.50-0.75); P<0.0001

reduced risk of death139%*

Regorafenib Is the First Systemic Treatment to

Demonstrate Significant OS Benefit in Second-line HCC

Treatment-emergent AEs (≥5%)

21

AEs, %

Regorafenib(n = 379)

Placebo(n = 194)

Any Gr 3 Gr 4 Any Gr 3 Gr 4

All TEAE 100 56 11 93 32 7

Drug-Related TEAE 93 46 4 52 16 1

HFSR 52 13 N/A 7 1 N/A

Fatigue 29 6 N/A 19 2 N/A

Hypertension 23 13 < 1 5 3 0

Bilirubin increased 19 6 < 1 4 2 0

AST increased 13 4 1 8 5 1

Ascites 2 1 0 1 1 0

Anemia 6 1 < 1 1 1 0

Hypophosphatemia 6 4 1 1 1 0

Lipase increased 5 4 < 1 2 1 0

Bruix J, et al. Lancet. 2017;389:56-66.

10% of patients discontinued from RESORCE due to dr ug-related AEs

Ogasawara S, et al. Invest New Drugs.2017

Better ECOG PS

Lower Child-Pugh Score

Who are more likely to be eligible for 2L therapy?Japanese experience from 185 patients starting sorafenib

Contributing Factors for

maintaining

CP-A ECOG

PS≤1

Worsenin

g

CP 6 @baseline

ECOG PS1 @baseline

On-treatment liver

failure

On-treatment New

extrahepatic lesions

P=0.00

4

P<0.00

1

P<0.00

1

P=0.01

3

P=0.030

P=0.015

P<0.001

P=0.013

Positive On treatment onset of

HSFR

P<0.00

1

P<0.001

37% of patients on sorafenib (69/185) were eligible for regorafenib therapy

• ECOG PS 0 or 1• Child Pugh A

• Tolerable to sorafenib

Evidence of HCC as an Immunogenic Tumor

24

1. Oquiñena S et al. Eur J Gastroenterol Hepatol. 2009;21(3):254-257. 2. Huz JI et al. HPB (Oxford). 2012;14(8):500-505. 3. Miamen AG et al. Liver Cancer. 2012;1(3-4):226-237. 4. Bertino G et al. Biomed Res Int. 2015;2015:731469. doi:10.1155/2015/731469. 5. Pardee AD, Butterfield LH. OncoImmunology. 2012;1(1):48-55.

The rate of spontaneous regression is among the highest for solid tumors, and some of them are likely

immunologic in nature1,2

Spontaneous tumor-specific CD8 and CD4 cell responses

have been reported3,4

Several immunological features of HCC correlate with outcome5

Presence of immune cells in tumor (eg, NK cells, T cells, DCs, macrophages)3

HCC expression of TAAs (eg, AFP, GPC3, NY-ESO-1, MAGE-A)4

AFP, alpha fetoprotein; CD, cluster of differentiation; DCs, dendritic cells; GPC3, glypican 3; HCC, hepatocellular carcinoma; MAGE-A, melanoma antigen gene-A; NK, natural killer; TAAs, tumor-associated antigens.

The Lancet 2017

http://dx.doi.org/1

0.1016

25

* Joint First Authors

CheckMate 040: Phase 1/2 Study of Nivolumab

in Patients With Advanced HCC

26

CT, computed tomography; MRI, magnetic resonance imaging; Q6W, every 6 weeks.

• Disease assessment imaging (CT or MRI) every 6 weeks

• Interim analysis data cutoff date: March 15, 2016

Key Eligibility Criteria and Study EndpointsCheckMate 040 Dose Escalation & Expansion

Eligibility criteria

Inclusion

•Histologically confirmed advanced HCC not amenable to

curative resection

•Child-Pugh scores ≤ 7 (escalation) or ≤ 6 (expansion)

•Progression on 1 prior line of systemic therapy,

or intolerant of or refused sorafenib

•AST and ALT ≤ 5 × upper limit of normal;

bilirubin ≤ 3 mg/dL

•For HBV-infected patients, viral load < 100 IU/mL and

concomitant effective antiviral therapy

Exclusion

•Any history of hepatic encephalopathy

•Prior or current clinically significant ascites

•Active HBV and HCV co-infection

Study endpoints

Primary

•Safety and tolerability (escalation)

•Objective response ratea (expansion)

Secondary

•Objective response rate (escalation)

•Disease control rate

•Time to response

•Duration of response

•Overall survival

Exploratory

•Biomarker assessments

27a RECIST v1.1 by BICR (blinded independent central review); BICR data are not yet available, and all efficacy assessments are per the local investigator analysis.

Baseline Characteristics and Prior Treatment HistoryCheckMate 040 Dose Escalation & Expansion

28

ParameterUninfected

(n = 135)

HCV Infected

(n = 61)

HBV Infected

(n = 66)

All Patients

(n = 262)

Age, median (range), years 65 (19–83) 65 (53–83) 56 (22–81) 63 (19–83)

Male, n (%) 106 (79) 49 (80) 52 (79) 207 (79)

Race, n (%)

White 90 (67) 38 (62) 5 (8) 133 (51)

Asian 40 (30) 20 (33) 59 (89) 119 (45)

Black 4 (3) 2 (3) 2 (3) 8 (3)

Other 1 (1) 1 (2) 0 2 (1)

Extrahepatic metastases, n (%) 103 (76) 36 (59) 59 (89) 198 (76)

Vascular invasion, n (%) 7 (5) 6 (10) 8 (12) 21 (8)

Child-Pugh score, n (%)a

5 98 (73) 35 (57) 58 (88) 191 (73)

6 36 (27) 23 (38) 8 (12) 67 (26)

> 6 1 (1) 3 (5) 0 4 (2)

α-fetoprotein > 200 µg/L, n (%)b 49 (36) 21 (34) 35 (53) 105 (40)

Prior treatment, n (%)

Surgical resection 81 (60) 27 (44) 53 (80) 161 (61)

Radiotherapyc 30 (22) 7 (11) 14 (21) 51 (19)

Local treatment for HCCd 69 (51) 37 (61) 52 (79) 158 (60)

Systemic therapy 97 (72) 38 (62) 61 (92) 196 (75)

Sorafenib 87 (64) 35 (57) 54 (82) 176 (67)a Four patients in the expansion cohort had Child-Pugh scores of 5 or 6 at screening and were enrolled; they later had scores of 7 to 9 on the first day of dosing; b Baseline α-fetoprotein (AFP) levels were not reported in 19 patients; c Internal or external, and could include radioembolization.d Includes transcatheter arterial chemoembolization, transcatheter embolization, radiofrequency ablation, and percutaneous ethanol injection.

Best Overall Response by Investigator AssessmentCheckMate 040 Dose Escalation & Expansion

29

Escalation Cohort

Parameter, n (%)Uninfected

(n = 23)

HCV Infected

(n = 10)

HBV Infected

(n = 15)

All Patients

(n = 48)

Objective responsea 3 (13) 3 (30) 1 (7) 7 (15)

Complete response 2 (9) 1 (10) 0 3 (6)

Partial response 1 (4) 2 (20) 1 (7) 4 (8)

Stable disease 13 (57) 5 (50) 6 (40) 24 (50)

Progressive disease 6 (26) 2 (20) 7 (47) 15 (31)

Not evaluable 1 (4) 0 1 (7) 2 (4)

Expansion Cohort

Uninfected (N = 112)

Parameter, n (%)

SorafenibNaive/Int

ol(n = 54)

SorafenibProgressors

(n = 58)

HCV Infected

(n = 51)

HBV Infected

(n = 51)

All Patients

(n = 214)

Objective responsea 11 (20) 11 (19) 7 (14) 6 (12) 35 (16)

Complete response 0 2 (3) 0 0 2 (1)

Partial response 11 (20) 9 (16) 7 (14) 6 (12) 33 (15)

Stable disease 32 (59) 27 (47) 29 (57) 23 (45) 111 (52)

Progressive disease 11 (20) 18 (31) 12 (24) 22 (43) 63 (29)

Not evaluable 0 2 (3) 3 (6) 0 5 (2)a RECIST v1.1

Figure 5. Overall SurvivalResults

Sorafenib Naive(ESC + EXP) Placeholder

Sorafenib Experienced

(ESC) Placeholder

Sorafenib Experienced

(EXP) Placeholder

Kaplan-Meier method.

ESC + EXP:Median OS (95% CI), mo = 28.6 (16.6–NE)

ESC:Median OS (95% CI), mo = 15.0 (5.0–28.1)

EXP:Median OS (95% CI), mo = 15.6 (13.2–18.9)

Time to Response and Duration of ResponseCheckMate 040 Dose Escalation & Expansion

31

Dose-Escalation Cohort

•Median DOR: 17 months

•Ongoing responses: 1 patient

Dose-Expansion Cohort

•Median DOR: not reached

•Ongoing responses: 30 patients

DOR, duration of response.

Time Since First Dose (months)

0 3 6 9 12 15 18 21 24 27 30

HBV: Nivo 0.1 mg/kg

HCV: Nivo 3 mg/kg

HCV: Nivo 1 mg/kg

HCV: Nivo 0.3 mg/kg

Uninfected: Nivo 10 mg/kg

Uninfected: Nivo 3 mg/kg

Uninfected: Nivo 1 mg/kg 24

NR

18

15

17

6

7

*

= First response

= Last nivolumab dose

= Ongoing response

*= Retreatment after recurrence

= Retreatment

0 3 6 9 12 15

HCV-infected

HBV-infected

Uninfected

sorafenib naive/intolerant

Uninfected

sorafenib progressors

Time Since First Dose (months)

DOR, months

• No treatment-related deaths occurred in either the escalation or expansion cohorts

SafetyCheckMate 040 Dose Escalation & Expansion

32

Uninfected

(n = 135)

HCV Infected

(n = 61)

HBV Infected

(n = 66)

All Patients

(n = 262)

Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Patients with any treatment-related

AE, n (%)91 (67) 24 (18) 45 (74) 21 (34) 41 (62) 6 (9) 177 (68) 51 (19)

Treatment-related AEs reported in

≥ 5% of all patients, n (%)

Fatigue 32 (24) 2 (1) 7 (11) 0 9 (14) 1 (2) 48 (18) 3 (1)

Pruritus 14 (10) 0 12 (20) 0 14 (21) 0 40 (15) 0

Rash 19 (14) 1 (1) 9 (15) 0 9 (14) 0 37 (14) 1 (< 1)

Diarrhea 18 (13) 2 (1) 4 (7) 0 2 (3) 1 (2) 24 (9) 3 (1)

Nausea 9 (7) 0 7 (11) 0 0 0 16 (6) 0

Decreased appetite 7 (5) 0 2 (3) 0 4 (6) 0 13 (5) 0

Laboratory treatment-related AEs

reported in

≥ 5% of all patients, n (%)

AST increase 13 (10) 4 (3) 10 (16) 10 (16) 0 0 23 (9) 14 (5)

ALT increase 11 (8) 3 (2) 9 (15) 6 (10) 2 (3) 0 22 (8) 9 (3)

Amylase increase 10 (7) 4 (3) 3 (5) 1 (2) 2 (3) 1 (2) 15 (6) 6 (2)

Lipase increase 10 (7) 7 (5) 5 (8) 4 (7) 2 (3) 2 (3) 17 (6) 13 (5)

Draft Only

Best Change in Target Lesion by Tumor-Cell PD-L1

Status

Tumor response assessed by BICR using RECIST v1.1; plots include patients who were evaluable for tumor response and had ≥ 1 postbaseline target lesion assessment (sorafenib naive, n = 72; sorafenib experienced [ESC], n =

32; and sorafenib experienced [EXP], n = 135). a Percent change truncated to 100%.

1. Crocenzi TS et al. Poster presentation at ASCO 2017. 4013.

33

Sorafenib Experienced (2L)

PD-L1+ PD-L1− UTD

ORR, n/N

(%)7/25 (28)

13/102

(13)1/18 (6)

PD-L1+ PD-L1− UTD

ORR, n/N

(%)2/9 (22) 5/26 (19) 0/2 (0)

Sorafenib ExperiencedESC

Sorafenib ExperiencedEXP

Bes

tch

ang

e fr

om

bas

elin

e in

targ

et le

sio

n, %

Patients

100

80

60

40

20

0

–20

–40

–60

–80

–100Patients

a100

80

60

40

20

0

–20

–40

–60

–80

–100

HBV DNA Levels on Treatment by Response

• HBV DNA elevations that occurred in 7 of 64 HBV-infected patients in the

setting of low-level viremia (< 1000 IU/mL) were asymptomatic and did not

result in changes in hepatic parameters or other serious AEsa Included patients with a baseline value and at least 1 on-treatment value.

1. Sangro B et al. Oral presentation at AASLD 2017.

34

Sorafenib Naive and Experienced (1L + 2L)

Partial Response to Nivolumab

• 63 year-old male, uninfected HCC, Child-Pugh score A5

• No prior sorafenib or other treatment for HCC

35

BaselineAFP: 21,000 IU/mL

Week 6AFP: 283 IU/mL

Pembrolizumab in Patients with

Advanced Hepatocellular

Carcinoma: KEYNOTE-224 Update

Zhu AX et al ASCO 2018

Abstract#4020

REACH-2: Phase III Second-line

Ramucirumab vs Placebo in Advanced

Hepatocellular Carcinoma With Elevated

Baseline AFP Following First-line

Sorafenib

REACH-2: Phase III Study Design

• Multicenter, double-blind, placebo-controlled, randomized

phase III trial

Advanced HCC patients

with baseline AFP ≥ 400

ng/mL, BCLC stage B/C,

Child-Pugh A,

ECOG PS 0/1 with prior

sorafenib

(N = 292)

Ramucirumab

8 mg/kg IV Q2W +

Best supportive care

(n = 197)

Placebo

Q2W +

Best supportive care

(n = 95)

Slide credit:Zhu AX, et al. ASCO 2018. Abstract 4003.

Until PD or

unacceptable

toxicity

� Primary: OS

� Secondary: PFS, TTP, ORR, time to deterioration,* safety, PK, immunogenicity

Stratified by

*Time to deterioration in FACT Hepatobiliary Symptom Index-8 and in ECOG PS.

Slide credit: clinicaloptions.com

� OS benefit favored ramucirumab in all subgroups except females (possibly due to small n)Zhu AX, et al. ASCO 2018. Abstract 4003.

OS

(%

)

Outcome

Ramuciru

mab

(n = 197)

Placeb

o

(n = 95)

HR (95% CI)

Median OS, mos

8.5 7.3

0.71 (0.531-

0.949)

P = .0199

12-mo survival, % 36.8 30.3 0.2930

18-mo survival, % 24.5 11.3 0.0187

Median follow-

up, mos7.9 6.6

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27

MosPatients at Risk, n

Ramucirumab

Placebo

197

95

172

76

121

50

87

36

56

19

37

12

26

4

14

1

4

0

0

0

Response RateRamucirumab

(n = 197)

Placebo

(n = 95)P Value

ORR, % (95% CI) 4.6 (1.7-7.5) 1.1 (0-3.1) .1697

DCR, % (95% CI) 59.9 (53.1-

66.7)

38.9 (29.1-

48.8).0006

Best OR, %

�CR

� PR

� SD

� PD

�NE

0

4.6

55.3

33.5

6.6

0

1.1

37.9

50.5

10.5

Slide credit: clinicaloptions.comZhu AX, et al. ASCO 2018. Abstract 4003.

TEAE in ≥ 15% of Patients in

Ramucirumab Arm, n (%)

Ramucirumab (n = 197) Placebo (n = 95)

Any Grade Grade ≥ 3Any

Grade

Grade ≥

3

Patients with ≥ 1 TEAE*

� Fatigue

� Peripheral edema

� Hypertension

� Decreased appetite

� Proteinuria

� Abdominal pain

� Nausea

� Ascites

� Diarrhea

191 (97)

54 (27.4)

50 (25.4)

48 (24.4)

46 (23.4)

40 (20.3)

39 (19.8)

37 (18.8

35 (17.8)

32 (16.2)

116 (58.9)

7 (3.6)

3 (1.5)

24 (12.2)

3 (1.5)

4 (2)

3 (1.5)

0 (0)

8 (4.1)

0 (0)

82 (86.3)

16 (16.8)

13 (13.7)

12 (12.6)

19 (20)

4 (4.2)

12 (12.6)

11 (11.6)

7 (7.4)

12 (14.7)

42 (44.2)

3 (3.2)

0 (0)

5 (5.3)

1 (1.1)

0 (0)

2 (2.1)

0 (0)

2 (2.1)

1 (1.1)

Discontinuation due to TRAE 21 (10.7) 3 (3.2)

Dose adjustment due to AE 68 (34.5) 13 (13.7)

Deaths due to TRAE 3 (1.5) 0 (0)

Slide credit: clinicaloptions.comZhu AX, et al. ASCO 2018. Abstract 4003.

*TEAEs in ≥ 15% patients in ramucirumab

arm.

Cabozantinib versus placebo in patients with advanced

hepatocellular carcinoma who have received prior sorafenib:

results from the randomised Phase III CELESTIAL trial

• Ghassan K. Abou-Alfa, Tim Meyer, Ann-Lii Cheng, Anthony El-Khoueiry, Lorenza Rimassa,

Baek-Yeol Ryoo, Irfan Cicin, Philippe Merle, YenHsun Chen, Joong-Won Park, Jean-Frederic

Blanc, Luigi Bolondi, Heinz-Josef Klümpen, Stephen L. Chan, Vincenzo Dadduzio, Colin

Hessel, Anne Borgman-Hagey, Gisela Schwab,

Robin Kate Kelley on behalf of the CELESTIAL investigators

Presented at ASCO GI, San Francisco February 2018 and ASCO, Chicago 2018 (encore)

Highly confidential Ipsen

CELESTIAL: cabozantinib vs placebo in advanced HCC (Phase III

randomised study)

Study Endpoints

• Primary: OS

• Secondary: PFS, ORR

• Other: safety/tolerability, PK, biomarkers, HRQoL

Stratification

• Region, aetiology, EHS and/or vascular invasion

Cabozantinib

60 mg daily

Advanced HCC (N≈760)• Pathologic diagnosis of HCC not

amenable to curative treatment

• Child-Pugh score A

• Received prior sorafenib

• Progressed following at least one prior

systemic treatment for HCC

• Received up to two prior systemic

regimens for advanced HCC

• ECOG performance status 0 or 1

• No uncontrolled hypertension, defined

as sustained BP > 150 mm Hg systolic

or > 100 mm Hg diastolic despite

optimal antihypertensive treatment

2:1

Placebo

Daily

EHS = extrahepatic spread

Abou-Alfa GK et al., ASCO 2018. Abstract 4019.

Tumour

assessment every

8 weeks

(RECIST 1.1)

Treatment until

loss of clinical

benefit or

intolerable toxicity

No crossover

allowed


CELESTIAL: Baseline characteristics

Cabozantinib (N=470)

Placebo (N=237)

Median age, years (range) 64 (22‒86) 64 (24‒86)

Male, % 81 85

ECOG Performance Status 0 / 1, % 52 / 48 55 / 45

AFP ≥ 400 ng/mL, % 41 43

Enrollment Region, %

Asia / Europe / North America / Pacific 25 / 49 / 23 / 3 25 / 46 / 25 / 5

Aetiology of HCC, %

HBV 38 38

HCV 22 22

Other 40 41

Extrahepatic spread of disease, % 79 77

Macrovascular invasion, % 27 34

Extrahepatic spread and/or macrovascular invasion, % 85 84

Asia : Hong Kong, South Korea, Singapore, Taiwan; Pacific : Australia and New Zealand



CELESTIAL: Prior therapy

Cabozantinib (N=470)

Placebo (N=237)

Prior systemic anticancer regimens for advanced HCC, %

One prior regimen 71 73

Two prior regimens 28 26

Prior systemic therapy, %

Sorafenib 100 100

Regorafenib 1 1

Lenvatinib 0 <1

Tivantinib <1 1

Anti-PD-1/PD-L1 3 1

Chemotherapy 9 13

Investigational agents 13 8

Local liver-directed non-radiation anticancer therapy, % 44 48

Median total duration of prior sorafenib, months 5.3 4.8

Median time from disease progression to randomisation,

months1.6 1.7



CELESTIAL- Primary endpoint : OS

Median OS

mo (95% CI)

No. of

Deaths

Cabozantinib (N=470) 10.2 (9.1–12.0) 317

Placebo (N=237) 8.0 (6.8–9.4) 167

Hazard ratio 0.76 (95% CI 0.63–0.92), p=0.0049*

No. at RiskCabozantinib 470 382 281 206 159 116 93 63 44 31 22 12 4 1 0Placebo 237 190 117 82 57 37 25 20 15 10 7 5 3 0 0

*Critical p-value ≤ 0.021 for second interim analysis


0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of O

S

Time (months)


CELESTIAL: All-causality Grade 3 or 4 AEs

Grade 3/4 events reported in at least 5.0% of patients in either treatment group

Cabozantinib

(n=6)

Hepatic failure, oesophagobronchial fistula, portal vein thrombosis, upper

gastrointestinal haemorrhage, pulmonary embolism, hepatorenal syndrome

Placebo (n=1) Hepatic failure

Treatment-related grade 5 adverse events:

Preferred Term, %

Cabozantinib (N = 467)

Placebo (N = 237)

Grade 3 Grade 4 Grade 3 Grade 4Any grade 3 or 4 AE 58 10 34 3

PPE 17 0 0 0

Hypertension 16 <1 2 0

AST increased 11 1 6 <1

Fatigue 10 0 4 0

Diarrhoea 10 <1 2 0

Asthenia 7 <1 2 0

Appetite decreased 6 0 <1 0


Conclusion: How to treat pts with

advanced disease?

Third lineFirst line

Sorafenib

Lenvatinib

Immunotherapy

?

Phase III trial of

nivolumab vs

sorafenib

Second line

Regorafenib

Nivolumab

Completed phase III study

of pembrolizumab vs BSC

Cabozantinib


Ramucirimab

Cabozantinib

GO30140 phase Ib atezolizumab + bevacizumab and/or other

treatments in solid tumours: study design

DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; HER2, human

epidermal growth factor 2

IV, intravenous; ORR, objective response rate; OS, overall survival; PD-1, programmed death 1; PD-L1, programmed death ligand 1; PFS, progression-

free survival

q3w, every three weeks; RECIST, Response Evaluation Criteria In Solid Tumours; TTRP, time to radiologic progression

• Primary objective : safety and tolerability

• Secondary objectives : ORR, DoR, PFS, TTRP per RECIST v1.1, OS

At data cut-off (11 January 2018), 43 patients were evaluable for safety and 23 patients were evaluable for efficacy with a minimum follow-up of 16

weeks

• Measurable disease per RECIST v1.1

• ECOG PS 0/1• Adequate

haematologic and end-organ function

• Resolution of any treatment-related toxicity from prior therapy

• No prior treatment with anti-CTLA4, anti-PD1 or anti-PDL1 therapeutic antibodies(N=130–310)

Arm A: HCCAtezolizumab 1,200mg IV + bevacizumab

15mg/kg IV q3w

Arm B: HER2-negative gastric cancerArm C: pancreatic cancer

Arm E: oesophageal cancer

Until disease

progression,

unacceptable toxicity

orloss of clinical benefit

Lenvatinib + Pembrolizumab for Unresectable HCC:

Phase Ib Study Design

� Open-label, multicenter phase Ib study

Patients with

unresectable HCC

BCLC stage B or C;

Child-Pugh A; ECOG

PS 0/1;

≥ 1 measurable target

lesion by mRECIST

criteria

(N = 30)

Lenvatinib 8 or 12 mg*/day PO +

Pembrolizumab 200 mg IV on Day 1 of

21-day cycle

(n = 6 patients ineligible for other therapies)


� Primary endpoint: safety

� Secondary/exploratory endpoints: ORR, PFS, DoR, TTP, OS, PK, antibodies to pembrolizumab

Ikeda M, et al. ASCO 2018. Abstract 4076.

Dose-Limiting Toxicity Evaluation

Lenvatinib 8 or 12 mg*/day PO +

Pembrolizumab 200 mg on Day 1 of

21-day cycle

(n ≈ 20 patients with no previous systemic

therapy for unresectable HCC)

Expansion Set

*Lenvatinib 8 mg for patients < 60 kg; 12 mg for ≥ 60 kg.

Nivo+Ipi in HCC

Advanced HCC

SorafenibTreated

Intolerant or Progressors

Uninfected, HCV-infected,

HBV-infected

Treat untilRECIST 1.1 –definedprogression orunacceptabletoxicity

A: Nivo 1 mg/kg+ Ipi 3 mg/kg Q3W x 4

B: Nivo 3 mg/kg+ Ipi 1 mg/kg Q3W x 4

Follow-up visit 1 and2and

Survival follow-up

C: Nivo 1 mg/kg Q2W

+ Ipi 3 mg/kgQ6W

Nivo 240 mg Flat DoseQ2

W

Nivolumab + Ipilimumab Combination Cohort (n=120)

1st Endpoints = Safety/tolerability & ORR

Dr. ThomasYau 49 AACR April,2018

� 148 SubjectsRandomized� Arm A

(n=50)� Arm B

(n=49)� Arm C

(n=49) Ratio = 1:1:1

� Minimun F/U at 17-Mar-2017 DBL= 4 months

CheckMate 040: Phase 1/2 Study of Nivolumabin Patie nts With AdvancedHCCStudy Design Cohort 4

Thank You

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