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
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Update on Medical Treatment for Advanced Hepatocellular ... · TKI-IO combo early phase? OPTIMIS OS for TACE-systemic therapy 1L nivolumab 2L regorafenIb 2016 ... P2 KEYNOTE 224 single-arm
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Update on Medical Treatment for
Advanced Hepatocellular Carcinoma
Dr Thomas Yau
Clinical Associate Professor
Principle Investigator in State Key laboratory for Liver
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
Presented By Ann-Lii Cheng at 2017ASCO Annual Meeting
Secondary Endpoint: Kaplan-Meier Estimate of PFS by mRECIST
Presented By Ann-Lii Cheng at 2017ASCO Annual Meeting
Most Frequent TEAEs ( ≥ 15%)
Presented By Ann-Lii Cheng at 2017ASCO Annual Meeting
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
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
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.
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
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.