A 15-minute presentation delivered at the monthly Hepatobiliary Conference, University of the Philippines - Philippine General Hospital.

1. Hepatocellular carcinoma:
treatment options for unresectable
and metastatic disease
Lance Catedral, MD
Section of Medical Oncology
UP–Philippine General Hospital

2. Options for first-line treatment

3. Sorafenib

4. • oral
• multi-kinase inhibitor→suppresses proliferation, angiogenesis

5. SHARP trialSorafenib in Advanced Hepatocellular Carcinoma
way to gain a further understanding of the drug’s
molecular mechanisms of action. In addition, the
safety profile compares well with those of previ-
ously reported systemic therapies, such as the
Figure 2. Kaplan–Meier Analysis of Overall Survival,
the Time to Symptomatic Progression, and the Time
to Radiologic Progression.
Among 602 patients (of whom 299 received sorafenib
and 303 received placebo), the median overall survival
was 10.7 months in the sorafenib group, as compared
with 7.9 months in the placebo group (hazard ratio for
death in the sorafenib group, 0.69; 95% CI, 0.55 to 0.87)
(Panel A). The median time to symptomatic progression
was 4.1 months in the sorafenib group, as compared
with 4.9 months in the placebo group (hazard ratio for
progression in the sorafenib group, 1.08; 95% CI, 0.88
to 1.31) (Panel B). The median time to radiologic pro-
gression was 5.5 months in the sorafenib group, as com-
pared with 2.8 months in the placebo group (hazard ra-
tio for progression in the sorafenib group, 0.58; 95% CI,
0.45 to 0.74) (Panel C).
1.00
0.75
0.50
0.25
0.00
1.00
0 1 5432 76 98 1211 13 14 15 1610 17
Sorafenib
PlaceboP<0.001
Sorafenib
Placebo
299
303
290
295
270
272
249
243
234
217
213
189
200
174
172
143
140
108
111
83
89
69
68
47
48
31
37
23
24
14
7
6
1
3
0
0
• phase III
• 602 patients: sorafenib
versus best supportive care
• Median OS: 10.7 months
(sorafenib) vs 7.9 months
(placebo)
• HR 0.69; 95% CI, 0.55 to
0.87
• 1 year survival rate: 44% vs
33%
Love et al. N Engl J Med 2008;359:378-390

6. • phase III
• 226 patients: sorafenib vs placebo
• HR 0.68; CI, 0.50–0.93; P = .014
• median OS: 6.5 months (sorafenib) vs. 4.2 months (placebo)
•
Asia-Pacific Study
Cheng et al. Lancet Oncol 2009;10:25-34

7. • Sorafenib (Nexavar™)
• Usual dose: 400 mg daily
• Box of 60 (200 mg/tab preparation): Php 149,000 per box
• Php 2483 per tablet → roughly Php 149,000 a month
• BayPap program: 2 plus 2

8. WS
Llovet et al. 2018 Nat Rev Clinical Oncdoi.org/10.1038/ s41571-018-0073-4

9. Lenvatinib

10. Lenvatinib
• inhibitor of VEGF, PDGF
• REFLECT trial
• phase III, randomized non-inferiority trial
• unresectable hepatocellular carcinoma, no treatment for advanced
disease
• lenvatinib vs sorafenib
• non-inferiority margin set at 1.08
Kudo et al, Lancet 2018; 391: 1163–73

11. REFLECT trial
(table 1).
Lenvatinib showed a statistically significant improve-
ment compared with sorafenib for all secondary effi-
cacy endpoints as determined by investigator tumour
assessments based on mRECIST. Median progression-
free survival for lenvatinib was longer than that for
sorafenib (table 2, figure 4). Median time to progression
was 8·9 months (95% CI 7·4–9·2) for patients in the
envatinib group compared to 3·7 months (3·6–5·4) for
patients in the sorafenib group (table 2, appendix).
Lenvatinib also showed a greater objective response
rate than did sorafenib (table 2, appendix). Improvements
n all secondary efficacy endpoints (progression-free
survival, time to progression, and objective response)
with lenvatinib compared to sorafenib were consistent
across all predefined subgroups (figure 3, appendix).
Analysis for overall survival with predefined subgroups
supports the robustness of the non-inferiority result
(appendix). Masked independent imaging review con-
firmed progression-free survival and time to progression
based on investigator assessments according to mRECIST
(table 2, figure 4). Similar progression-free survival and
time-to-progression results were observed for mRECIST
and RECIST 1.1 based on masked independent imaging
review. Masked independent imaging review confirmed a
significantly higher objective response rate in the
envatinib arm than in the sorafenib arm by mRECIST
and RECIST 1.1 (table 2).
156 (33%) patients in the lenvatinib arm and
184 (39%) in the sorafenib arm received post-study anti- sorafenib arm. In the lenvatinib arm, 11 (7%) patients in
Figure 2: Overall survival outcomes
Kaplan-Meier estimates of overall survival by treatment group. HR=hazard ratio.
Number at risk
Lenvatinib
Sorafenib
0
478
476
3
436
440
6
374
348
9
297
282
12
253
230
15
207
192
18
178
156
21
140
116
24
102
83
27
67
57
30
40
33
33
21
16
36
8
8
42
0
0
39
2
4
Time (months)
0
10
20
30
40
50
60
70
80
90
100
Overallsurvival(%)
Lenvatinib
Sorafenib
13·6 (12·1–14·9)
12·3 (10·4–13·9)
Median overall survival duration
(months; 95% CI)
HR 0·92 (95% CI 0·79–1·06)
procedures
Radiotherapy 49 (10%) 60 (13%) 109 (11%)
Data are mean (SD) or n (%) unless otherwise specified. *One patient had no baseline target lesion.
Table 1: Demographic and disease characteristics at baseline
Median OS: 13.6 months
(lenvatinib) vs. 12.3 months
(sorafenib)
HR 0.92; 95% CI, 0.79—
1.06
PFS: HR 0.66, (CI,
0.57-0.77), ,<0.0001
Less hand-foot syndrome
but more hypertension
Kudo et al, Lancet 2018; 391: 1163–73

12. Price
• Usual dose: If ≥ 60 kg: 12 mg daily; if <60 kg: 8 mg once daily
• LEAP or Lenvima Easy Access Program
• Lenvima 10 mg is P92,000 per box of 20 capsules
• Lenvima 4 mg is P76,800 per box of 20 capsules
• Php 3,840 per tablet → roughly Php 115,200 a month
• With the LEAP, patients enrolled will be given 2 additional boxes of the
same preparation free when they purchase 1 box of either preparation

13. After sorafenib, what are
second-line therapy options?

14. Fig. 3 | Overall survival outcomes of phase III clinical trials testing molecularly targeted therapies or radioembolization
with 90
Y in patients with advanced-stage HCC. The figure illustrates the estimated overall survival hazard ratios (HRs)Llovet et al. 2018 Nat Rev Clinical Oncdoi.org/10.1038/ s41571-018-0073-4

15. 1. Regorafenib
• oral fluorinated sorafenib analog→anti-angiogenic, modulates tumor
microenvironment
• RESORCE trial
• phase III
• 573 patients with HCC, Child-Pugh A liver function who progressed on
sorafenib
Bruix et al. Lancet 2017;389:56-66

16. s
s
d
s
o
s
d
;
s
d
e
s
t
G
e
n
s
e
n
s
t
.
s
o
n
)
s
e
o
e
o
(160 mg/day) with no reductions.
At the cutoff date for the final analysis (Feb 29, 2016) and
a median follow-up of 7·0 months (IQR 3·7–12·6),
Number at risk
Regorafenib
Placebo
Regorafenib
Placebo
379
194
316
149
224
95
170
62
122
37
78
26
54
16
34
8
21
5
10
3
0
0
4
1
HR 0·63 (95% CI 0·50–0·79); one-sided p<0·0001
0
10
20
30
40
50
60
70
80
90
100
Probabilityofsurvival(%)
A
Number at risk
Regorafenib
Placebo
379
194
166
37
76
15
43
6
27
3
14
2
8
1
7
1
4
0
0
0
0
0
0
0
HR 0·46 (95% CI 0·37–0·56); one-sided p<0·0001
0
10
20
30
40
50
60
70
80
90
100
Probabilityofprogression-freesurvival(%)
B
0 3 6 9 12 15 18 21 24 27 30 33
0 3 6 9 12 15 18 21 24 27 30 33
to baseline demographics, tumour burden, ECOG
performance status, aetiology, and severity of liver disease
(table 1). We also assessed the pattern of progression
during sorafenib treatment because this parameter has
been shown to influence outcomes and could distort the
results of second-line studies.26
A potential imbalance in
the pattern of progression on previous sorafenib was
ruled out because the distribution of the different
categories was similar across the treatment groups.
Specifically, the development of new extrahepatic sites
during previous sorafenib, which was recently shown to
be associated with a worse prognosis,26
was present in
153 (40%) patients in the regorafenib group and 80 (41%)
in the placebo group. Similarly, growth of existing lesions
(intrahepatic or extrahepatic; 307 [81%] patients in the
regorafenib group and 156 [80%] patients in the placebo
group) or new intrahepatic sites (168 [44%] patients in the
regorafenib group and 88 [45%] patients in the placebo
group) were balanced between treatment groups.
Median time on sorafenib was 7·8 months
(IQR 4·2–14·5) in the regorafenib group and 7·8 months
(4·4–14·7) in the placebo group. Median time from
progression on sorafenib was similar in both groups
(1·4 months [IQR 0·9–2·3] in the regorafenib group
vs 1·4 months [0·9–2·2] in the placebo group), as was the
median time from discontinuation of sorafenib to the
start of study treatment (0·9 months [IQR 0·7–1·3] in
both groups).
Of patients who started treatment, 309 (83%) receiving
regorafenib and 183 (95%) receiving placebo discontinued
study treatment (figure 1). The most common reason for
discontinuation was disease progression (226 [60%] in
Number at risk
Regorafenib
Placebo
379
194
316
149
224
95
170
62
122
37
78
26
54
16
34
8
21
5
10
3
0
0
4
1
Number at risk
Regorafenib
Placebo
379
194
166
37
76
15
43
6
27
3
14
2
8
1
7
1
4
0
0
0
0
0
0
0
HR 0·46 (95% CI 0·37–0·56); one-sided p<0·0001
0
10
20
30
40
50
60
70
80
90
100
Probabilityofprogression-freesurvival(%)
B
0 3 6 9 12 15 18 21 24 27 30 33
0 3 6 9 12 15 18 21 24 27 30 33
0 3 6 9 12 15 18 21 24 27 30 33
Months from randomisation
HR 0·44 (95% CI 0·36–0·55); one-sided p<0·0001
0
10
20
30
40
50
60
70
80
90
100
Probabilityofprogression(%)
C
OS: HR 0.63; 95% CI, 0.50–0.79; P < .
001
Medial survival: 10.6 months
(regorafenib) vs 7.8 months (placebo)
PFS: HR 0.46; 95% CI, 0.37–0.56; P < .
001
Bruix et al. Lancet 2017;389:56-66

17. • TTP (HR, 0.44; 95% CI, 0.36–0.55; P < .001)
• objective response (11% vs. 4%; P = .005)
•
Bruix et al. Lancet 2017;389:56-66

18. • Usual dose: 160 mg once daily for 3 weeks, then 1 week off
• Regorafenib (Stivarga™)
• GloboAsiatico
• 1 box of 40 mg/tablet (28 tablets) = Php 89,937.26
• Php 3212 per tablet
• In three weeks: Php 67,452

19. 2. Cabozantinib
• multi-TKI, activity against MET, VEGFR2 and RET
• CELESTIAL trial
• phase III
• 707 incurable patients with HCC who progressed with sorafenib
Abou-Alfa et al. N Engl J Med 2018;379:54-63

20. CELESTIAL trial
• OS: HR 0.76, 95% CI
0.63-0.92, P=0.005
• Median survival: 10.2 months
(cabozantinib) vs 8 months
(placebo)
• PFS: HR 0.44; 95% CI, 0.36—
0.52; P < .001
•
Cabozantinib in Advanced Hepatocellular Carcinoma
the cabozantinib group and in 28 (12%) in the
placebo group and were commonly related to dis-
ease progression. Grade 5 adverse events that were
considered to be related to cabozantinib or pla-
cebo were reported in 6 patients in the cabozan-
tinib group (one event each of hepatic failure,
bronchoesophageal fistula, portal-vein thrombosis,
upper gastrointestinal hemorrhage, pulmonary em-
bolism, and the hepatorenal syndrome) and in
1 patient in the placebo group (hepatic failure).
Discussion
This randomized, phase 3 trial showed that
cabozantinib treatment significantly prolonged
survival in patients with previously treated ad-
vanced hepatocellular carcinoma. The median
overall survival was 10.2 months with cabozan-
tinib and 8.0 months with placebo, with a haz-
ard ratio for death of 0.76. Corresponding to this
survival benefit, a longer duration of progression-
ProbabilityofOverallSurvival
1.0
0.8
0.4
0.2
0.6
0.0
0 9 15 24 33 42
Months
B Progression-free Survival
A Overall Survival
Hazard ratio for death, 0.76 (95% CI, 0.63–0.92)
P=0.005
No. at Risk
Cabozantinib
Placebo
470
237
93
25
63
20
6
159
57
206
82
116
37
3
328
190
281
117
31
10
12
44
15
4
3
21
12
5
18
22
7
3027
1
0
3936
0
0
Cabozantinib
Cabozantinib
Placebo
317
167
470
237
10.2 (9.1–12.0)
8.0 (6.8–9.4)
No. of
Patients
Median Overall
Survival
No. of
Events
Placebo
mo (95% CI)
No. of
Patients
Median Progression-free
Survival
No. of
Events
Abou-Alfa et al. N Engl J Med 2018;379:54-63

21. 3. Ramucirumab
• recombinant monoclonal antibody, binds to VEGFR2 receptor
• REACH trial (phase III), failed to demonstrate OS benefit
• BUT: some benefit in those with AFP >400 ng/mL
•

22. REACH II
• 387 patients with HCC, BCLC stage C or B disease refractory or not
amenable to locoregional therapy, baseline AFP ≥400 ng/mL, Child-
Pugh A, had progressed on or following, or were intolerant to sorafenib
• OS: 8.5 months vs 7.3 months
• HR 0.710; 95% CI 0.53–0.95; p = 0.019
• PFS: 2.8 months vs 1.6 months
• HR 0.452; 95% CI 0.40–0.60; p < 0.0001)
•
Zhu et al. Journal of Clinical Oncology 2018 36:15_suppl, 4003-4003

23. –John B.A.G. Haanen, MD, PhD
“Never before has a new treatment paradigm had such an impact on
survival—even for cancer types that seemed incurable, we now see
long-term remission extending to the metastatic setting.”

24. Immuno-oncology

25. (a) The CTLA-4-mediated immune checkpoint is induced inT cells at the time of their initial response to antigen.
The level of CTLA-4 induction depends on the amplitude of the initialT cell receptor (TCR)-mediated signalling.
High-affinity ligands induce higher levels of CTLA-4,which dampens the amplitude of the initial response.After the
TCR is triggered by antigen encounter,CTLA-4 is transported to the cell surface.Therefore,CTLA-4 functions as
b
DC
CD86
Co-stimulating
ligand
PD-L1
or PD-L2 PD-1
Co-stimulating
receptor
Tissue
CD28
MHC
Peptide
TCR
Intracellular
vesicle
cell surface
Trafficking
of T cells to
peripheral
tissues
Priming of
T cells
Signal 1 Signal 1
Signal 1
Signal 1
Inflammation
Naïve or resting
T cell
Antigen-experienced
T cell
CTLA-4
SIGNAL 1: T cell receptor/Major histocompatibility complex
Dendritic cell–T cell interaction,
highlighting PD-1 and PD-L1/2
EMSO Handbook 2018 on Immuno-Oncology, ESMO Press

26. 4. Nivolumab
• Anti-PD1 antibody

27. Checkmate 040
• phase I/II non-randomized trial
• 214 patients in dose-expansion cohort (3 mg/kg), progressed on or after
sorafenib
• objective response rate: 20%
• disease control rate: 64%
• 9-month OS: 74%
• US FDA approval in 2017
• On-going: CheckMate 459: nivolumab vs sorafenib in the first-line setting
El-Khoueiry et al. Lancet 2017; 389:2492-2502

28. 5. Pembrolizumab
• phase II, non-randomized trial
• 169 patients, progressed on or intolerant to sorafenib, HCC, Child-Pugh
A
• pembrolizumab vs placebo
• endpoint: objective response (i.e., complete + partial response to at
least one dose of pembrolizumab)
• OR 17% (18 out of 104 patients)
Zhu et al. Lancet Oncol 2018;19:940-952

29. • Usual dose: 200 mg once every 3 weeks
• Pembrolizumab 100 mg/vial = Php 157,624
• About Php 300,000 per cycle
• Available programs in KeyPAP:
• If 2 vials needed: 1st cycle on full price, 2nd and 3rd cycles are 50 percent off
• If 1 vial needed: 1st and 2nd cycles on full price, then 3rd and 4th cycles are on
50% off

30. All treated participants
(n=104)
Objective response* 18 (17%; 11–26)
Best overall response†
Complete response 1 (1%)
Partial response 17 (16%)
Stable disease 46 (44%)
Progressive disease 34 (33%)
Not assessable‡ 6 (6%)
Disease control§ 64 (62%; 52–71)
Mediantimeto response, months (IQR)¶ 2·1 (2·1–4·1)
Mediandurationof response, months
(range) ¶||
Not reached (3·1–14·6+**)
Duration of response ≥9 months¶|| 12 (77%)
Data are n (%)or n (%; 95%CI),unlessotherwise indicated. *Includes complete and
partial responses. †Confirmed by independent central reviewwith Response
EvaluationCriteria in SolidTumors. ‡These patients had a baseline assessment by
investigator reviewor central radiology but no assessment after baselineonthedata
cutoffdate, includingdiscontinuationordeath beforethe first scan after baseline.
100
90
B
0 12
Individualresponders
A
Zhu et al. Lancet Oncol 2018;19:940-952

31. NCCN Guidelines Version 2.2019
Hepatocellular Carcinoma
N
• First-line systemic therapy
Preferred
◊ Sorafenib (Child-Pugh Class A [category 1] or B7)a,b,1,2
◊ Lenvatinib (Child-Pugh Class A only)3
Other Recommended
◊ Systemic Chemotherapy (category 2B)c
• Subsequent-line therapy if disease progression:
Regorafenib (Child-Pugh Class A only) (category 1)d,4
Cabozantinib (Child- Pugh Class A only) (category 1)d,5
Ramucirumab (AFP ≥ 400 ng/mL only) (category 1)d,6
Nivolumab (Child-Pugh Class A or B7)7
Sorafenib (Child-Pugh Class A or B7)a,b (after first-line lenvatinibe)
Pembrolizumab (Child-Pugh Class A only)8 (category 2B)
PRINCIPLES OF SYSTEMIC THERAPY
Printed by Lance Catedral on 3/8/2019 7:04:26 AM. For personal use only. Not approved for distribution. Copyright © 2019 National Comprehensive Cancer Network, Inc., All Rights Reserved.

32. New Targeted Agents and Immunotherapies in HCC
• Phase III RESORCE
(NCT01774344)
FDA Approval 04/2017
EMA Approval 08/2017
1 LINE
Sorafenib
(Nexavar®)
Bayer
Lenvatinib
(Lenvima®)
Eisai/MSD
• Phase III REFLECT
(NCT01761266)
FDA Approval 08/2018
EMA Approval 08/2018
Regorafenib
(Stivarga®)
Bayer
Cabozantinib
(Cabometyx®)
Exelixis
• Phase III CELESTIAL
(NCT01908426)
FDA Approval 01/2019
EMA Approval 11/2018
• Phase III REACH-2
(NCT02435433)
Advanced
HCC (BCLC C)
Nivolumab
(Opdivo®)
BMS
Durvalumab
(Imfinzi®) +
Tremelimumab
AstraZeneca
Cabozantinib
(Cabometyx®)
Exelixis
Pembrolizumab
(Keytruda®)
MSD
Nivolumab
(Opdivo®)
BMS
• Phase III CELESTIAL
• NCT01908426
FDA Approval 01/2019
EMA Approval 11/2018
• Phase III CM-459
(NCT02576509)
• Phase III HIMALAYA
(NCT03298451)
• Phase III IMbrave150
(NCT03434379)
• Phase III
(NCT03412773)
• Phase II Keynote-224
(NCT02702414)
FDA Approval 11/2018
• Phase I/II CM-040
(NCT01658878)
FDA Approval 09/2017
• Phase III SHARP
(NCT00105443)
FDA Approval 11/2007
EMA Approval 10/2007
Ramucirumab
(Cyramza®)
Eli Lilly
2 LINE
3 LINE
Tislelizumab
(BGB-A317)
BeiGene/Celgene
Tyrosinkinase-Inhibitor
Angiogenesis-Inhibitor
Checkpoint-Inhibitor
EMA + FDA approved
FDA approved
Approval awaited
Under clinical invesƟgaƟon
Bevacizumab
(Avastin®) +
Atezolizumab
(Tecentriq®)
Roche
Fig. 1 Sequencing options for targeted therapies and immune checkpoint inhibitors in advanced HCC. BCLC C Barcelona clinic liver cancer
Marquardt et al. Nature Switzerland AG 2019. https://doi.org/10.1007/s11523-019-00624-w

33. Table 1 | Recurrent somatic genetic alterations detected in HCCs
Altered pathway Altered gene Effect of alteration Percentage (range)
Mutations
Telomere maintenance TERT promoter Activating 54 (44–59)
Cell cycle control TP53 Loss of function 28 (23–31)
ATM Loss of function 4 (2–5)
RB1 Loss of function 4 (3–5)
CDKN2A Loss of function 2 (1–3)
WNT–β-catenin signalling CTNNB1 Activating 29 (23–36)
AXIN1 Loss of function 7 (5–10)
APC Loss of function 2 (1–3)
Chromatin modifiers ARID1A Loss of function 8 (4–12)
ARID2 Loss of function 7 (3–10)
KMT2A Loss of function 3 (0–4)
KMT2B Loss of function 3 (0–4)
KMT2C Loss of function 3 (2–5)
BAP1 Loss of function 2 (0–5)
ARID1B Loss of function 1 (1–3)
RTK–RAS–PI3K signalling RPS6KA3 Unclassified 4 (3–6)
PIK3CA Activating 2 (1–4)
KRAS Activating 1 (0–1)
NRAS Activating 1 (0–1)
PDGFRA Unclassified 1 (0–2)
EGFR Activating 1 (0–2)
PTEN Loss of function 1 (0–2)
Oxidative stress NFE2L2 Activating 4 (3–6)
KEAP1 Activating 3 (2–5)
Hepatocyte differentiation ALB Unclassified 9 (5–13)
iClust2 subtype that shares molecular and patho-
logical characteristics (for example, CTNNB1 muta-
tions and less frequent microvascular invasion) with
the non-proliferation class. The third TCGA cluster,
iClust3, generated a TP53 sign
chromosomal instability and po
Beyond tumour cell-intrinsic
an altered tumour microenviro
Oxidative stress NFE2L2 Activating
KEAP1 Activating
Hepatocyte differentiation ALB Unclassified
APOB Unclassified
JAK–STAT signalling IL6ST Unclassified
JAK1 Unclassified
TGFβ signalling ACVR2A Loss of function
IGF signalling IGF2R Unclassified
Copy number alterations
Cell cycle control MYC High-level focal amplification
CCND1 High-level focal amplification
CDKN2A Homozygous deletion
RB1 Homozygous deletion
TP53 Homozygous deletion
RTK–RAS–PI3K signalling VEGFA High-level focal amplification
FGF19 High-level focal amplification
Telomere maintenance TERT High-level focal amplification
Mutation frequencies are reported for a total of 1,289 patients included in multiple whole-exome sequen
promoter mutations were assessed using Sanger sequencing (n=1,213 patients). Copy number alteration
single-nucleotide polymorphism (SNP) arrays (n=704 patients). HCC, hepatocellular carcinoma; RTK, rece
STAT, signal transducer and activator of transcription.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
NATURE REVIEWS | CLINICAL ONCOLOGY
Llovet et al. 2018 Nat Rev Clinical Oncdoi.org/10.1038/ s41571-018-0073-4

34. β
Llovet et al. 2018
Nat Rev Clinical
Oncdoi.org/
10.1038/
s41571-018-007
3-4