Gut talk

15. Drug; Trial
Name
Mode of Action N
Median OS, Mos
(vs Placebo)
HR (95% CI)
Regorafenib
(RESORCE)[1] Multitargeted TKI 573 10.6 vs 7.8 0.63 (0.50-0.79)
Cabozantinib
(CELESTIAL)[2] Multitargeted TKI 707 10.2 vs 8.0 0.76 (0.63-0.92)
Ramucirumab
(REACH-2)[3] Anti-VEGFR2 mAb 292 8.5 vs 7.3 0.71 (0.53-0.95)

16. Pts with HCC with
documented
radiologic
progression on
sorafenib
(N = 573)
Until PD, unacceptable
toxicity, or withdrawal
Regorafenib 160 mg PO QD
Days 1-21 of 28-day cycle
+ BSC
(n = 379)
Placebo
Days 1-21 of 28-day cycle
+ BSC
(n = 194)
Bruix J, et al. Lancet. 2017;389:56-66.
Randomized 2:1
Stratified by geography (Asia vs other), macrovascular invasion, extrahepatic
disease, ECOG PS (0 vs 1), AFP (< 400 ng/mL vs ≥ 400 ng/mL)

17. Response, %
mRECIST RECIST 1.1
Regorafenib
(n = 379)
Placebo
(n = 194)
Regorafenib
(n = 379)
Placebo
(n = 194)
ORR
10.6 4.1 6.6 2.6
2-sided P = .01 1-sided P = .02 (1-sided)
DCR
65.2 36.1 65.7 34.5
2-sided P < .001 1-sided P < .0001
Bruix J, et al. Lancet. 2017;389:56-66.
Regorafenib
(n = 379)
Placebo
(n = 194)
Events, n (%) 233 (61) 140 (72)
Censored, n (%) 147 (39) 54 (28)
Median OS, mos
(95% CI)
10.6 (9.1-12.1) 7.8 (6.3-8.8)
(HR: 0.63; 95% CI: 0.50-0.79; 1-sided P < .0001)
Placebo
Regorafenib
Mos From Randomization
Probability
of
Survival
(%)
100
80
60
40
20
0
33
0 3 6 12 15 18 21 24 27 30
9
Placebo
Regorafenib
Mos From Randomization
Probability
of
PFS
(%)
100
80
60
40
20
0
33
0 3 6 12 15 18 21 24 27 30
9
Regorafenib
(n = 379)
Placebo
(n = 194)
Events, n (%) 293 (77) 181 (93)
Censored, n (%) 86 (23) 13 (7)
Median PFS,
mos (95% CI)
3.1
(2.8-4.2)
1.5
(1.4-1.6)
(HR: 0.46; 95% CI: 0.37-0.56; 1-sided P < .0001)

18. Finn RS, et al. ASCO 2014. Abstract TPS4153.
O
O
CI
H
N
H
N
N
H2N
O
O
VEGFR FGFR
Angiogenesis
X
T202/Y204
S235/S236
T389
T421/S424
RAS
RAF
MEK
ERK1/2
Lenvatinib
PI3K
AKT
mTOR
S6K
S6
P
P
P
P

19. Pts with unresectable HCC, no prior
systemic therapy, ≥ 1 measurable target
lesion, BCLC stage B/C, Child-Pugh A,
ECOG PS 0/1, and adequate organ function
(N = 954)
Lenvatinib
8 mg (BW < 60 kg) or 12 mg (BW ≥ 60 kg) QD
(n = 478)
Sorafenib
400 mg BID
(n = 476)
Cheng AL, et al. ASCO 2017. Abstract 4001.
Stratified by region (Asia-Pacific vs Western),
MVI and/or EHS (yes vs no), ECOG PS (0 vs
1), and BW (< vs ≥ 60 kg)
 Primary endpoint: OS
– Noninferiority margin 1.08; criteria
met if upper limit of 2-sided 95% CI
for HR < 1.08
 Secondary endpoints: PFS, TTP, ORR,
QoL, lenvatinib PK
 Other endpoints: DCR, CBR,
exploratory biomarker analysis

20. Cheng AL, et al. ASCO 2017. Abstract 4001. Reproduced with permission.
Probability
of
OS
Mos
Pts at Risk, n
Median, mos (95% CI)
Lenvatinib: 13.6 (12.1−14.9)
Sorafenib: 12.3 (10.4−13.9)
1.0
0.8
0.6
0.4
0.2
0
HR: 0.92 (95% CI: 0.79-1.06)
0.9
0.7
0.5
0.3
0.1
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
478
476
436
440
374
348
297
282
253
230
207
192
178
156
140
116
102
83
67
57
40
33
21
16
8
8
2
4
0
0

21. Cheng AL, et al. ASCO 2017. Abstract 4001. Reproduced with permission.
Probability
of
PFS
Mos
Pts at Risk, n
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
478
476
345
262
223
140
172
94
106
56
69
41
44
33
28
22
14
14
9
9
4
4
2
2
0
2
0
0
Median, mos (95% CI)
Lenvatinib: 7.4 (6.9−8.8)
Sorafenib: 3.7 (3.6−4.6)
HR: 0.66 (95% CI: 0.57-0.77)
Log-rank test: P < .00001

22. Adult patients with advanced HCC
who experienced PD after
sorafenib; may have received up to
two previous systemic regimens;
Child-Pugh class A; ECOG 0/1
(N = 707)
Cabozantinib 60 mg PO QD
(n = 470)
Placebo PO QD
(n = 237)
Abou-Alfa. NEJM. 2018;379:54.
Until loss of clinical
benefit or unacceptable
toxicity

23. Mos
42
0 3 6 9 12 15 21 24 27 30 33 36 39
18
Probability
of
OS
1.0
0.8
0.6
0.4
0.2
0
Cabozantinib
Placebo
Mos
24
0 3 6 9 12 15 21
18
1.0
0.8
0.6
0.4
0.2
0
Cabozantinib
Placebo
Probability
of
PFS
Abou-Alfa. NEJM. 2018;379:54.
Median OS, Mos
Cabozantinib
Placebo
10.2
8.0
HR: 0.76 (95% CI: 0.63-0.92;
P = .005)
Median PFS, Mos
Cabozantinib
Placebo
5.2
1.9
HR: 0.44 (95% CI: 0.36-0.52;
P < .001)

24. Patients with advanced
HCC, AFP > 400 ng/mL,
BCLC stage B/C,
Child-Pugh class A, ECOG
0/1, prior sorafenib
(N = 292)
Treatment continued until
unacceptable toxicity or
withdrawal
Ramucirumab + BSC
8 mg/kg IV Q2W
(n = 197)
Placebo + BSC
Q2W
(n = 95)
1. Zhu. Lancet Oncol. 2019;20:282. 2. Zhu. Lancet Oncol. 2015;16:859.
 Primary endpoint: OS; secondary endpoints: PFS, ORR, time to radiographic progression, time to FHSI-8 score
decline, time to ECOG PS decline

25. Mos Since Randomization
0 3 6 9 12 15 18 21 24 27
OS
(%)
100
80
60
40
20
0
Mos Since Randomization
0 3 6 9 12 15 18 21 24
PFS
(%)
100
80
60
40
20
0
Median OS, Mos
Ramucirumab
Placebo
8.5
7.3
HR: 0.710 (95% CI: 0.531-0.949;
P = .0199)
Median PFS, Mos
Ramucirumab
Placebo
2.8
1.6
HR: 0.452 (95% CI: 0.339-0.603;
P < .0001)
Zhu. Lancet Oncol. 2019;20:282.

28. 1. SOR/LENV
2. ICI+ TKI
3. ICI+ ICI
4. ICI+ ANTI VEGF
5. ICI+ ICI + ANTI VEGF

34. Greten TF, et al. Gut. 2015;64:842-848.

35. Greten TF, et al. Clin Cancer Res. 2013;19:6678-6685.
Tumor
ablation
Antibody
Dendritic
cells
Peptides
Cytokines
T-cell activation
and priming
CTL mediated lysis
T-cell
activation
T-cell
Enhanced
T-cell function
Foxp3+ Treg
MDSC
IL-10, TGF-β
Oncolytic
virus
Antibody
Cancer vaccines
Elimination of
suppressor cells
Blockade of
immunosuppressive
cytokines
Checkpoint
blockade
Cytokines (GM-CSF,
IL-2, IFN-γ, etc)
Tumor cell
death

36. El-Khoueiry AB, et al. Lancet. 2017;[Epub ahead of print].
Dose Escalation (n = 48)
3 + 3 design
Dose Expansion (n = 214)
3 mg/kg
Without
viral
hepatitis
0.1 mg/kg
(n = 1)
0.3 mg/kg
(n = 3)
1.0 mg/kg
(n = 3)
3.0 mg/kg
(n = 3)
10 mg/kg
(n = 13)
n = 6 n = 9 n = 10 n = 10 n = 13
HCV
infected
0.3 mg/kg
(n = 3)
1.0 mg/kg
(n = 4)
3.0 mg/kg
(n = 3)
HBV
infected
0.1 mg/kg
(n = 5)
0.3 mg/kg
(n = 3)
1.0 mg/kg
(n = 3)
3.0 mg/kg
(n = 4)
Sorafenib untreated or intolerant
(n = 56)
Sorafenib progressor
(n = 57)
HCV infected
(n = 50)
HBV infected
(n = 51)
Phase I/II

37. El-Khoueiry AB, et al. Lancet. 2017;[Epub ahead of print].
Sorafenib Untreated or Intolerant Without Viral Hepatitis
Change
From
Baseline
in
Target
Lesion
Tumor
Burden
(%)
100
75
50
25
0
-25
-50
-75
-100
Sorafenib Progressor Without Viral Hepatitis
Change
From
Baseline
in
Target
Lesion
Tumor
Burden
(%)
100
75
50
25
0
0 72
60
48
36
24
12 66
54
42
30
18
6
0 72
60
48
36
24
12 66
54
42
30
18
6
-25
-50
-75
-100
HCV Infected
100
75
50
25
0
-25
-50
-75
-100
100
75
50
25
0
0 72
60
48
36
24
12 66
54
42
30
18
6
0 72
60
48
36
24
12 66
54
42
30
18
6
-25
-50
-75
-100
HBV Infected
Wks on Treatment
Wks on Treatment
First occurrence of new lesion
Off treatment
% change truncated to 100%
CR or PR
Slide credit: clinicaloptions.com

38. Outcome Uninfected
Untreated/intolerant (n
= 56)
Uninfected
Progressor
(n = 57)
HCV Infected
(n = 50)
HBV
Infected
(n = 51)
All Pts
(N = 214)
ORR, % 23 21 20 14 20
 CR 0 4 0 2 1
 PR 23 18 20 12 18
 SD 52 40 46 41 45
 PD 23 32 28 45 32
Median OS, mos NR 13.2 NR NR NR
OS at 6/9 mos, % 89/82 75/63 85/81 84/70 83/74
Median PFS, mos 5.4 4.0 4.0 4.0 4.0
El-Khoueiry AB, et al. Lancet. 2017;[Epub ahead of print].

39. Melero I, et al. ASCO GI 2017. Abstract 26.
PD-L1 < 1% PD-L1 ≥ 1%
ORR, n/N (%) 4/26 (15.4) 2/9 (22.2)
PD-L1 < 1% PD-L1 ≥ 1%
ORR, n/N (%) 17/99 (17.2) 8/25 (32.0)
Dose Escalation Dose Expansion
100
50
0
-50
-100
Pts
Change
in
Target
Lesion
Size
From
Baseline
(%)
< 1%
PD-L1: NA
≥ 1% < 1%
PD-L1: NA
≥ 1%
Pts

40. Event, %
0.1 mg/kg (n = 6) 0.3 mg/kg (n = 9) 1 mg/kg (n = 10) 3 mg/kg (n = 10) 10 mg/kg (n = 13) All Pts (N = 48)
Any
Grade
Grade 3/4
Any
Grade
Grade 3/4
Any
Grade
Grade 3/4
Any
Grade
Grade 3/4
Any
Grade
Grade 3/4
Any
Grade
Grade 3/4
Serious TRAEs* 17 17 11 11 0 0 0 0 8 0 6 4
AEs leading to d/c 0 0 11 11 0 0 10 10 8 8 6 6
Pts with TRAE 67 33 89 33 80 50 90 20 85 0 83 25
TRAEs
 Rash
 Pruritus
 Diarrhea
 Anorexia
 Fatigue
 Asthenia
 Weight ↓
 Nausea
 Dry mouth
17
33
0
17
17
0
0
0
0
0
0
0
0
17
0
0
0
0
22
33
33
22
22
11
11
11
11
0
0
0
0
0
0
0
0
0
20
0
0
10
10
0
0
0
10
0
0
0
0
0
0
0
0
0
20
10
10
0
0
10
0
10
0
0
0
0
0
0
0
0
0
0
31
23
8
8
0
8
15
8
8
0
0
0
0
0
0
0
0
0
23
19
10
10
8
6
6
6
6
0
0
0
0
2
0
0
0
0
Laboratory TRAEs
 AST ↑
 ALT ↑
 Lipase ↑
 Amylase ↑
 Anemia
 Albumin ↓
 Hyponatremia
0
0
17
17
0
0
0
0
0
17
0
0
0
0
22
22
11
0
11
11
0
22
22
0
0
0
0
0
30
10
40
40
10
10
20
20
0
40
10
10
0
0
10
20
20
20
0
0
0
10
10
10
10
0
0
0
31
15
15
15
15
8
8
0
0
0
0
0
0
0
21
15
21
19
8
6
6
10
6
13
4
2
0
0
El-Khoueiry AB, et al. Lancet. 2017; [Epub ahead of print]
*No treatment-related deaths

41. 1. Finn. JCO. 2020;38:193. 2. Zhu. Lancet Oncol. 2018;19:940.
Patients with advanced HCC with
intolerance to or PD on or after sorafenib;
Child-Pugh A; BCLC stage B/C; ECOG PS ≤1;
no invasion of main portal vein
(N = 413)
Placebo + BSC
(n = 135)
Pembrolizumab 200 mg Q3W + BSC
(n = 278)
 Coprimary endpoints: PFS,* OS
‒ Efficacy boundaries: PFS at first interim
cutoff, P = .0020 (primary analysis for
PFS); OS at final analysis cutoff, P = .0174
 Secondary endpoints: ORR,* DoR, DCR,
TTP, safety
*PFS, secondary response outcomes centrally reviewed.

42. respecified P = .0174 [OS] and P = .002 [PFS] required)
 (median 10.6-13.8 mo)
Finn. JCO. 2020;38:193. Merle. ASCO GI 2021. Abstr 268. Finn. ASCO 2021. Abstr 4072.
0
20
40
60
80
100
OS
(%)
0 4 8 12 16 20 24 28 32 36 40 44 48
Mo
0
20
40
60
80
100
OS
(%)
0 4 8 12 16 20 24 28 32 36 40 44
Mo
24-mo rate
11.8%
4.8%
24-mo rate
28.8%
20.4%
36-mo rate
17.7%
11.7%
Pembrolizumab
Placebo
Median OS, Mo (95% CI)
13.9 (11.6-16.0)
10.6 (8.3-13.5)
HR (95% CI) 0.77 (0.62-0.96)
Nominal P = .0112
36-mo rate
9.0%
0
Pembrolizumab
Placebo
Median PFS, Mo (95% CI)
3.3 (2.8-4.1)
2.8 (1.6-3.0)
HR (95% CI) 0.70 (0.56-0.89)
Nominal P = .0011

43. 1. Finn. NEJM. 2020;382:1894. 2. Lee. Lancet Oncol. 2020;21:808.
Treatment until
PD or intolerable
toxicity
Patients with locally advanced
or metastatic and/or
unresectable HCC with no
previous systemic therapy,
Child-Pugh A, and
ECOG PS ≤ 1*
(N = 501)
Atezolizumab 1200 mg Q3W +
Bevacizumab 15 mg/kg Q3W
(n = 336)
Sorafenib 400 mg BD
(n = 165)
 Coprimary endpoints: OS and PFS

44. 0
20
40
60
80
100
Median follow-up: 15.6 mos.
Finn. NEJM. 2020;382:1894. Finn. ASCO GI 2021. Abstr 267.
Median OS, mos
(95% CI)
Atezo + Bev
(n = 336)
19.2
(17.0-23.7)
Sorafenib
(n = 165)
13.4
(11.4-16.9)
Stratified HR (95% CI) 0.66 (0.52-0.85)
P = .0009
OS
(%)
0 2 4 6 8 10 12
Mos
6-mo OS
85%
14 16 18 20 22 24 26 2829
72%
12-mo OS
67%
56%
18-mo OS
52%
40%
0
20
40
60
80
100
PFS
(%)
Mos
6-mo PFS
55%
0 2 4 6 8 10 12 14 16 18 20 22 24 2627
38%
12-mo PFS
35%
21%
18-mo PFS
24%
12%
Median PFS, mos
(95% CI)
Atezo + Bev
(n = 336)
6.9
(5.7-8.6)
Sorafenib
(n = 165)
4.3
(4.0-5.6)
Stratified HR (95% CI) 0.65 (0.53-0.81)
P = .0001

45. Cheng. ESMO Asia 2019. Abstr LBA3. Finn. NEJM. 2020;382:1894.
≥ 10% frequency in either arm and > 5% difference between arms.
60 50 40 30 20 10 0 10 20 30 40 50 60
Diarrhea
PPE
Decreased appetite
Hypertension
Abdominal pain
Alopecia
Asthenia
Pyrexia
ALT increased
Proteinuria
Infusion-related
reaction
All-grade AEs
Grade 3/4 AEs
Atezo + Bev Sorafenib

46. 1. Finn. JCO. 2020;38:2960. 2. Kelley. ASCO 2020. Abstr 4508. 3. Abou-Alfa. NEJM. 2018;379:54.
4. Agarwal. ESMO 2018. Abstr 872P. 5. Yau. ASCO 2019. Abstr 4012.
Trial Treatment Key Supporting Data
LEAP-002
(NCT03713593)
Lenvatinib + pembrolizumab
vs lenvatinib
 KEYNOTE-524 (phase Ib study*): ORR 36%,† mOS
22 mos with lenvatinib + pembrolizumab (N = 104)[1]
HIMALAYA
(NCT03298451)
Durvalumab ± tremelimumab
vs sorafenib
 Study 22 (phase I/II study*): ORR 24%†, mOS 19 mos
with a single dose of tremelimumab 300 mg followed
by monthly durvalumab (N = 332)[2]
COSMIC-312
(NCT03755791)
Cabozantinib + atezolizumab
vs sorafenib
 Cabozantinib active 2L and 3L therapy for HCC
(phase III CELESTIAL study); early studies in solid
tumors suggest efficacy of combination[3,4]
CheckMate 9DW
(NCT04039607)
Nivolumab + ipilimumab
vs sorafenib or lenvatinib
 CheckMate 040 (phase Ib study*): ORR up to 32%,†
mOS up to 23 mos (N = 148)[5]
*Patients previously treated with systemic therapy included. †RECIST v1.1.

48. Based on RCTs Based on non-randomized trials
Regorafenib Cabozantinib
Pembrolizumab
Ramucirumab
Nivolumab
+ ipilimumab
Lenvatinib
Sorafenib
Atezo + bev
Nivolumab

49. Regorafenib
OS vs placebo
Cabozantinib
OS vs placebo
Ramucirumab
OS vs placebo for
AFP ≥ 400 ng/mL
Sorafenib
Better than placebo
Nivolumab or lenvatinib
Not worse than sorafenib
Pembrolizumab,
nivolumab ± ipilimumab
Some durable responses
Atezolizumab + bevacizumab
Better than sorafenib
Anti-VEGF I-O