Download Advanced stage HCC Management

Advanced stage HCC Management
Patients with advanced HCC have a
poor prognosis
Overall, 70–80% of patients with HCC present with
intermediate/advanced disease at diagnosis, limiting use of potentially
curative treatments1
Prognosis for patients with advanced disease is very poor2
Univariate and multivariate analysis has been used to assess OS among
102 patients with HCC:2
 No patient was suitable for radical therapies* or presented with end-stage disease†
Disease stage
Intermediate
Advanced
1 year
80
29
OS (%)
2 years
65
16
3 years
50
8
OS = overall survival.
*Surgical resection, liver transplantation or ethanol injection.
†Okuda stage 3 or performance status ≥3.
1. Llovet JM. Gatroenterology 2005; 40: 225–235. 2. Llovet JM. Hepatology 1999; 29: 62–67.
No survival benefit demonstrated for systemic
therapies for advanced HCC
Before the introduction of sorafenib, no systemic therapy (used either as mono- or
combination therapy) had shown a consistent survival benefit for patients with
advanced HCC
Survival
Hormone analogues
Tamoxifen vs. Placebo1
1 year: 23% vs. 20%
Anti-androgens* + tamoxifen vs. Tamoxifen2
1 year: 23% vs 28%
Octreotide vs. Placebo3
Median OS: 1.9 m vs. 1.9 m
Chemotherapy
Doxorubicin vs. PIAF4
Median OS: 8.7 m vs. 6.8 m
Seocalcitol vs. Placebo5
Median OS: 9.6 m vs. 9.2 m
Nolatrexed vs. Doxorubicin6
Median OS: 5.2 m vs. 7.5 m
NOTE: expected median OS for patients with advanced HCC receiving BSC is 7.9 months (SHARP study)7
HCC, hepatocellular carcinoma; PIAF, Cisplatin/interferon-α-2b/doxorubicin/fluorouracil.
1. Barbare JC, et al. J Clin Oncol 2005;23:4338–46; 2. GRETCH. Hepatology 2004;40:1361–9; 3. Pan DY, et al. Hepatobiliary Pancreat Dis Int 2003;2:211–5;
4. Yeo W, et al. J Natl Cancer Inst 2005;97:1532–8; 5. Beaugrand M, et al. J Hepatol 2005;42:abstr 37; 6. ClinicalTrials.gov: NCT NCT00051532; 7. Gish RG, et
al. J Clin Oncol 2007;25;306975.
BCLC Staging System and Treatment Strategy
HCC
Stage 0
Stage A–C
Stage D
PST 0, Child–Pugh A
PST 0–2, Child–Pugh A–B
PST >2, Child–Pugh C
Very early stage (0)
Early stage (A)
1 HCC <2cm
Carcinoma in situ
1 HCC or 3 nodules
<3cm, PST 0
Portal pressure/
bilirubin
Increased
Resection
Multinodular,
PST 0
Portal invasion,
N1, M1, PST 1–2
3 nodules ≤3cm
1 HCC
Normal
Intermediate stage (B) Advanced stage (C) End stage (D)
Associated diseases
No
Liver transplantation
Curative treatments
Yes
PEI/RFA
TACE
Sorafenib
Randomised controlled trials
Symptomatic
treatment
Llovet JM, et al. J Natl Cancer Inst. 2008; 100: 698–711
Sorafenib in HCC
Sorafenib: structure
CF3
O
CI
O
O
N
H
N
H
NH
N
CH3

Sorafenib is an orally active bi-aryl urea

Sorafenib was originally identified through its inhibitory effects on
the serine/threonine kinase Raf-1

Biochemical and cellular mechanistic assays demonstrated further
activity against B-Raf and additional receptor tyrosine kinases,
including VEGFR-2, PDGFR, Flt-3 and c-KIT
VEGFR=vascular endothelial growth factor receptor
PDGFR=platelet-derived growth factor receptor
Wilhelm SM, et al. Cancer Res 2004;64:7099–109
Sorafenib (BAY 43-9006) Inhibited Both Serine/Threonine
and Receptor Tyrosine Kinases in Vitro*
Serine/threonine kinases
Receptor tyrosine kinases
Targets not inhibited
Kinase
IC50 (nM)
CRAF
6
BRAF
22
V600E BRAF mutant
38
VEGFR-2
90
mVEGFR-2
15
mVEGFR-3
20
mPDGFR-b
57
FLT-3
33
KIT
68
FGFR-1
580
MEK-1, ERK-1, EGFR, HER2, c-met, IGFR-1,
PKA, PKB, cdk1/cyclin B, pim-1, PKC-, PKC
* In vitro studies are not intended to imply clinical effectiveness.
1. Wilhelm SM et al. Cancer Res. 2004;64:7099-7109. 2. Data on file. Bayer Pharmaceuticals Corporation.
>10,000
Sorafenib: Dual Mechanism of Action
Tumour cell
Endothelial cell or pericyte
Paracrine
stimulation
PDGF-BB
GF
VEGF-C
VEGFR-2
Mitochondria
GFR
P
Mitochondria
P
RAS
Raf-1
x
P
P
HIF-1
HIF-2
PDGF
VEGF
PDGF
VEGF
Apoptosis
x
P
Apoptosis
Nucleus
ERK
P
x
x
MEK
PDGFR-b
x
RAS
Raf-1
VEGF-A
x
P
MEK
P
ERK
P
P
VEGFR-3
x
Nucleus
Angiogenesis:
Proliferation
Survival
X
Differentiation
Proliferation
Migration
Tubule formation
sorafenib
Modified from Wilhelm S, et al. Mol Cancer Ther 2008; 7: 3129–40
Sorafenib: Therapeutic Indications
Hepatocellular carcinoma
Sorafenib is indicated for the treatment of hepatocellular carcinoma
Renal cell carcinoma
Sorafenib is indicated for the treatment of patients with advanced renal
cell carcinoma who have failed prior interferon-alpha or interleukin-2
based therapy or are considered unsuitable for such therapy.
Nexavar - Summary of Product Characteristics
Preclinical Data
 Sorafenib is active in models of HCC
– inhibits proliferation in vitro
– induces apoptosis in vitro
– decreases pERK phosphorylation in vivo
– decreases vascular density in vivo
– increases apoptosis in tumours in vivo
 Block of tumor cell proliferation and angiogenesis
in a wide variety of tumors
 Broad-spectrum antitumour activity in xenograft models
 Combining sorafenib with a variety of chemotherapeutic agents could
result in additive anti-tumor activity
 Sorafenib is an attractive approach for the treatment of HCC by
simultaneously inhibiting both tumor angiogenesis (VEGF and PDGF
signaling) and tumor cell survival (RAF kinase signaling-dependent
and signaling independent mechanisms)
Liu L et al. Cancer Res 2006; 66(24): 11851-11858; Wilhelm S et al. Cancer Res 2004; 64: 7099-7109;
Richly H et al. Ann of Oncol 2006; 17(5): 866-873
Clinical Studies
Clinical studies that led to the approval of sorafenib for the treatment
of HCC
• Five Phase I open-label, non-randomized, non-controlled,
dose-escalation studies
• Phase II Study of Sorafenib in Patients with Advanced
Hepatocellular Carcinoma
• SHARP: Phase III, randomised, placebo-controlled trial of
sorafenib in patients with advanced hepatocellular carcinoma
• Asia-Pacific Study Phase III, a randomized, placebocontrolled trial sorafenib in patients with advanced
hepatocellular carcinoma
Strumberg D et al. The Oncologist 2007; 12: 426-437;
Furuse J et al. Cancer Sci 2008; 99: 159-165;
Abou-Alfa GK et al. J Clin Oncol 2006; 24: 4293-4300;
Llovet JM, et al. N Engl J Med 2008; 359: 378-90;
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Clinical development of
sorafenib in HCC: Phase I studies
Phase I Studies

Sorafenib has been investigated as monotherapy in 5 Phase I trials,
each following a dose–escalation procedure and different treatment
schedule:
•
•
•
•
•

7 days on/7 days off
21 days on/7 days off
28 days on/7 days off
Continuous dosing
1 day on/7 days off/ continuous dosing
These studies were performed to evaluate:
•
•
•
•
•
•
Safety
Pharmacokinetic profile
Preliminary antitumor activity
Biomarkers
Optimum dosing schedule to achieve effective tumor inhibition
Acceptable level of toxicities
Strumberg D et al. The Oncologist 2007; 12: 426-437; Furuse J et al. Cancer Sci 2008; 99: 159-165
Safety and Tolerability

Generally well tolerated, particularly at doses ≤ 400 mg bid

Toxicities were mostly mild to moderate in severity and easily
manageable

Most DLTs occurred at the highest doses (≥ 600 mg bid)
• most commonly reported DLTs: skin toxicities, HFSR, diarrhea,
and fatigue

The MTD was defined as 400 mg bid continuously in 3 of the
four trials, as this dose was not associated with significant
toxicity; 600 mg bid was determined to be MTD in the 7 days
on/7 days off trial
DLT, dose limiting toxicities; MTD, maximum tolerated dose; HFSR, hand foot skin reaction
Strumberg D et al. The Oncologist 2007; 12: 426-437; Furuse J et al. Cancer Sci 2008; 99: 159-165
Pharmacokinetics and Metabolism

High interpatient pharmacokinetic variability, not related to the
incidence or severity of drug-related adverse events

Relative bioavailability: 38-49%

Elimination half-life: 25-48 hours

Metabolism: primarily hepatic, oxidative metabolism (CYP3A4)
and glucuronidation (UGT1A9)

No age- or body weight or gender-related differences noted

A moderate-fat meal does not change the AUC significantly,
whereas a high-fat meal reduces the AUC by about 30%
Strumberg D et al. The Oncologist 2007; 12: 426-437; Furuse J et al. Cancer Sci 2008; 99: 159-165
Nexavar - Summary of Product Characteristics
Sorafenib: pharmacokinetic summary

Peak plasma concentrations: ~3 hours

99.5% bound to plasma proteins in vitro

Elimination half-life ~25–48 hours

Metabolized primarily in the liver
• Oxidative metabolism via CYP 3A4
• Glucuronidation mediated by UGT1A9

Pharmacokinetic properties unaffected by:
• Age (up to 65 years)
• Gender
• Body weight
• Mild/moderate hepatic impairment
• Mild/moderate renal impairment
Nexavar - Summary of Product Characteristics.
Sorafenib: dose selection for clinical
development

Sorafenib doses of 600/800 mg bid associated with dose-limiting toxicities

Sorafenib 400 mg bid selected for further clinical development
Multiple, twice-daily oral dosing to patients with advanced refractory solid
tumors

AUC0-12
(Geometric mean)
Cmax
(Geometric mean)
12
11
10
9
8
7
6
5
4
3
2
1
0
80
Cmax (mg/L)
AUC0-12 (mg*h/L)
100
60
40
20
0
0
100
200
400
600
Sorafenib (mg)
800
0
100
200
400
600
800
Sorafenib (mg)
Strumberg D et al. J Clin Oncol 2005; 23: 965-972
Tumour Response
Objective responses*
Number of
evaluable
patients*
7 days on/7 days off
19
21 days on/7 days off
32
28 days on/7 days off
41
Continuous dosing
45
PR
(n)
1†
1‡
SD
(n)
PD
(n)
Median TTP
(days)
5
14
42
16
15
69
9
32
63
25
18
83
*136/173 patients were evaluable for antitumor activity across the 4 phase I studies
†In a patient with renal cell carcinoma; ‡In a patient with HCC
PR, partial response; SD, stable disease; PD, progressive disease; TTP, time to progression
Clark JW et al. Clin Cancer Res 2005; 11: 5472-5480; Awada A et al. Br J Cancer 2005; 92: 1855-1861;
Moore M et al. Ann Oncol 2005; 16: 1688-1694; Strumberg D et al. J Clin Oncol 2005; 23: 965-972;
Strumberg D et al. The Oncologist 2007; 12: 426-437
Overall Summary of Phase I Results

Sorafenib was generally well tolerated, most adverse events
were mild to moderate in severity up to the defined MTD of 400
mg bid

High interpatient variability in plasma pharmacokinetics across
these studies not associated with an increased incidence or
severity of toxicity

Sorafenib demonstrated preliminary antitumor activity

Sorafenib 400 mg bid was chosen as the optimal regimen for
phase II/III studies
Strumberg D et al. The Oncologist 2007; 12: 426-437
Clinical development of
sorafenib in HCC: Phase II studies
Phase II Study
Trial Design
137 patients with advanced hepatocellular carcinoma (HCC) received
continuous sorafenib 400 mg twice daily (b.i.d.) in 4-week cycles


Eligibility criteria
• Inoperable HCC
• Child–Pugh A/B
status
• No prior systemic
therapy
sorafenib
400 mg bid
Endpoints
• Efficacy
• Toxicity
• Pharmacokine
tics
• Biomarkers
Abou-Alfa GK et al. J Clin Oncol 2006; 24: 4293-4300
Median Time to Progression (TTP)
Median TTP (independent assessment)
5.5 months (n=137)
Survival distribution function
Survival distribution function
Median TTP (investigator assessment)
4.2 months (n=137)
1.00
0.75
0.50
0.25
0
0
100 200 300 400 500 600 700 800
Time from start of study treatment (days)
1.00
0.75
0.50
0.25
0
0
100
200
300
400
500
Time from start of study treatment (days)
Abou-Alfa GK et al. J Clin Oncol 2006; 24: 4293-4300
Overall Survival (OS)
Median OS (investigator assessment)
Survival distribution function
1.00
9.2 months (n=137)
0.75
0.50
0.25
0
0 100 200 300 400 500 600 700 800
Time from start of study treatment (days)
Abou-Alfa GK et al. J Clin Oncol 2006; 24: 4293-4300
Tumor Response
Best response (n=137) based on independent assessment
Best response
n (%)
PR
3 (2.2)
MR
8 (5.8)
SD*
46 (33.6)
PD (by radiologic assessment)
48 (35.0)
Not available for independent review
32 (23.4)
*To be classified as stable disease (SD), patients needed to have SD for 16 weeks
PR, partial response; MR, minor response; PD, progressive disease
Abou-Alfa GK et al. J Clin Oncol 2006; 24: 4293-4300
Safety Results:
Drug-related Adverse Events (AEs)
Drug-related adverse events in 10% of all 137 patients
All grades
n (%)
Grade 3
n (%)
Grade 4
n (%)
- HFSR
42 (30.7)
7 (5.1)
0
- Rash/desquamation
23 (16.8)
1 (0.7)
0
- Alopecia
14 (10.2)
0
0
41 (29.9)
13 (9.5)
0
- Diarrhoea (without colostomy)
59 (43.1)
11 (8.0)
0
- Nausea
22 (16.1)
0
0
- Anorexia
19 (13.9)
2 (1.5)
0
- Stomatitis
15 (10.9)
1 (0.7)
0
- Vomiting
14 (10.2)
0
0
AE
Dermatology
Constitutional symptoms
- Fatigue
Gastrointestinal
HFSR, hand–foot skin reaction
Abou-Alfa GK et al. J Clin Oncol 2006; 24: 4293-4300
Tumor Necrosis
Tumor necrosis was assessed rigorously in 11 patients
Baseline
Follow-up 1
Follow-up 2
Baseline
Follow-up 1
Follow-up 2
Tumor volume (cm3)
295
341
285
Tumor necrosis (%)
2.1
53.1
51.0
Abou-Alfa GK et al. J Clin Oncol 2006; 24: 4293-4300
Conclusions

Sorafenib was well tolerated and showed antitumor
activity in advanced HCC

Grade 3-4 drug-related toxicities included fatigue
(9.5%), diarrhea (8.0%) and HFSR (5.1%)

No significant pharmacokinetic differences between
Child–Pugh A (CPA) and B (CPB) status patients
Clinical development of
sorafenib in HCC: Phase III studies
Phase III SHARP Trial:
SHARP trial design
Multicenter, double blind, placebo-controlled trial
Eligibility criteria
•
•

Advanced HCC
Child–Pugh A
status
ECOG PS 0–2
No prior
systemic
therapy
Stratification
•
•
•
Region
ECOG PS
(0 vs 1–2)
MVI/EHS
(present/absent)

Sorafenib
400 mg b.i.d.
(n=602)
•
•
Randomization (1:1)


Placebo
Primary endpoints
•
OS
•
TTSP
Secondary
endpoints
•
TTP
•
DCR
•
Safety*
ECOG PS = Eastern Cooperative Oncology Group Performance Status; MVI = macroscopic vascular invasion;
EHS = extrahepatic spread; BID = twice daily; OS = overall survival; TTSP = time to symptomatic progression;
TTP = time to progression; DCR = disease control rate
*Assessed using version 3.0 of the USA National Cancer Institute
Common Terminology Criteria for Adverse Events
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Patient baseline demographics
Variable – n (%)
Male*
Age* – mean years ± SD
Sorafenib (n=299)
Placebo (n=303)
260 (87)
264 (87)
64.9 ± 11.2
66.3 ± 10.2
Region*
Europe and Australia/New Zealand
263 (88)
263 (87)
North America
27 (9)
29 (10)
Central and South America
9 (3)
11 (4)
Hepatitis C only
87 (29)
82 (27)
Alcohol only
79 (26)
80 (26)
Hepatitis B only
56 (19)
55 (18)
Unknown
49 (16)
56 (19)
Other
28 (9)
29 (10)
Absent
90 (30)
91 (30)
Present
209 (70)
212 (70)
Etiology*
MVI and/or EHS*
*No significant difference between arms (p>0.05)
SD = standard deviation; MVI = macroscopic vascular invasion
EHS = extrahepatic spread
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Patient baseline demographics
Variable – n (%)
Sorafenib (n=299)
Placebo (n=303)
ECOG Performance Status*
0
161 (54)
164 (54)
1
114 (38)
117 (39)
2
24 (8)
22 (7)
54 (18)
51 (17)
BCLC stage*
Stage B (intermediate)
Stage C (advanced)
244 (82)
252 (83)
284 (95)
297 (98)
Child–Pugh status*
A
B
14 (5)
6 (2)
Biochemistry* – median (range)
Albumin (g/dL)
3.9 (2.7–5.3)
4.0 (2.5–5.1)
Total bilirubin (mg/dL)
0.7 (0.1–16.4)
0.7 (0.2–6.1)
44.3 (0–208x104)
19%
39%
99.0 (0–5x105)
21%
41%
α-fetoprotein (ng/mL)
Prior therapies: surgical resection
locoregional therapies
*No significant difference between arms (p>0.05)
BCLC = Barcelona Clinic Liver Cancer
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
SHARP patients and Risk Factors
% of Patients With Risk Factor
in SHARP
Sorafenib
(n=299)
29
Asia/Africa*
Europe/N. America
Placebo
(n=303)
27
Japan
All
20%
50%-70%
Hepatitis C
70%
70%
19
19
10%-20%
Hepatitis B
10%-20%
26
26
Alcohol
9
10
Other
10%-20%
≤10%
0
20
40
60
80
Cases (%)
*Excluding Japan
Llovet JM et al. Lancet 2003; 362: 1907-1917; Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Summary of Trial Conduct
902 HCC patients screened
602 patients randomised
Not randomised
n=300
Protocol exclusion
criteria
n=244
Consent withdrawn
n=24
Adverse events
n=15
Death
n=4
Lost to follow-up/missing
n=6
sorafenib (n=299)
Intent-to-treat
Placebo (n=303)
Intent-to-treat
2 did not receive treatment
1 did not receive treatment
Accrual: March 2005 to April 2006
2° interim analysis OS
Events: 321 deaths
date: Oct 17°, 2006
DMC (Data Monitoring Committee)
recommended stopping the trial in
February 2007
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Overall Survival (OS)
Median OS (intention-to-treat)
Sorafenib: 10.7 months – Placebo: 7.9 months
Placebo (n=303)
Sorafenib (n=299)
Survival probability
100
75
50
25
HR: 0.69 (95% CI: 0.55-0.88)
p<0.001
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Months from randomization
CI, confidence interval
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Time to Progression (TTP)
Median TTP (Independent Central Review)
Sorafenib: 5.5 months – Placebo: 2.8 months
Placebo (n=303)
Sorafenib (n=299)
Progression - probability
100
75
50
25
HR: 0.58 (95% CI: 0.44-0.74)
p<0.001
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Months from randomization
CI, confidence interval
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
SHARP Phase III Trial in Advanced HCC:
Sorafenib prolongs OS by 44% and TTP by 74%
Time to Progression
Overall Survival
Sorafenib (n=299) = 10.7 months
Placebo (n=303) = 7.9 months
0.75
0.50
0.25
HR = 0.69 (95% CI: 0.55–0.87)
p<0.001
1.00
Probability
of radiologic progression
Survival probability
1.00
(independent central review)
Sorafenib (n=299) = 5.5 months
Placebo (n=303) = 2.8 months
0.75
0.50
0.25
HR = 0.58 (95% CI: 0.45–0.74)
p<0.001
0
0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17
Time from randomisation (months)
0
1
2
3
4
5
6
7
8
9
10
11
12
Time from randomisation (months)
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Response Assessment*
and TTSP**
Sorafenib
(n=299)
Placebo
(n=303)
Overall response
Complete response (CR)
Partial response (PR)
Stable disease (SD)
Progressive disease (PD)
Progression-free rate at 4 mo
Duration of treatment (Median; weeks)
0
0
7 (2.3%)
2 (0.7%)
211 (71%)
204 (67%)
54 (18%)
73 (24%)
62 %
42 %
23
19
*RECIST; independent review
**FSHI-8 –TSP: No significant differences between treatment groups (p=0.77)
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Exploratory Sub-group
Survival Analysis
Sorafenib benefit
Placebo benefit
0
ECOG PS
1-2
Extrahepatic
spread
Macroscopic
vascular
invasion (VI)
Macroscopic VI/
extrahepatic
spread
No
Yes
No
Yes
No
yes
0.0
0.5
1.0
1.5
Hazard Ratio
Llovet JM, et al. N Engl J Med 2008;359:378-90
SHARP: sorafenib prolonged OS irrespective of
patient characteristics
Median Overall Survival (months)
Sorafenib
Placebo
HR=0.69
HR=0.79
HR=0.75
HR=0.68
HR=0.71
HR=0.52
HR=0.77
HR=0.47
HR=0.59
HR=0.58
HR=0.76
Llovet JM et al. N Engl J Med 2008;359:378–90; Galle P et al. EASL 2008; Bolondi L et al. ASCO-GI 2008;
Craxi A et al. ASCO 2008; Raoul J et al. ASCO 2008; Sherman M et al. ASCO 2008; Bruix J et al. EASL 2009
SHARP: effectiveness of sorafenib in
intermediate and advanced stage disease
Favours sorafenib
Favours placebo
BCLC B
OS
BCLC C
BCLC B
TTP
BCLC C
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
OS = overall survival; BCLC = Barcelona Clinic Liver Cancer;
TTP = time to tumour progression.
Hazard ratio
Bruix J. Presented at EASL April 22–26, 2009; Copenhagen, Denmark: abstract 67.
Adverse Events
Sorafenib (n=297)
Placebo (n=302)
Incidence (%) at grade
Adverse event
Overall incidence
Constitutional symptoms
Fatigue
Weight loss
Dermatology/skin
Alopecia
Dry skin
Hand-foot skin reaction
Pruritus
Rash/desquamation
Gastrointestinal
Anorexia
Diarrhea
Nausea
Vomiting
Hepatobiliary
Liver dysfunction
Pain
Pain, abdomen NOS
Bleeding
p-value for between
group
comparison
Any
3-4
Any
80
3
4
Any
52
3
4
22
9
3
2
1
0
16
1
3
0
<1
0
0.07
<0.001
1.00
0.03
14
8
21
8
16
0
0
8
0
1
0
0
0
0
0
2
4
3
7
11
0
0
<1
<1
0
0
0
0
0
0
<0.001
0.04
<0.001
0.65
0.12
N/A
N/A
<0.001
1.00
0.12
14
39
11
5
<1
8
<1
1
0
0
0
0
3
11
8
3
1
2
1
1
0
0
0
0
<0.001
<0.001
0.16
0.14
1.00
<0.001
0.62
0.68
<1
<1
0
0
0
0
0.496
0.496
8
7
2
1
0
0
3
4
1
1
0
<1
0.007
0.07
0.17
1.00
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Conclusions

Sorafenib prolonged OS versus placebo in advanced
HCC
• median OS 10.7 versus 7.9 months
• HR: 0.69 (95% CI: 0.55-0.88) p<0.001

Sorafenib prolonged TTP versus placebo
• median TTP 5.5 vs 2.8 months
• HR: 0.58 (95% CI: 0.44-0.74) p<0.001

Sorafenib improve OS and TTP in all subgrup patients

Sorafenib was well tolerated with manageable side
effects
Llovet JM, et al. N Engl J Med 2008; 359: 378-90
Asia-Pacific Study Phase III
Asia-Pacific Study was requested by Asian health authorities
Eligibility criteria
•
•
•

Advanced
HCC
Child–Pugh A
status
ECOG PS 0–2
No prior
systemic
therapy
Stratification
•
•
•
Region
ECOG PS
(0 vs 1–2)
MVI/EHS
(present/absen
t)
n=150
Sorafenib
400 mg b.i.d.
(n=226)
•
Randomization (2:1)


End points
•
Overall survival
•
Time to symptom
progression
•
Time to
progression
•
Response
(RECIST)
•
Safety
n=76
Placebo
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Overall Survival (OS)
Sorafenib: 6.5 months (95% Cl: 5.6-7.6) – Placebo: 4.2 months (95% Cl: 3.7-5.5)
Placebo
sorafenib®
Survival probability
1.00
0.75
0.50
0.25
HR (S/P): 0.68 (95% CI: 0.50-0.93)
p=0.014
0
0
2
4
6
8
10
12
14
16
18
20
22
Months
Patients at risk
Sorafenib
150
134
103
78
53
32
21
15
13
4
1
0
Placebo
76
62
41
26
23
15
9
5
4
1
0
0
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Time to Progression (TTP)
Sorafenib: 2.8 months (95% Cl: 2.6-3.6) - Placebo: 1.4 months (95% Cl: 1.3-1.5)
Placebo
sorafenib®
Progression-free probability
1.00
0.75
0.50
0.25
HR (S/P): 0.57
(95% CI: 0.42-0.79)
p<0.001
0
0
2
4
6
8
10
12
14
16
18
20
22
Months
Patients at risk
Sorafenib
150
80
38
19
11
8
5
2
1
0
0
0
Placebo
76
19
10
8
3
0
0
0
0
0
0
0
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Adverse Events
Adverse event %
Overall incidence
Sorafenib (n=149)
Placebo (n=75)
Incidence (%) at grade
Any
3/4
Any
3/4
81.9
38.7
Drug related adverse eventsin ≥10% of patients in anystudy group
Constitutional symptoms
Fatigue
Dermatology/skin
Alopecia
Hand-foot skin reaction
Rash/desquamation
Gastrointestinal
Anorexia
Diarrhea
Nausea
Hypertension
20.1
3.4
8.0
1.3
24.8
45.0
20.1
0
10.7
0.7
1.3
2.7
6.7
0
0
0
12.8
25.5
11.4
18.8
0
6.0
0.7
2.0
2.7
5.3
10.7
1.3
0
0
1.3
0
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Sorafenib: standard of care in
Child–Pugh B patients?
Treatment-related AEs (%)2

Child–Pugh A (n = Child–Pugh B (n =
98)
38)
A growing body of
All
97
97
evidence from
All serious AEs
52
68
independent studies
Fatigue
41
37
HFSR
30
13
Diarrhea
59
47
Bilirubin increase
18
40
Pugh B liver
Ascites
11
18
function1–12
Encephalopathy
2
11
24.9 weeks
12.9 weeks
31%
21%
suggests that
sorafenib may be
tolerable in selected
patients with Child–
Length of therapy
Dose reductions
1. Bruix J, Sherman M. Hepatology. In press 2010.
Available from http://www.aasld.org. Last accessed September 2010.
2. Abou-Alfa GK, et al. J Clin Oncol. 2006; 24: 4293-00.
3. Furuse J, et al. ILCA 2007, Barcelona, Spain.
4. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V1.2010. Available
from: www.nccn.org. Last accessed September 2010.
5. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
6. Omata M, et al. Hepatol Int. 2010;4:439–474
7. Sorafenib EU Summary of Product Characteristics.
8. Reig M, et al. AASLD 2008. San Francisco, CA, USA [abstract 1476].
9. Ertle J, et al. ILCA 2008. Chicago, IL, USA [abstract p120].
10. Worns MA, et al. J Clin Gastroenterol. 2009;43:489-95.
11. Pinter M, et al. Oncologist. 2009;14:70-6.
12. Yau T, et al. Cancer. 2009;115:428-36.
The pharmacokinetic profile of sorafenib is not
significantly different in Child–Pugh A and B patients1
In a phase 2 study of patients with unresectable HCC receiving 400 mg b.i.d. of sorafenib,
Child–Pugh A and B patients had similar plasma concentrations of sorafenib2
Plasma concentration (mg/L)
10
Child–Pugh A (n = 98)
Child–Pugh B (n = 38)
8
6
4
2
0
0
2
4
6
8
Time (hours)
10
12
1. Bruix J, Sherman M. Hepatology. 2010 In press. Available from http://www.aasld.org. Last accessed September 2010.
2. Abou-Alfa GK, et al. J Clin Oncol. 2006;24:4293-300.
Current recommendations for treating
Child–Pugh B patients with sorafenib

NCCN guidelines1
•

AASLD guidelines2 and BCLC treatment algorithm3
•


sorafenib is recommended for patients with advanced HCC, performance
status 1–2, and Child–Pugh A or B liver function
APASL guidelines4
•

sorafenib is recommended for selected patients with Child–Pugh class A or B liver function with
unresectable (extensive liver disease, ECOG PS1–2, inadequate hepatic reserve) or metastatic
HCC
sorafenib is recommended for the treatment of advanced stage patients (portal vein invasion or
extrahepatic spread) with Child–Pugh A or B liver function
EMEA: EU SmPC (EU summary of product characteristics)5
•
no dose adjustment of sorafenib is required in Child–Pugh B patients
•
caution is recommended in treating patients with Child–Pugh B liver function with sorafenib1,2,4
The prospective, non-interventional GIDEON study will provide the largest data set on the safety and
efficacy of sorafenib in HCC patients, including those with Child–Pugh B liver dysfunction6
1. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer.
V2.2010. Available from: www.nccn.org.
2. Bruix J, Sherman M. Hepatology. In press 2010.
Available from http://www.aasld.org. Last accessed September 2010.
3. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
4. Omata M, et al. Hepatol Int. 2010;4:439–474
5. Sorafenib EU Summary of Product Characteristics.
6. http://clinicaltrials.gov/ct2/show/NCT00812175.
Analysis of sorafenib
RCT in HCC
Trial design and characteristics of patients
Variables
Asia Pacific
SHARP
Multiple
OS, TTSP
Randomization ratio
2:1
1:1
Sample size
226
602
Geographical region
Asia
Europe/America/Pacific
Age (median)
51 yr
65 yr
HBV (75%)
HCV 28%, alcohol 26%
HBV 18%
End points
Target population
Etiology
Tumor status –BCLC
Advanced (95%)
Extrahepatic spread
69%
51%
26% vs 74%
54% vs 46%
97%
95%
ECOG 0 vs 1-2
Child-Pugh A
Advanced (82%)
Intermediate (18%)
Llovet JM, et al. N Engl J Med 2008; 359: 378-90. Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Analysis of sorafenib
RCT in HCC
Summary of efficacy measures and toxicities
Variables
Asia Pacific
SHARP
6.5 mo vs 4.2 mo
10.7 mo vs 7.9 mo
0.68 (95%CI, 0.50-0.93)
0.014
0.69 (95% CI, 0.55-0.87)
<0.001
2.8 mo vs 1.4 mo
5.5 mo vs 2.8 mo
0.57 (95% CI, 0.42-0.79)
<0.001
0.58 (95% CI, 0.45-0.74)
<0.001
<3%
<3%
81.9 %
80%
45% (11%)
21% (8%)
Overall survival
Median OS
Magnitude benefit (HR)
p value
Time to progression
Median TTP
Magnitude benefit (HR)
p value
Objective response rate
Drug-related AEs
Overall
Hand-foot Sd. (Any: grade 3-4)
Llovet JM, et al. N Engl J Med 2008;359:378-90. Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Levels of evidence in the assessment of benefits
in HCC treatment
Treatments assessed
Benefit
Evidence
Increased survival
Uncertain
Increased survival
Treatment response
3iiA
1iiA
3iiA
2iiDiii
Increased survival
3iiA
Better local control
Increased survival
Treatment response
Treatment response
1iiD
1iiA
3iiDiii
3iiDiii
Increased survival
No benefit
No benefit
No benefit
1iA
1iA
1iiA
1iiA
Surgical treatments
Surgical resection
Adjuvant therapies
Liver transplantation
Neoadjuvant therapies
Locoregional treatments
Percutaneous ablation
Ethanol injection
Radiofrequency ablation
Chemoembolization
Arterial chemotherapy
Internal radiation (I131, Y90)
Systemic treatments
Sorafenib
Tamoxifen
Systemic chemotherapy
Interferon
Classification of evidence adapted from the National Cancer Institute (from Llovet JM, et al. J Natl Cancer Inst 2008;100:698-711)
Level 1 = Randomized, controlled trial, meta-analysis (double-blinded, 1i; non-blinded, 1ii)
Level 2 = Non-randomized controlled trial
Level 3 = Case series (population-based, 3i; non-population-based, consecutive; 3ii; non-population-based, non-consecutive, 3iii)
Endpoints: A = Survival, B = Cause-specific mortality, C = quality of life, D = indirect surrogates (DFS, PFS, tumor response)
Llovet JM et al J Natl Cancer Inst 2008;100: 698 – 711
Improvement in Oncology…
Tumor type
Treatment (n)
Primary
End-Point
Secondary
HCC
Sorafenib (n=299)
Placebo (n=303)
OS
HR 0.69 (0.55-0.87)
TTP
HR 0.58 (0.45-0.74)
OS
PFS
HR 0.61 (0.51-0.74)
NSCLC
Erlotinib (n=488)
Placebo (n=243)
HR 0.70 (0.58-0.85)
Colon
Chemotherapy + bevacizumab (n=402)
Chemotherapy (n=411)
OS
HR 0.66
PFS
HR 0.54
Breast
Chemotherapy + trastuzumab (n=1672)
Chemotherapy (n=1679)
PFS
HR 0.48 (0.39-0.59)
OS
HR 0.67 (0.48-0.93)
Llovet JM and Bruix J. J Hepatol 2008; 48 Suppl 1: S20-37
Sorafenib in the treatment of HCC: conclusions
•
Sorafenib is a multikinase inhibitor that target both tumor
cell proliferation and tumor angiogenesis
•
Sorafenib is the first systemic therapy to prolong survival in
HCC patients
•
Sorafenib has been shown to prolong survival and delay
progression across a broad range of patient groups
•
Sorafenib is generically well tolerated with a predictable
side-effect profile
•
Sorafenib is the new reference standard for systemic
therapy of HCC patients
Importance of Biomarkers in Cancer


Roles of biomarkers in cancer research:
•
Screening, prognosis, predicting drug metabolism
•
Predicting drug response: identification of patients who would benefit most from specific molecular
targeted therapies
Targeted Therapies:
Agent
Cancer Type
Validated Biomarker
Trastuzumab
Breast
HER2+ (IHC, FISH)1
CML/ALL
Ph+ (FISH, PCR)2
GIST
c-Kit+ (IHC)2,3
Colon
K-Ras mutation status (PCR)4
Imatinib
EGFR Inhibitors
(eg, cetuximab)
Herceptin (trastuzumab) PI: San Fransisco, CA, Genentech, Inc. 2002; 2Gleevec (imatinib mesylate) PI: East Hanover, NJ, Novartis Pharma AG.
2003; 3Burger. et al. Cancer Biol Ther. 2005; 4Karapetis et al. N Engl J Med. 2008
Predictors of Survival
Sorafenib and placebo cohorts (multivariate analysis)
Sorafenib Cohort
Multivariate Analysis
Variable
P-value
HR
Macrovascular invasion
0.005
Extrahepatic spread
0.016
2.530
Baseline AFP
0.014
1.473
Baseline alkaline phosphatase
0.001
1.802
Baseline c-KIT
0.006
0.562
Baseline HGF
0.014
1.678
Baseline AFP
0.008
1.599
Macroscopic vascular invasion
<0.001
2.077
Baseline alkaline phosphatase
0.015
0.039
Baseline Ang2
0.002
1.629
Baseline VEGF
0.002
1.979
Placebo Cohort
Llovet et al, EASL 2009.
Baseline plasma c-KIT and Sorafenib
Sorafenib and placebo cohorts (multivariate analysis)
Patients with High Baseline c-KIT
Patients with Low Baseline c-KIT
1.00
1.00
Sorafenib
Median OS = 9.4 months
0.75
Placebo
Median OS = 7.4 months
0.50
0.25
HR = 0.90
Survival Probability
Survival Probability
Sorafenib
Median OS = 14.1 months
Placebo
0.75
Median OS = 8.7 months
0.50
0.25
HR = 0.58
(95% CI: 0.41, 0.81)
(95% CI: 0.66, 1.22)
(n=245)
0
0
2
4
6
8 10 12 14 16 18 20 22 mo
(n=244)
0
0
2
4
6
8 10 12 14 16 18 20 22
Patients with high c-KIT showed a trend of better survival benefit with sorafenib
(interaction P-value=0.081).
Llovet et al, EASL 2009.
Optimizing the Management
of Adverse Events
Safety profile for sorafenib
Common adverse events:
 Hand-foot skin reactions (HFSRs)
 Fatigue
 Diarrhea
 Hypertension
Myocardial ischemia/infarction, congestive heart failure and
increased bleeding have been identified as potential risks with
sorafenib, but were not seen in the SHARP study
HFSRs are generally perceived as the most troublesome
adverse event associated with sorafenib treatment
Nexavar- Summer of Product Cjaracteristic
Sorafenib: Safety and Tolerability Profile
Phase II study
– Diarrhoea (43,1%), hand-foot skin reactions (30,7%), fatigue (29,9%)
– No grade 4-related AE
 Phase III study
– Well tolerated, manageable adverse event profile
– Most common events: diarrhoea, hand-foot skin reactions, anorexia,
alopecia, nausea, weight loss, abdominal pain, bleeding, vomiting
– Serious AE: 13%
– Hypertension: 9%
Simpson D et al. Drugs 2008; 68(2): 251-258
Overview of sorafenib tolerability
Sorafenib is generally well tolerated; in the SHARP study, the
overall incidence of serious adverse events with sorafenib was
comparable to placebo.
Sorafenib
Placebo
(n=297)
(n=302)
Serious treatment-emergent
adverse event, %
52
54
Drug-related treatment-emergent
serious adverse event, %
13
9
Adverse event leading to
discontinuation of study
medication, %
38
37
Llovet JM, et al. N Engl J Med 2008; 359: 378–390
Sorafenib toxicity: RCC vs HCC
All grades
RCC*
Grade 3
HCC**
RCC*
HCC**
Hypertension 12
5
2
2
Diarrhea
38
39
2
8
Nausea
16
11
<1
<1
Vomit
10
5
<1
<1
Fatigue
15
22
2
3
*Escudier B et al. N Engl J Med 2007; 356:125-34
**Llovet JM et al. N Engl J Med 2008; 359:378-90
Sorafenib toxicity: RCC vs HCC
All grades
Grade 3
RCC*
HCC**
RCC*
HCC**
Rash
28
16
<1
<1
Alopecia
25
14
<1
0
HFSR
19
21
4
8
Pruritus
17
8
<1
0
Eritema
15
Xerosis
11
0
8
0
0
*Escudier B et al. N Engl J Med 2007; 356:125-34
**Llovet JM et al. N Engl J Med 2008; 359:378-90
Hand-Foot Skin Reaction (HFSR)
HFSR usually appears during the first 6 weeks of treatment, often as
early a s 1-2 weeks after treatment is started
HFSR refers to a group of signs and symptoms that can affect, usually
bilaterally, the hands and/or feet of patients
Common symptoms of HFSR
 Dysaesthesya, paraesthesia, erythema, oedema, hyperkeratosis, dry and/or
cracked skin callous-like blisters and desquamation
Grade 1
Grade 2
Grade 3
Porta C et al. Clin Exp Med 2007; 7: 127-134; Photos courtesy of Elizabeth Manchen, RN, MS, OCN.
Hand-Foot Skin Reaction (HFSR)
HFSR grading system (modified criteria)
Grade
Clinical Characteristics
1
Numbness, dysaesthesia, paraesthesia, tingling, painless swelling,
erythema or discomfort of hands or feet, which does notdisrupt patient’s
normal activities
2
One or more of the following symptoms: painful erythema, swelling,
hyperkeratosis of the hands or feet, discomfort affectingthe patient’s normal
activities
3
One or more of the following symptoms: moist desquamation, ulceration,
blistering, hyperkeratosis, severe pain of the hands and feet, severe
discomfort that causes the patient to be unable to work or perform daily
activities
Porta C et al. Clin Exp Med 2007; 7: 127-134
Management of HFSR
Early intervention may prevent progression of symptoms
Patients are advised to:
 Wear cotton socks, soft shoes or padded insoles (e.g. silicon ones)
and keep their skin well moisturised with an appropriate lotion
 Apply urea and/or salicylate- containing creams
 Cover hands and feet with cotton socks and gloves (overnight)
Despite these measures, treatment dose reductions may be
needed if signs and symptoms progress and become
distressing. Typically, signs and symptoms of HFSR may not
relapse at treatment restart.
Porta C et al. Clin Exp Med 2007; 7: 127-134
Diarrhea
Changes in bowel habits and stool consistency are common for
patients receiving Sorafenib.
Diarrhea grading system
Grade
Characteristics
1
Increase of <4 stools per day over baseline; mild
increase in ostomy output compared to baseline
2
Increase of 4 – 6 stools per day over baseline; IV fluids
indicated <24hrs; moderate increase in ostomy output
compared to baseline; not interfering with ADL
3
Increase of ≥7 stools per day over baseline;
incontinence; IV fluids ≥24 hrs; hospitalization; severe
increase in ostomy output compared to baseline;
interfering with ADL
4
Life-threatening consequences (e.g., hemodynamic
collapse)
Wood LS. Commun Oncol 2006; 3: 558-562;
Cancer Therapy Evaluation Program, Common terminology Criteria for Adverse Events, Version 3.0, 2006
Management of Diarrhea
 Adding bananas and rice to the diet can help increase stool
consistency
 Fruit or vegetables juices do not appear to aggravate diarrhoea
when taken in normal quantities
 Bulking and antidiarrheal agents may also increase stool
consistency and reduce the frequency of bowel movements
 Loperamide and diphenoxylate should be initiated on a prn basis
 If diarrhoea persists oral antibiotics may be started as prophylaxis
for infection
Wood LS. Commun Oncol. 2006; 3:558-562; Benson Al B et al. J Clin Oncol 2004; 22: 2918-2926
Fatigue
Fatigue is a common compliant among receiving Sorafenib
Is a distressing, persistent, subjective sense of tiredness or exhaustion
that is not proportional to recent activity and interferes with usual
functioning
Most occurs with other symptoms, such as pain, distress, anemia and
sleep disturbances
Fatigue severity is measured on a 10 to 10 rating scale
(0 = no fatigue, 10 = worst fatigue imaginable)
Moderate fatigue is indicated as a score of 4 to 6, severe fatigue
as 7 to 10
Wood LS. Commun Oncol. 2006; 3:558-562; National Comprehensive Cancer Network – Practice Guidelines 2009
Management of Fatigue
Most patients can maintain their normal activity with minor
modifications; for others patients treatment interruption or
dose modification may reduce fatigue
Encourage patients to:
 Stay as active as possible, as that will help them sleep better
 Maintain normal work and social schedules
 Take breaks as needed
 Tell their doctor or nurse if they cannot tolerate activity or if their
fatigue worsens
Wood LS. Commun Oncol 2006; 3: 558-562.