Sorafenib and HCC: Is It All About VEGF?

Sorafenib and HCC: Is It All About VEGF?

Bert H O'Neil

UNC Lineberger Comprehensive Cancer CenterChapel Hill, NC

Sorafenib Phase II: Child-Pugh B Cirrhosis

TherapyChild-Pugh A

n=98Child-Pugh B

n=38

Length of therapy (weeks) 25 13

Dose reduction 31% 21%

OutcomesChild-Pugh A

n=98Child-Pugh B

n=38

SD (≥4 months) 49% 26%

TTP (median) 21 weeks 13 weeks

OS 41 weeks 14 weeks

OS=overall survival; SD=stable disease; TTP=time to tumor progression.Abou-Alfa GK et al. J Clin Oncol. 2008;26(15S):Abstract 4518.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Adverse Events (Note Half Exposure for C P B Patients)

Events (%)Child-Pugh A

n=98Child-Pugh B

n=38

All adverse events 97 97

Serious adverse events 52 68

Fatigue 41 37

Diarrhea 59 47

Hand-foot syndrome 30 13

Increased bilirubin 18 40

Encephalopathy 2 11

Worsening ascites 11 18

C-P=Child-Pugh.Abou-Alfa GK et al. J Clin Oncol. 2008;26(15S):Abstract 4518.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

GIDEON and C-P B

GIDEON is a registry that tracks the ‘real-world’ use of sorafenib in about 3200 patients in 32 countries without a prespecified hypothesis

The SHARP study was comprised almost exclusively of patients with well-compensated C-P A) cirrhosis

GIDEON can provide us with important information on safety and single-arm efficacy in the C-P B population

GIDEON=Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib; SHARP=Study of Heart and Renal Protection.Llovet J et al. N Engl J Med. 2008;359:378-390.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

GIDEON and C-P B (cont’d)

Similar numbers started with standard dose sorafenib

Mean and median dose was similar

Surprisingly, dose interruptions and modifications were similar

Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Overview of Treatment-Emergent Safety Data by Child-Pugh Status*

% of nTotal†

(n=1571)

Child-Pugh A(<7)

(n=957)

Child-Pugh B(7-9)

(n=367)

Child-Pugh C(>9)

(n=35)

AEs (all Grades) 83 82 89 86

Drug-related AEs (all Grades) 64 67 63 46

AEs (Grade 3/4) 30 29 31 34

Drug-related AEs (Grade 3/4) 23 24 22 23

SAEs‡ 37 29 56 63

Drug-related SAEs‡ 9 8 15 6

AEs resulting in permanent discontinuation of sorafenib§ 28 24 38 51

Deaths║ 22 16 34 37

* Data at study entry; †Child-Pugh status missing or not evaluable for 56 patients; ‡An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death, life-threatening, hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, medically important event; §Any AE; ║Treatment-emergent deaths occurring up to 30 days after last sorafenib dose.

AEs=adverse events; SAEs=serious adverse events.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Total(n=1571)

Child-Pugh A(<7)

(n=957)

Child-Pugh B(7-9)

(n=367)

Child-Pugh C(>9)

(n=35)

≤4 weeks, % 17 13 23 46

>4-8 weeks, % 18 17 23 23

>8-20 weeks, % 35 38 28 23

>20-28 weeks, % 12 13 9 0

>28 weeks, % 16 18 14 6

Median treatment duration, weeks 12 14 9 4

Duration of Sorafenib Therapy by Child Pugh Status*

* Data at study entry.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

30% 46%

Preliminary Time-to-Progression* by Child-Pugh Status† at Study Entry

* TTP was documented radiological disease progression; RECIST v. 1.0 used for tumor evaluation; † 207 patients not evaluable.

RECIST=Response Evaluation Criteria in Solid Tumors.

Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Child-Pugh A (<7)(n=984), median (95% CI) 129 (119, 146) days4.2 months

0.0

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P d

istr

ibu

tio

n f

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cti

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Child-Pugh B (7-9)(n=376), median (95% CI) 109 (93, 140) days3.6 months

Child-Pugh C (>9)(n=36), median (95% CI) 64 (28, 110) days2.1 months

Time since start of treatment (days)

Preliminary Overall Survival by Child-Pugh Status* at Study Entry

* 207 patients not evaluable.

CI=confidence interval.

Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Child-Pugh A (<7)(n=984), median (95% CI) 312 (284, 341) days10.3 months

0.0

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0 100 200 300 400 500 600

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Time since start of treatment (days)

Child-Pugh B (7-9)(n=376), median (95% CI) 147 (126, 189) days4.8 months

Child-Pugh C (>9)(n=36), median (95% CI) 62 (46, 94) days2.0 months

What Does GIDEON Add?

GIDEON suggests that safety is similar between C P A and C-P B patients

However, duration of therapy for the C-P B population was exceedingly short—8.5 weeks

This suggests that equivalent numbers of adverse events occur in a shorter period of time

The low number of dose reductions in the C P B population is also interesting, but is also affected by the short treatment duration


What Does GIDEON Add? (cont’d)

Does GIDEON suggest we should be starting sorafenib at full dose in future studies in the C P B population?

YES

Do GIDEON’s results support the routine use of sorafenib in the C P B population?

NO—this use should be considered investigational and standard of care remains best supportive care

Authors’ conclusions appropriately conservative in this regard

Reminds us that testing drugs in C P A population is best

Adapted from O'Neil BH et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Sunitinib vs Sorafenib

Sunitinib has good efficacy in RCC compared to sorafenib and produced Phase II results in HCC comparable to those seen with sorafenib

Different kinase inhibition profiles might suggest differential activity between these agents in HCC

However, no strong a priori hypothesis regarding non–VEGF-related targets

HCC=hepatocellular carcinoma; RCC=renal cell carcinoma; VEGF=vascular endothelial growth factor.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Cross-Trial Characteristics

SHARPn=299

Asian Studyn=150

Sun vs SorN=544

Median age 65 yrs 52 yrs 59 yrs

Male 87% 85% 84%

Viral hepatitis B/C 19/29% 71/11% 53/22%

Child-Pugh (A/B) 95/5% 97/3% 100/0

ECOG performance status 0/1 54/38% 25/70% 53/47

Vascular invasion/Extrahepatic spread 36/53% 36/69% 31/76%

Surgical resectionLoco-regional therapy

19%48% NR 100%?

ECOG=Eastern Cooperative Oncology Group; NR=no response.Llovet J et al. N Engl J Med. 2008;359:378-390; Cheng AL et al. Lancet Oncology. 2009;10:25-34.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

OS—Primary Endpoint(ITT Population)

Sunitinib 530 354 208 112 41 8 0 0 0

Sorafenib 544 388 245 139 61 12 1 0 0

Time (months)

OS

pro

bab

ility

(%

)

0 5 10 150.0

20 25 30 35 40

SunitinibMedian 7.9 months (95% CI: 7.4-9.2)SunitinibMedian 7.9 months (95% CI: 7.4-9.2)

SorafenibMedian 10.2 months (95% CI: 8.9-11.4)SorafenibMedian 10.2 months (95% CI: 8.9-11.4)

1.00

0.75

0.50

0.25

HR 1.30 (95% CI: 1.13-1.50)P=.0010HR 1.30 (95% CI: 1.13-1.50)P=.0010

Patients at risk

P-value based on stratified log-rank test. CI=confidence interval; HR=hazard ratio.Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

What Can We Learn From This Negative Trial (Other Than the Obvious)?

Was toxicity the main difference-maker?


Overview of Treatment-Emergent AEs(All Causes; As-Treated Population)

Sunitinib(n=526)

Sorafenib(n=542)

Any AE 100% 100%

Serious AEs 45% 37%

Grade* 3 or 4 AEs 82% 74%

Grade* 5 AEs 19% 17%

Discontinued due to AEs 13% 13%

Temporarily discontinued due to AEs 77% 59%

Dose reduced due to AEs 30% 35%

* National Cancer Institute—Common Terminology Criteria for AEs (NCI-CTCAE) v3.0.Adapted from O'Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Deaths on Study*

EventSunitinib(n=526)

Sorafenib(n=542)

Deaths (all causes; n, %) 92 (17%) 83 (15%)

Cause (% of total deaths: SU n=92; SO n=83)†

Disease progression 76% 86%

Toxicity 18% 2%

Dehydration ± organ failure 3% 0

CNS hemorrhage 3% 0

Esophageal varices/GI hemorrhage† 3% 1%

Other/unknown cause 7% 13%

Pneumonia 2% 1%

Septic shock/sepsis 1% 2%

Unknown reason 0 2%

* Deaths during the study or within 28 days after the last dose of study medication. Participants may have more than one cause of death; †Includes deaths attributed to tumor hemorrhage.

CNS=central nervous system; GI=gastrointestinal; SU=sunitinib; SO=sorafenib.Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

What Can We Learn From This Negative Trial (Other Than the Obvious)?

Are there potential biologic explanations for differential results?

VEGFRs?

RAFs

Other?


Kinase Profiles

PDGFRB 0.075 MLCK 23 KIT 0.1

KIT 0.37 TNIK 25 DDRI 1.5

FLT3 0.47 MERTK 26 XAK 6.3

PDGFRA 0.79 CLK4 29 DDR 2 6.6

DRAK 1 1 RIOK1 35 FLT 3 13

VEGFR2 1.5 LKB1 38 PET 13

VEGFR1 (FLT-1) 1.8 PIP5K2B 39 CFS 1R 28

BIKE 5.5 MAP4K5 41 VEGFR1 (FLT-1) 31

PHKG 1 5.5 ARK 5 48 B 37

PHKG 2 5.9 JAK 1 49 FLK 8 46

AXL 9 MYLK2 49 VEGFR2 59

AAK 1 11 TYRO3 49 PDGFRA 62

RET 12 FLT4 50 TIE 1 68

CSNK 1E 13 MST 2 56 FLT 4 95

ITK 13 SLK 56

BRAF V600E 260CSNK 1D 15 MST 3 63

SgK 085 15 TTK 63

MAP4K1 16 BLK 65

RAF1 (c-RAF) 230PAK 3 16 CAMK2A 80

STK 33 17 CSNK 2A1 81

AMPK 1 19 PTK 2B 82

LOK 19 AMPK 2 89

MST 1 19 PLK 100

CLK 2 20 TRKA 100

GAK 20

CLK 1 22

DAPK3 22

Karaman MW et al. Nat Biotechnol. 2008;26(1):127-132.


Sunitinib Sorafenib

Inhibited by Sunitinib

Inhibited by both

Inhibited by Sorafenib

No Activity With MEK Inhibitor Selumetinib (AZ6244) in HCC

O’Neil B et al. J Clin Oncol. 2011; in press.


pERK1/2

ERK1/2

Bas

elin

e

Pos

ttrea

tmen

tB

asel

ine

Pos

ttrea

tmen

t

Bas

elin

e

Pos

ttrea

tmen

tB

asel

ine

Pos

ttrea

tmen

tB

asel

ine

Pos

ttrea

tmen

t

Zero radiographic responsesTTP ≈8 weeks

Sorafenib and HCV-Related HCC

Subgroup analysis of HCV-infected patients in SHARP

Placebo 7.9 mo

Sorafenib group 14 mo

HCV=hepatitis C virus.Bolondi L et al. ASCO GI Annual Meeting; January 25-27, 2008; Orlando, FL.


OS in Patients With HCV Infection(Exploratory Analysis)

P-values based on stratified log-rank test.Adapted from O’Neil BH. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

0,00

0,25

0,50

0,75

1,00

0 5 10 15 20 25 30

OS

pro

bab

ility

(%

)

Time (months)

SunitinibITT

SorafenibITT

SunitinibAsia

SorafenibAsia

SunitinibEx-Asia

Sorafenibex-Asia

Median OS, months 9.2 17.6 9.7 12.6 8.6 18.3

HR (95% CI) 1.52 (1.09-2.13) 1.40 (0.92-2.14) 1.76 (0.99-3.10)

P-value (1-sided) .0165 .0721 .0544

Sunitinib (n=113)Median 9.2 months (95% CI: 7.0-12.0)

Sorafenib (n=119)Median 17.6 months (95% CI: 11.4-)

ITT Population

HR 1.52 (95% CI: 1.09-2.13)P=.0165

HCV NS5A and HCC

Nonstructural HCV protein that interacts with a large number of cellular proteins, including oncogenes

Recent evidence suggests c-RAF is part of the HCV replication complex

Sorafenib produced c-RAF dependent decrease in HCV replication

This effect was not replicated with 2 different MEK inhibitors!

Himmelsbach K et al. Gut. 2009;58:1644-1653.


Himmelsbach K et al. Gut. 2009;58:1644-1653.


Patient 1 Patient 2 Patient 3

Before therapy

During therapy

1.00E-02

1.00E-03

1.00E-04

1.00E-05

1.00E-06

1.00E-07

Ge

no

me

s/m

L

6-cont0

20,000

40,000

60,000

10,000

30,000

50,000

70,00080,00090,000

5 Msorafenib

7.5 Msorafenib

10 Msorafenib

15 Msorafenib

20 Msorafenib

untre

ated

5 M 7.5 M

10

M12

.5

M

15

M20

M

H 2O

HCV

actin

sorafenib

Act

ivit

y

HCV replication inhibition

Do HCV-Associated miRNAs Sensitize Cells to Sorafenib?

miRNA=micro RNA.Braconi C et al. Clin Cancer Res. 2010;16(3)957-966.


Cells transfected with HCV genome Cells transfected with miRNAinduced by HCV

0.001 0.1 10

0

20

40

60

80

100

120

140

0.001 0.1 10 1000

Sorafenib (M)

0

20

40

60

80

100

120Hep-SWX cells

Hep-394 cellsControl pre-miR

Pre-miR-193b

Ce

ll v

iab

ilit

y (

%)

Ce

ll v

iab

ilit

y (

%)

Sorafenib (M)

Summary

Sorafenib can be used with relative safety in the C P B HCC population

But OS appears to be short

Sorafenib was superior to sunitinib for HCC

The superiority of sorafenib over sunitinib in HCV-infected patients raises interesting questions about non–VEGFR-related activities of sorafenib


Do We Need More VEGF Inhibitors for HCC?

Experience in RCC might suggest yes

A better-tolerated VEGFR agent would be welcome

Sunitinib does not fill this role

Others may, including bevacizumab

Studies of brivanib and linifanib vs sorafenib should report in the near future

Caution that Phase II data for all of these agents have looked similar, risk of Phase III trial failure may be high


Sorafenib and HCC: Is It All About VEGF?

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