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Final Results From a Phase II, Randomized, Double-blind Study of Sorafenib Plus Doxorubicin Versus Placebo Plus

Doxorubicin in Patients With Advanced Hepatocellular Carcinoma

Authors: Abou-Alfa GK, Johnson P, Knox J, Davidenko I, Lacava J, Leung T, Mori A, Leberre M-A, Voliotis D, & Saltz LB

Date posted: October 22, 2007

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R

Treatment 6 cycles of:•Doxorubicin 60 mg/m2 IV* Day 1 in 21-day cycles•Sorafenib 400 mg po bid

Then Sorafenib 400 mg po bid

Treatment 6 cycles of:•Doxorubicin 60 mg/m2 IV* Day 1 in 21-day cycles•Placebo 2 tablets po bid

Then Placebo 2 tablets po bid

Advanced

Hepatocellular CA

• ECOG 0-2

• Child’s Pugh A

• No Previous

Chemoembolization

N= 96

Primary Outcome: TTP

Randomized Phase II Study

* In approved circumstances , doxorubicin doses of up to 450 mg/m2 allowed

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RESULTS - Demographics

DXR/sorafenib (n=47)

DXR/placebo (n=49)

Gender n (%) Male 31 (66) 42 (86)

Female 16 (34) 7 (14)

Age (years) Mean 63 62

ECOG n (%) 0 22 (47) 16 (33)

1 18 (38) 25 (51)

2/3 4 (9) 4 (8)

Missing 4 (9) 4 (8)

Child’s Pugh n (%) A 47 (100) 48 (98)

B 0 (0) 1 (2)

Extrahepatic disease n (%) Yes 24 (51) 32 (65)

No 23 (49) 17 (35)

Macroscopic Vascular Invasion n (%)

Yes 13 (28) 16 (33)

No 33 (70) 32 (65)

Missing 1 (2) 1 (2)

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RESULTS

• Considering the interim results of the Phase III SHARP trial

(sorafenib vs placebo), an Independent Data Monitoring Committee (DMC) performed an interim analysis in January 2007

• “DMC would advise the sponsor to consider discontinuation of this Phase II trial”

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RESULTS

Adria/

Sorafenib

Adria/

PlaceboP Value

Response Rate (%)

4% 2%

Stable Disease

77% 55%

TTP (median,

mos)8.6 4.8

HR 0.6

P=0.076

PFS (median,

mos) 6.9 2.8

HR 0.57

P=0.012

OS

(median, mos)

13.7 6.5HR=0.45

P=0.0049

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TOXICITY

Adria/

Sorafenib

Gr 3/4

Adria/

Placebo

Gr 3/4

Diarrhea 11% 10%

Febrile Neutropenia

4% 10%

Hand Foot

Syndrome9% 0

LV Dysfunction

2% 0

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STUDY COMMENTARY

• This randomized phase II trial demonstrated a statistically and clinically significant survival benefit for adriamycin and sorafenib vs adriamycin and placebo

• Coupled with the SHARP trial (Sorafenib vs Placebo - Llovet, ASCO 2007) supports growing body of evidence for sorafenib in HCC

• Larger trials necessary to determine optimal role of adriamycin/sorafenib in HCC

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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS

• Sorafenib and adriamycin and sorafenib as a single agent could be considered for use in patients with HCC who are candidates for systemic therapy

•Cost and reimbursement of sorafenib may limit its widespread use in Canada