Final results of phase II, randomized, Final results of phase II, randomized, double-blind study of sorafenib plus double-blind study of sorafenib plus

doxorubicin and placebo plus doxorubicin in doxorubicin and placebo plus doxorubicin in patients with advanced hepatocellular patients with advanced hepatocellular

carcinomacarcinoma

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

Memorial Sloan-Kettering Cancer Center, New York, USA, The University of Memorial Sloan-Kettering Cancer Center, New York, USA, The University of Birmingham, Birmingham, UKBirmingham, Birmingham, UK, Princess Margaret Hospital, Toronto, Canada,, Princess Margaret Hospital, Toronto, Canada, Krasnodar City Oncology Center, Krasnodar, Russia,Krasnodar City Oncology Center, Krasnodar, Russia, Unidad Oncologica de Unidad Oncologica de

Neuquen, Neuquen, ArgentinaNeuquen, Neuquen, Argentina, Hong Kong Sanatorium & Hospital, Hong Kong, , Hong Kong Sanatorium & Hospital, Hong Kong, Bayer Healthcare Pharma, Puteaux, FranceBayer Healthcare Pharma, Puteaux, France, , Bayer HealthCare, FranceBayer HealthCare, France, , Bayer Bayer

HealthCare, West Haven, USAHealthCare, West Haven, USA

HCC and SorafenibHCC and Sorafenib

Hepatocellular carcinoma is the fifth most Hepatocellular carcinoma is the fifth most common cancer worldwide common cancer worldwide

Sorafenib Sorafenib is a VEGFR/PDGFR and raf is a VEGFR/PDGFR and raf kinase inhibitorkinase inhibitor

Sorafenib has shown prolonged overall Sorafenib has shown prolonged overall survival and time to progression in patients survival and time to progression in patients with advanced HCC and Child-Pugh Awith advanced HCC and Child-Pugh A

1. McGlynn, KA., at al. Int J Cancer. 2001 Oct 15;94(2):290-6 2. Wilhelm S et al. Cancer Res. 2004;64:7099-7109 3. Llovet, J, et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: LBA1

Phase I Sorafenib and Doxorubicin Phase I Sorafenib and Doxorubicin PharmacokineticsPharmacokinetics

Concomitant administration of doxorubicin 60 Concomitant administration of doxorubicin 60 mg/m2 and sorafenib revealed a 21% increase mg/m2 and sorafenib revealed a 21% increase in AUC of doxorubicinin AUC of doxorubicin

The toxicity profile was not markedly worse The toxicity profile was not markedly worse compared with that expected with either compared with that expected with either compound administered individually compound administered individually

All 4 patients accrued with HCC (out of 34), had All 4 patients accrued with HCC (out of 34), had stability of disease as best response and stability of disease as best response and remained on therapy for more than one yearremained on therapy for more than one year

Richly, H, et al. Ann Oncol. 2006 May;17(5):866-73. Epub 2006 Feb 24.

Study DesignStudy Design

*Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent

Eligibility

Child-Pugh A

ECOG PS: 0, 1, 2

(1:1

) Ran

dom

izat

ion

(N~9

6)

Period 1 Period 2

Continue until withdrawal, PD, or death

6 cycles of:• Doxorubicin 60 mg/m2 IV*

Day 1 in 21-day cycles• Sorafenib 400 mg po bid

6 cycles of:• Doxorubicin 60 mg/m2 IV*

Day 1 in 21-day cycles• Placebo 2 tablets po bid

Placebo2 tablets po

bid

Sorafenib400 mg po

bid

Study ObjectivesStudy Objectives Primary objective: Primary objective:

TTP, TTP, defined as the time from randomization to defined as the time from randomization to radiological disease progression. radiological disease progression.

Secondary objectives:Secondary objectives: Overall survival (OS)Overall survival (OS) Progression Free Survival (PFS)Progression Free Survival (PFS) Overall response rate (RECIST criteria)Overall response rate (RECIST criteria) Exploratory evaluation of TTP, OS and PFS between Exploratory evaluation of TTP, OS and PFS between

the 2 study populationsthe 2 study populations SafetySafety

Key Inclusion CriteriaKey Inclusion Criteria ≥ ≥ 18 years of age18 years of age Histologically confirmed HCCHistologically confirmed HCC Measurable disease by RECISTMeasurable disease by RECIST ECOG 0-1-2ECOG 0-1-2 Child-Pugh AChild-Pugh A Adequate bone marrow, liver, and kidney Adequate bone marrow, liver, and kidney

functionsfunctions No prior cardiac historyNo prior cardiac history

Key Exclusion CriteriaKey Exclusion Criteria

Prior systemic therapyPrior systemic therapy Prior chemoembolizationPrior chemoembolization EF < 45% or below normal limitEF < 45% or below normal limit Significant GI bleed within 30 daysSignificant GI bleed within 30 days Major surgery within 4 weeksMajor surgery within 4 weeks History of organ allograftHistory of organ allograft

A reasonable sample size of 90 patients was A reasonable sample size of 90 patients was selected given the exploratory nature of the selected given the exploratory nature of the studystudy

Each study population was compared to Each study population was compared to historical control TTP of about 4 monthshistorical control TTP of about 4 months

Each arm had 80% power to detect a Each arm had 80% power to detect a difference of 100% in median TTP compared difference of 100% in median TTP compared to historical controls at type I error rate of 0.1to historical controls at type I error rate of 0.1

All analyses were based on intent-to-treatAll analyses were based on intent-to-treat No interim analysis was plannedNo interim analysis was planned

Statistical DesignStatistical Design

Demographics (n=96)Demographics (n=96)DXR/sorafenib DXR/sorafenib

(n=47)(n=47)DXR/placebo DXR/placebo

(n=49)(n=49)

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

FemaleFemale 16 (34)16 (34) 7 (14)7 (14)

Age (years)Age (years) MeanMean 6363 6262

ECOG ECOG n(%) n(%) 00 22 (47)22 (47) 16 (33)16 (33)

11 18 (38)18 (38) 25 (51)25 (51)

2/32/3 4 (9)4 (9) 4 (8)4 (8)

MissingMissing 3 (6)3 (6) 4 (8)4 (8)

Child-Pugh Status Child-Pugh Status n(%) AA 47 (100)47 (100) 47 (96)47 (96)

BB 0 (0)0 (0) 2 (4)2 (4)

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

NoNo 23 (49)23 (49) 17 (35)17 (35)

Macroscopic Vascular Invasion Macroscopic Vascular Invasion n(%)n(%)

YesYes 13 (28)13 (28) 16 (33)16 (33)

NoNo 33 (70)33 (70) 32 (65)32 (65)

MissingMissing 1 (2)1 (2) 1 (2)1 (2)DXR=Doxorubicin

Interim Analysis of DXR/Sorafenib Interim Analysis of DXR/Sorafenib Randomized Phase II StudyRandomized Phase II Study

Considering the interim results of the Phase III SHARP trialConsidering the interim results of the Phase III SHARP trial11, , an Independent Data Monitoring Committee (DMC) an Independent Data Monitoring Committee (DMC) performed an interim analysis in January 2007performed an interim analysis in January 2007

In this preliminary analysis: “TTP and OS in the In this preliminary analysis: “TTP and OS in the sorafenib/doxorubicin arm appear to be encouraging”sorafenib/doxorubicin arm appear to be encouraging”

““The results for the Phase II trial, although immature, indicate The results for the Phase II trial, although immature, indicate that the patients randomized to receive doxorubicin may be at that the patients randomized to receive doxorubicin may be at a considerable disadvantage.”a considerable disadvantage.”

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

1Llovet, J, et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: LBA1

ResultsResultsDXR/sorafenibDXR/sorafenib

(n=47)(n=47)DXR/placeboDXR/placebo

(n=49)(n=49)TTP (months)TTP (months) 8.68.6 4.84.8

OS (months)OS (months) 13.813.8 6.56.5

PFS (months)PFS (months) 6.96.9 2.82.8

ResponseResponse(CR+PR) n(%)(CR+PR) n(%)

2 (4)2 (4) 1 (2)1 (2)

Response (SD)Response (SD) 36 (77)36 (77) 27 (55)27 (55)

Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 51 events, PFS: 70 events )

1.00

Exploratory Comparison Per Protocol :Exploratory Comparison Per Protocol : Time to Time to Progression Based on Independent Tumor Assessment Progression Based on Independent Tumor Assessment

Prop

ortio

n of

Pat

ient

s

0.00

0.25

0.50

0.75

Months From Randomization0.0 2.5 5.0 7.5 10.0 12.5 15.0 months

STRATA: Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenibDoxorubicin + placebo Censored treatment: Doxorubicin + placebo

Median TTP: Doxorubicin + sorafenib: 8.6 (95% CI: 4.8-12.6) Doxorubicin + placebo: 4.8 (95% CI: 2.2-8) Hazard Ratio: 0.6 p=0.076 Total # of events: 38

Exploratory Comparison Per Protocol: Exploratory Comparison Per Protocol: Overall SurvivalOverall Survival

Surv

ival

Dis

trib

utio

n Fu

nctio

n

0.00

0.25

0.50

0.75

1.00

Months From Randomization0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

STRATA:

Median OS: Doxorubicin + sorafenib: 13.8 (95% CI: 9.1-can not be estimated) Doxorubicin + placebo: 6.5 (95% CI: 4.9-11.3) Hazard Ratio: 0.51 p= 0.0129 Total # of events: 51

Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenibDoxorubicin + placebo Censored treatment: Doxorubicin + placebo

Exploratory Comparison Per Protocol :Exploratory Comparison Per Protocol : Progression-Free Survival Progression-Free Survival Based on Independent Tumor AssessmentBased on Independent Tumor Assessment

Prop

ortio

n of

Pat

ient

s

0.00

0.25

0.50

0.75

1.00

Months From Randomization0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 months

STRATA:Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenibDoxorubicin + placebo Censored treatment: Doxorubicin + placebo

Median PFS: Doxorubicin + sorafenib 6.9 (95% CI: 4.4-10.3) Doxorubicin + placebo 2.8 (95% CI: 2.3-5.2) Hazard Ratio: 0.57 p=0.012 Total # of events: 70

•March 2007 data cut-off•Based on independent radiological assessment population: subjects valid for ITT

-100

-80

-60

-40

-20

0

20

40

60

80

100Doxorubicin + placebo (n=49)Doxorubicin + sorafenib (n=47)

Percent Change in Target Lesion From Baseline Percent Change in Target Lesion From Baseline (Independent Assessment)(Independent Assessment)

Cha

nge

in T

arge

t Les

ion

From

Bas

elin

e (%

) 62% 29%

Safety and Study Drug AdministrationSafety and Study Drug Administration

DXR/sorafenib DXR/sorafenib (n=48)(n=48)

DXR/placebo DXR/placebo (n=49)(n=49)

All cause adverse events (AE) (%)All cause adverse events (AE) (%) 100100 100100

Drug-related AE (%)Drug-related AE (%) 9292 8888

Serious all cause AE (SAE) (%) Serious all cause AE (SAE) (%) 3838 4242

Drug related SAE (%)Drug related SAE (%) 2121 1515

AE leading to discontinuation (%)AE leading to discontinuation (%) 3838 3333

Death within 30 days (%)Death within 30 days (%) 1111 2020

Median daily dose study drug (mg)Median daily dose study drug (mg) 570570 763763

Median total doxorubicin dose (mg/mMedian total doxorubicin dose (mg/m22)) 165165 120120

All Cause Toxicities With > 10% Grade 3-4 Reported Events All Cause Toxicities With > 10% Grade 3-4 Reported Events DXR/sorafenib (n=48)DXR/sorafenib (n=48) DXR/placebo (n=49)DXR/placebo (n=49)

n(%)n(%) All grades All grades Grade 3-4 Grade 3-4 All gradesAll grades Grade 3-4Grade 3-4

FatigueFatigue 35 (75)35 (75) 7 (15)7 (15) 31 (65)31 (65) 7 (15)7 (15)

Abdominal painAbdominal pain 16 (34)16 (34) 5 (10)5 (10) 14 (29)14 (29) 4 (8)4 (8)

NeutropeniaNeutropenia 31 (66)31 (66) 26 (55)26 (55) 29 (60)29 (60) 22 (46)22 (46)

Febrile Febrile NeutropeniaNeutropenia

2 (4)2 (4) 2 (4)2 (4) 7 (15)7 (15) 7 (15)7 (15)

DiarrheaDiarrhea 24 (51)24 (51) 5 (11)5 (11) 12 (25)12 (25) 5 (10)5 (10)

BilirubinBilirubin 16 (34)16 (34) 5 (11)5 (11) 15 (31)15 (31) 3 (6)3 (6)

Hand footHand foot 14 (30)14 (30) 4 (9)4 (9) 2 (4)2 (4) 0 (0)0 (0)

LV DysfunctionLV Dysfunction 9 (19)9 (19) 1 (2)1 (2) 1 (2)1 (2) 0 (0)0 (0)

HypertensionHypertension 8(17) 8(17) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0)

NCI-CTC (version 3); NCI-CTC=National Cancer Institute–Common Toxicity Criteria

ConclusionsConclusions This randomized phase II study of doxorubicin This randomized phase II study of doxorubicin

plus sorafenib and doxorubicin plus placebo, plus sorafenib and doxorubicin plus placebo, showed encouraging TTP and OS outcome for showed encouraging TTP and OS outcome for the doxorubicin plus sorafenib the doxorubicin plus sorafenib

The increased incidence of mostly grade 1-2 left The increased incidence of mostly grade 1-2 left ventricular dysfunction (19%) with the ventricular dysfunction (19%) with the combination requires careful further investigation combination requires careful further investigation

Any synergistic role between sorafenib plus Any synergistic role between sorafenib plus doxorubicin in HCC needs to be further defineddoxorubicin in HCC needs to be further defined

AcknowledgmentsAcknowledgments

All patients who participated in the study and their families

All principal investigators and healthcare teams at each center

Study teams at Bayer and Onyx