JB 11-11 2009

KAROLINSKA INSTITUTET Radiumhemmet, Karolinska Oncology, CCK, Breast-Sarcoma Section & Clinical Trial Unit Professor Jonas Bergh

Sunitinib in Combination with Docetaxel vs. Docetaxel Alone for the First-line Treatment of Advanced Breast Cancer

J Bergh,1 R Greil,2 NL Voytko,3 AN Makhson,4 J Cortes,5 A Lortholary,6 X Huang,7 C Giorgetti,8 KA Kern,7 MR Lichinitser9

1Karolinska Institutet and University Hospital, Sweden; 2Salzburger Landeskliniken, Austria; 3 Kyiv City Oncologic Hospital, Russian Federation; 4City Oncology Clinical Hospital, Russian Federation;

5Hospital General Universitario Vall D'Hebron,Spain; 6Centre Catherine de Sienne, France; 7Pfizer Oncology, USA; 8Pfizer Oncology, Italy; 9National Cancer Research Center, Russian Federation

Sunitinib plus Docetaxel in Advanced Breast Cancer (ABC) − Rationale

● Sunitinib inhibits multiple RTKs

● These RTKs may be of importance in the pathogenesis, microvascular support, and metastatic progression of BC

● Sunitinib alone and in combination with docetaxel inhibited tumor growth and increased survival in preclinical BC models1

● An exploratory clinical study suggested that sunitinib in combination with docetaxel had promising antitumor activity in patients with HER2-negative ABC (N=22):2

– ORR: 74%– Duration of response: 7.2 months– PFS: 8.7 months

1Abrams TJ, et al. Mol Cancer Ther 2003;2:10112Mariani G, et al. J Clin Oncol 2008;26:suppl (abstr 14534)

SUN 1064 Design

Stratification

• ≤2/>2 metastatic sites

• Estrogen receptor status

• Disease-free interval ≤/>12 months

Key eligibility criteria

• HER2-negative ABC

• Measurable or bone-only disease

• Disease-free ≥12 months after neo/adjuvant taxane

• No prior chemotherapy for ABC

Docetaxel 75 mg/m2 IV day 1 q3w

+Sunitinib 37.5 mg po

days 2−15 q3w

N=296

Docetaxel 100 mg/m2 IV q3w

N=297

1:1

RANDOMIZATION

Trial funded and conducted by Pfizer Inc.

Europe

Asia−Pacific

North America

South America

Africa

United Kingdom

FranceGermany

Italy

Spain Turkey

Australia

Korea

Columbia

Argentina

Canada

SUN 1064 was funded by Pfizer Inc.

Editorial support was provided by Wendy Sacks at ACUMED® (Tytherington, UK) and funded by Pfizer Inc.

593 patients; 127 centers; 27 countries

Austria

Belgium

Czech Republic

Finland

HungaryIreland

Netherlands

Panama

Poland

Portugal Romania

RussianFederation

SlovakiaSweden

Ukraine

USA

Endpoints and Statistical Hypothesis

● Primary endpoint: PFS– Hypothesis: 50% increase in median PFS (from 6 to 9 months)

in ITT population (independent central review), based on 285 events, power of 90%, alpha error 0.025, one sided log-rank test

● Secondary endpoints– PFS (investigator assessment)– ORR, duration of response– OS– Safety

● Median follow-up: 18.0 months (95% CI: 17.6−18.4)

Patient Characteristics (ITT Population)

CharacteristicSU + DOC

N=296DOC

N=297

Median age, years (range) 54 (31−84) 56 (28−78)

ECOG performance status 0/1, % 56/42 54/46

Prior neoadjuvant/adjuvant chemotherapy, % 83 82

Anthracycline 77 74

Taxane 19 25

No prior chemotherapy, % 17 17

Estrogen receptor-positive, % 74 70

Triple-negative disease, % 20 23

>2 metastatic sites, % 47 48

Disease-free interval ≤12 months, % 28 28

Treatment Administration (AT Population)

SU + DOCN=295

DOCN=293

SU DOC DOC

Median dose per cycle (range)

37.5 mg*(26−41)

73 mg/m2 (39−87)

96 mg/m2

(65−112)

Median relative dose intensity, % (range)

94(14−142)

92(52−108)

93(57−112)

Median duration of treatment, weeks (range)

26(23−29)

18(17−21)

18(16−19)

Cycles started, median(range)

8(1−32)

7(1−23)

6(1−26)

AT = as-treated*Median daily dose

Objective Response in Patients with Measurable Disease

P=0.001 P=0.016

55%

42%

58%

Investigator assessment

Central review

Median duration of response (months):

70

60

50

40

30

20

10

0

Ob

ject

ive

resp

on

ses

(%)

SU + DOC n=269

7.5

DOC n=269

7.2

SU + DOC n=269

6.9

DOC n=269

5.8

48%

CRPR

Patients at risk

SU + DOC 296 241 162 80 40 19 8 2 0

DOC 297 224 96 43 23 16 6 2 2

Progression-free Survival(Central Review; ITT Population)

SU + DOCN=296

DOCN=297

PFS events, n (%) 147 (50) 109 (37)

Median, months 8.6 8.3

HR (95% CI) 0.92 (0.72−1.19)

0.265P value (1-sided)

0 3 6 9 12 15 18 21 24 27

Time (months)

100

80

60

40

20

0

PF

S p

rob

abil

ity

(%)

Overall Survival (ITT Population)

SU + DOCN=296

DOCN=297

OS events, n (%) 107 (36) 91 (31)

Median, months 24.8 25.5

HR (95% CI) 1.21 (0.91−1.60)

P value (1-sided ) 0.904

0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

100

80

60

40

20

0

OS

pro

bab

ilit

y (%

)

Patients at risk

SU + DOC 296 284 264 235 213 164 95 50 26 8 3 2

DOC 297 290 269 246 222 173 104 52 23 6 1 0

Common All-Causality AEs (AT Population)Patients (%)

SU + DOCN=295

DOCN=293

AE Any grade Grade 3/4 Any grade Grade 3/4

Neutropenia 56 46 49 44

Hand−foot syndrome 41 17* 9 1

Fatigue 43 12 34 8

Diarrhea 60 10 38 4

Asthenia 33 9 30 7

Stomatitis 32 5 26 1

Decreased appetite 32 4 24 1

Hypertension 12 2 1 0

Nausea 40 1 39 2

Dysgeusia 30 <1 23 0

*P<0.001 vs. DOC

AEs Leading to Treatment Discontinuation in ≥2% of Pts in Either Arm (AT Population)

Reason for discontinuation

Patients (%)

SU + DOC

N=295

DOCN=293

SU DOC DOC

Any AE 27 29 21

Asthenia/fatigue 3 6 3

Hand−foot syndrome 4 3 0

Neuropathy/sensory neuropathy <1 2 4

Peripheral edema 0 2 2

Fatalities

Cause of death

n (%)

SU + DOC

N = 296

DOC

N = 297

All deaths 107 (36) 91(31)

On-treatment deaths 12 (4) 4 (1)

Disease progression 6 (2) 4 (1)

Cardiac arrest 1 (<1) 0

Cardiac failure 1 (<1) 0

Cardiovascular collapse 1 (<1) 0

Hypovolemic shock, pneumothorax 1 (<1) 0

Severe pulmonary embolism 1 (<1) 0

Unknown 1 (<1) 0

Conclusions

● The combination of sunitinib and docetaxel improved ORR, but despite this, it did not prolong PFS or OS compared with docetaxel alone when given as first-line treatment for ABC

● The frequency of common AEs was higher with the sunitinib−docetaxel combination

– Treatment discontinuations and dosing modifications occurred more frequently in the combination arm

● The sunitinib−docetaxel regimen evaluated in this study is not recommended for the treatment of patients with ABC

Adapted from Loges et al. Cancer Cell 2009;15:167−170with permission from Elsevier

EC = endothelial cellEMT = epithelial-mesenchymal transition

Hypothesis for VEGF-targeted Resistance in Preclinical Models

Prolongation of PFS

Shortening of OS

Primary tumor shrinkage and inhibition of progression

Tumors need blood and lymphatic vessels to grow

VEGF-targeted therapies may also induce mechanisms that increase

malignant potential

Hypoxia tolerance, EMT, rescue angiogenesis

Intravasation

Extravasation, premetastatic nichebone marrow cellrecruitment

Vessel co-option

EC dysfunctionthrombosis

Increased metastasis

VEGF-targeted therapies may therefore enhance tumor invasiveness and metastasis and reduce OS benefit

Increased tumor invasiveness

VEGF-targetedtherapy

Comments

● These results add to the available data on anti-angiogenic therapies; contrary to expectations based on some preclinical results, no or minimal effect on overall survival in unselected patient populations

● No predictive markers have been identified for anti-angiogenic therapies

– All trials involving targeted therapies should collect biological material (at least blood, if not tissue from metastatic lesions)

● Sub-study at the Karolinska Institutet

– Cytological aspirates and 18FDG-PET performed at baseline and on day 14 of treatment (18/21 patients)

– Gene expression analyses (Affymetrix 133A and B) on 14 paired samples ongoing.

Thanks to all the participating patients and their families, as well as the global network of investigators and Pfizer Oncology staff

Country SUN 1064 Investigators

Argentina M. Chacon, N. A. Giacomi, S. Kahl

Australia E. Abdi, M. Brown, A. Chan, J. Chirgwin, G. Richardson

Austria C. Dittrich, R. Greil, H.-P. Ludwig, G. Steger

Belgium F. Cardoso, J.-P. Salmon, D. Verhoeven

Canada P. M. Ellis, Y. Madarnas-Casimiri, G. Pansegrau, A. G. Robinson

Columbia J. I. Godoy, G. Rojas

Czech Republic B. Donocikova, M. Palacova, J. Prausova, V. Stahalova

Finland R. Huovinen, M. Tanner

France P. Bougnoux, B. Coudert, S. Delaloge, N. Dohollou, T. Facchini, M. Gutierrez, J.-P. Jacquin, A. Lortholary, J.-P. Wagner

Germany U.-S. Albert, J. Bischoff, T. Decker, J. Dietl, N. Fersis, P. Kiewe, C.-H. Koehne, N. Niederle, R. Pihusch, O. Tome, C. Uleer, A. Welt

Hungary M. Kispal, L. Landherr, I. Lang, K. Pali

Ireland J. P. Crown, M. Keane, M. J. Kennedy

Italy M. Antimi, G. Bernardo, L. Blasi, G. Carteni, M. Caruso, A. Falcone, V. Gebbia, S. Iacobelli, L. Latini, M. Lopez, V. Lorusso, A. Ravaioli

Korea, Republic of S.-B. Kim, S. Y. Rha, J. Ro

Country SUN 1064 Investigators

Netherlands P. B. Ottevanger, A. J. van de Wouw, E. E. Voest

Panama J. C. Alcedo

Poland J. Jassem, T. Pienkowski, G. Slomian

Portugal N. Afonso, J. L. P. Coelho, J. E. Macedo, G. Sousa

Romania F. Badulescu, L. Ciule, M. Dediu, A. Eniu

Russian Federation L. V. Demidov, M. R. Lichinitser, A. N. Makhson, L. A. Nelyubina, L. D. Roman, V. F. Semiglazov, E. E. Topuzov

Slovakia I. Koza, V. Malec, M. Mikulova, M. Stresko

Spain J. E. Ales, R. Andres, N. Batista, J. I. Chacon, M. A. Climent, J. Cortes, A. Lluch, R. Lopez, J. Rifa, J. Salvador

Sweden K. Bachmeier, J. Bergh, H. Lindman

Turkey K. Altundag, G. A. Basaran, M. Gumus

Ukraine I. M. Bondarenko, I. Y. Sedakov, Y. V. Shparyk, N. L. Voytko

United Kingdom R. K. Agrawal, A. Armstrong, K. Benstead, M. Churn, R. Jyothirmayi, S. S. Mitra, A. J. Neal, S. M. O'Reilly

United States D. H. Irwin, R. D. Page, S. T. Ramachandran

Thanks to all the participating patients and their families, as well as the global network of investigators and Pfizer Oncology staff (cont’d)

Back-up SlidesBack-up Slides

Treatment Administration (AT Population)SU + DOC

N=295DOC

N=293

SU DOC DOC

Median relative dose intensity, % (range)

94(14−142)

92(52−108)

93(57−112)

Median duration of treatment, weeks (range)

26(23−29)

18(17−21)

18(16−19)

Cycles started, median(range)

8(1−32)

7(1−23)

6(1−26)

Dose reductions, % of pts 39 35 38

Dosing delays, % of pts 60 48 39

Dosing interruptions, % of pts 25 NA NA

Average dose per cycle, median (range)

37.5 mg*(26−41)

73 mg/m2 (39−87)

96 mg/m2

(65−112)

AT = as-treated*Median average daily dose

Hypothesis for VEGF-targeted Resistance Hypothesis for VEGF-targeted Resistance in Preclinical Modelsin Preclinical Models11

● VEGF-targeted therapies induce primary tumor shrinkage and inhibit tumor progression

● Therapies may also initiate mechanisms that increase malignant potential– Hypoxia tolerance, epithelial−mesenchymal transition– Bone marrow cell recruitment, rescue angiogenesis– Vessel co-option– Endothelial cell dysfunction, thrombosis

● VEGF-targeted therapies may therefore enhance tumor invasiveness and metastasis and reduce OS benefit

1Loges et al. Cancer Cell 2009;15:167

Progression-free Survival (Investigator Assessment; ITT Population)

SU + DOCN=296

DOCN=297

PFS events, n (%) 198 (67) 162 (55)

Median, months 8.2 6.9

HR (95% CI) 0.86 (0.69−1.06)

0.075P value (1-sided)

0 3 6 9 12 15 18 21 24 27

Time (months)

100

80

60

40

20

0

PF

S p

rob

abil

ity

(%)

Patients at risk

SU + DOC 296 237 158 80 35 13 5 2 0

DOC 297 218 102 41 21 16 9 2 2