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transcript
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