sabcs 2011 metastatic breast cancer shiuh-wen luoh md phd clinical associate professor
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SABCS 2011
Metastatic Breast Cancer
Shiuh-Wen Luoh MD PhDClinical Associate Professor
Comprehensive Breast Cancer ClinicHematology and Medical Oncology
Knight Cancer Institute, OHSU
Portland VA Medical Center
BOLERO-2
SWOG-0226
A phase III randomized trial of anastrozole versus anastrozole and fulvestrant as first-line therapy for
postmenopausal women with metastatic breast cancer: SWOG
S0226Mehta RS, Barlow WE, Albain KS,
Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR,
Livingston RB, and Hortobagyi GN
BackgroundAnastrozole lowers estrogen levels and fulvestrant
down-regulates the estrogen receptorThe combination of anastrozole and fulvestrant may
be additive in postmenopausal breast cancerFulvestrant has a high efficacy in low-estrogen in
vivo model (Osborne JNCI 1995)The combination of fulvestrant and anastrozole
down-regulates several resistance proteins in in vivo model (Macedo et al. Cancer research 2008)
S0226: Main Eligibility Criteria• Postmenopausal women with metastatic breast cancer
(measurable or non-measurable)
• ER-positive or PgR-positive by local institutional standards
• No prior chemotherapy, hormonal therapy, or immunotherapy for metastatic disease
• Prior adjuvant tamoxifen allowed (stratification factor)
• Prior adjuvant AI allowed if completed 12 months earlier
• Neoadjuvant or adjuvant chemotherapy completed more than 12 months prior
• Patients were not allowed chemotherapy or other hormone therapy while on treatment
• Must have given informed consent
RANDOMIZE
Arm 1Anastrozole only: 1 mg PO daily
Treat until progression; crossover to fulvestrant strongly encouraged after progression
Arm 2Anastrozole: 1 mg PO dailyFirst cycle of 28 days: Fulvestrant 500mg IM ( 2 x 5 mL) Day 1 Fulvestrant 250mg IM ( 1 x 5 mL) Day 14 Fulvestrant 250mg IM ( 1 x 5 mL) Day 28Subsequent cycles of 28 days: Fulvestrant 250mg IM ( 1 x 5 mL) Day 28
Treat until progression
S0226: Schema
S0226: Statistical Design• Accrual goal: 690 eligible patients equally allocated and
stratified by use of adjuvant tamoxifen• Primary endpoint: Progression-free survival (PFS)
– 90% power to detect an increase in median PFS from 10 months (monotherapy) to 13 months (combination) with 2-sided α = 0.05 overall
• Planned analyses of the primary endpoint– Two interim analyses at 50% and 75% of the events– Final analysis at 2-sided α = 0.04• Subset analyses were not planned and are not
adjusted for multiplicity• Overall survival is a secondary endpoint
Primary Comparisons• Intent-to-treat analysis of eligible patients• Analysis stratified by prior adjuvant tamoxifen• Results to be presented today:
– Population characteristics• 707 patients randomized in the period
June 2004 to June 2009• 694 analyzed excluding 12 ineligible patients
and one who withdrew consent– Progression-free survival– Overall survival– Toxicity
Patient CharacteristicsCharacteristic Anastrozole Anastrozole +
FulvestrantTotal
Randomized 352 355 707Ineligible or withdrew consent 7 (2.0%) 6 (1.7%) 13 (1.8%)
Analyzed 345 349 694Age median (range) 65 (36-91) 65 (27-92) 65 (27-92)Prior adjuvant tamoxifen 139 (40.3%) 141 (40.4%) 280 (40.3%)Prior adjuvant chemo 103 (29.9%) 129 (37.0%) 232 (33.4%)Disease characteristics Measurable 54.5% 53.9% 54.2% Bone only 22.0% 21.5% 21.8% De novo metastatic disease 41.8% 36.0% 38.9%
> 10 years since previous dx 26.1% 30.7% 28.4%
HER2-positive 8.5% 10.4% 9.5%
Use of adjuvant AI is being determined retrospectively, but only 12 users of adjuvant AI’s have been identified.
Crossover• Patients in the anastrozole arm were strongly
encouraged to crossover to fulvestrant after progression
• After Feb 15, 2011 patients on either arm could crossover to 500 mg fulvestrant dosing after progression
• 143 of 345 patients (41%) on anastrozole did crossover to fulvestrant after progression (including 5 who took the 500 mg dosing)
• 9 of 349 patients on the combination took500 mg dosing after progression
HR = 0.80 (95% CI 0.68 - 0.94)
Median PFS
Combination 15.0 mos (95% CI 13.2-18.4)Anastrozole 13.5 mos (95% CI 12.1-15.1)
0.00
0.25
0.50
0.75
1.00
Prog
ress
ion-
free
surv
ival
345 193 92 39 11 3 0AN + FV349 199 114 53 21 8 2AN
N at risk
0 12 24 36 48 60 72Months since registration
Anastrozole + Fulvestrant (268 events)Anastrozole (297 events)Stratified log-rank p = 0.0070
All eligible patients (n=694)Progress ion-Free Surv ival in S0226
HR = 0.89 (95% CI 0.69 - 1.15)
Anastrozole 14.1 mos (95% CI 12.0-16.8)Median PFS
Combination 13.5 mos (95% CI 11.0-19.3)
0.00
0.25
0.50
0.75
1.00
Prog
ress
ion-
free
surv
ival
139 80 32 17 3 1 0AN + FV141 74 43 17 5 2 1AN
N at risk
0 12 24 36 48 60 72Months since registration
Anastrozole + Fulvestrant (114 events)Anastrozole (119 events)
Log-rank p = 0.37
Prior adjuvant tamoxifen (n=280)Progress ion-Free Surv ival in S0226
HR = 0.74 (95% CI 0.59-0.92)
Median PFSAnastrozole 12.6 mos (95% CI 11.2-15.6)Combination 17.0 mos (95% CI 13.8-19.9)
0.00
0.25
0.50
0.75
1.00
Prog
ress
ion-
free
surv
ival
206 113 60 22 8 2 0AN + FV208 125 71 36 16 6 1AN
N at risk
0 12 24 36 48 60 72Months since registration
Anastrozole + Fulvestrant (154 events)Anastrozole (178 events)
Log-rank p = 0.0055
No prior adjuvant tamoxifen (n=414)Progress ion-Free Surv ival in S0226
Median OSAnastrozole 41.3 mos (95% CI 37.2-45.0)Combination 47.7 mos (95% CI 43.4-55.7)
HR = 0.81 (95% CI 0.65 - 1.00)
0.00
0.25
0.50
0.75
1.00
Over
all S
urvi
val
345 306 239 136 54 22 4AN + FV349 315 259 145 62 26 4AN
N at risk
0 12 24 36 48 60 72Months since registration
Anastrozole + Fulvestrant (154 deaths)Anastrozole (176 deaths)Stratified log-rank p = 0.049
All eligible patients (n=694)Overall Surv ival in S0226
HR = 0.91 (95% CI 0.65-1.28)
Median OSAnastrozole 44.5 mos (95% CI 38.0-54.8)
Combination 49.6 mos (95% CI 37.9-71.2)
0.00
0.25
0.50
0.75
1.00
Over
all S
urvi
val
139 125 100 59 24 10 2AN + FV141 125 101 54 28 13 3AN
N at risk
0 12 24 36 48 60 72Months since registration
Anastrozole + Fulvestrant (63 deaths)Anastrozole (68 deaths)
Log-rank p = 0.59
Prior adjuvant tamoxifen (n=280)Overall Surv ival in S0226
HR = 0.74 (95% CI 0.56-0.98)
Median OSAnastrozole 39.7 mos (95% CI 33.1-43.9)
Combination 47.7 mos (95% CI 43.4-58.3)
0.00
0.25
0.50
0.75
1.00
Over
all S
urvi
val
206 181 139 77 30 12 2AN + FV208 190 158 91 34 13 1AN
N at risk
0 12 24 36 48 60 72Months since registration
Anastrozole + Fulvestrant (91 deaths)Anastrozole (108 deaths)
Log-rank p = 0.0362
No prior adjuvant tamoxifen (n=414)Overall Surv ival in S0226
Prior tamoxifen as a predictive factor?
• Overall planned analysis is highly significant
• Unplanned analysis by prior tamoxifen may suggest benefit only in the tamoxifen naive group
• Prior tamoxifen use is confounded with time between adjuvant diagnosis and metastatic diagnosis
• Need to better understand other possible predictive factors since the prior tamoxifen factor could be a false lead from an unplanned analysis
Forest Plot
Ov e ra l l
Pri o r ta mNo p ri o r ta m
Me a s u ra b l eNo n -me a s u ra b l e
Ag e 6 5 +Ag e < 6 5
De n o v o0 -5 y e a rs5 -1 0 y e a rs1 0 y e a rs +
Bo n e o n l yVi s c e ra lNo n -v i s c e ra l
HER2 -n e g a ti v eHER2 -p o s i t i v e
No p ri o r c h e moPri o r c h e mo
Co mb in a ti o n wo rs eCo mb in a ti o n b e tte r
Ov e ra l l HR = 0 .8 0
.4 .6 .8 1 1.2 1.4 1.6Hazard ratio
Unplanned subset analysisPFS treatment hazard ratio with 95% confidence interval
S0226 Toxicity: Grade 4 and 5• Three patients on the combination had grade 5
toxicities:
– two had pulmonary embolism
– one had cerebrovascular ischemia
• Two other patients on the combination had grade 4 toxicities:
– one had pulmonary embolism
– one had neutropenia and lymphopenia
• Four patients on anastrozole alone had Grade 4 toxicities (thrombosis/embolism, arthralgia, thrombocytopenia, dyspnea)
S0226 Toxicity• Grade 3 toxicities:
– 46 (13%) on the combination
– 38 (11%) on anastrozole alone
• Includes musculo-skeletal pain, fatigue, hot flashes, mood alterations and gastrointestinal symptoms with frequency 1-4%
• Adverse events did not differ significantly by treatment group
• Few patients went off treatment early due to adverse events or side effects (anastrozole alone 4; combination 11)
First-Line Hormonal Agent Phase-III Studies in Breast Cancer: Overall Survival
Study N Control Arm (months)
Experimental Arm (months)
HR for OS P-value
S0226 694 Anastrozole (→fulvestrant
(41.3)
Anastrozole + Fulvestrant
(47.7)
0.80 0.049
Bergh SABCS 2009
514 Anastrozole
(38.2)
Anastrozole + Fulvestrant
(37.8)
1.00 1.00
Nabholtz 2003 Eur J C
1021 Tamoxifen (40.1)
Anastrozole(39.2)
0.97 ?
Mouridsen 2003 JCO
916 Tamoxifen (30)
Letrozole (34)
? 0.53
Paridaens JCO 2008
371 Tamoxifen (43.3)
Exemestane (37.2)
1.04 0.82
Howell JCO 2004
587 Tamoxifen(38.7)
Fulvestrant(36.9)
1.29 0.04
S0226 Conclusions:• The combination of anastrozole and fulvestrant
improves PFS and OS, the primary and secondary endpoints, respectively, in first-line therapy of hormone receptor positive breast cancer in postmenopausal women
• The toxicity of the combination treatment is comparable to single agent treatment though Grade 5 toxicity was seen only with the combination
CLEOPATRA
AVEREL
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