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