Update on the 2006 San Antonio Breast Cancer Symposium

Update on the 2006 San Antonio Breast Cancer Symposium

Helen K. Chew, MD, FACP

UC Davis Cancer Center

Objectives

• To review the 4 most clinically relevant abstracts:

• Adjuvant trastuzumab (abstract #52)• Trastuzumab combined with aromatase

inhibitors in the advanced setting (abstract #3)• Taxanes in the adjuvant setting (abstract #53)• Endocrine therapy in metastatic disease

(abstract #49)

High-risk node negative

• T > 2 cm or

• ER and PgR negative or

• Histological grade 2-3 or

• Age < 35 y/o

How does this affect clinical practice?

• Platinum doublet appears as effective as anthracycline-containing regimen in the adjuvant setting

• Toxicities of regimens distinct and acceptable

• Role of Topo II amplification unclear in this patient population

Trastuzumab prolongs progression-free survival in hormone-dependent and HER2‑positive metastatic

breast cancer

John R. Mackey MD Cross Cancer Institute, Edmonton, Canada

On behalf of the TAnDEM investigators

Cross-talk between signal transduction and endocrine pathways

Adapted from Johnston 2005

SOSRAS

RAF

Basaltranscription

machineryp160

ERE ER target gene transcription

ER CBPPP P P

ER

Pp90RSK

AktP

MAPKP

Cellsurvival

Cytoplasm

Nucleus

ER

PI3-KP

P

PPP

P

Cellgrowth

MEKP

Plasmamembrane

Anastrozole

HER2

IGFRGrowth factorEstrogen

Trastuzumab

TAnDEM study design

• Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone

HER2-positive, hormone receptor-

positive MBC (n=208a)

R

Anastrozole 1 mg daily + trastuzumab 4 mg/kg loading dose

2 mg/kg qw until disease progression

Anastrozole 1 mg daily until disease progression

aOne patient did not receive study drug and was excluded from analysesMBC, metastatic breast cancer

End points

Primary efficacy

• PFS

Secondary efficacy

• Clinical benefit rate

• Overall response rate

• TTP

• Duration of response

• OS

• 2-year survival

Safety

• AEs and SAEs

• Cardiac function

PFS, progression-free survival; TTP, time to progression; OS, overall survival; AE, adverse event; SAE, serious adverse event

Key inclusion criteria• Postmenopausal women with MBC

• HER2 positive (IHC 3+ and / or FISH+, centrally confirmed)

• ER and / or PgR positive (local testing)

• Tamoxifen allowed for adjuvant and 1st treatment of MBC

• No chemotherapy for metastatic disease

• ECOG performance status 0-1

• Baseline LVEF >50% without serious cardiac conditions

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; ER, estrogen receptor; PgR, progesterone receptor; ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction

Baseline patient demographics

All data are median (range) unless otherwise noted; A, anastrozole; H, trastuzumab

A+H (n=103)

56 (31-85)

25.6 (0.6-419)

1.6 (0.3-67)

2 (1-5)

4 (1-14)

4232624570

6053 45

62 (50-82)

Age, years

Time from initial diagnosis, months

Duration of metastatic disease, months

No. metastatic sites/patient

No. lesions/patient

Sites of metastases, % patientslungliverbonesoft tissueother

Previous therapy, % patients hormonalchemotherapy anthracycline

LVEF, %

A (n=104)

54 (27-77)

27.3 (0.6-154)

1.2 (0.3-19)

2 (1-5)

4 (1-13)

4628514263

6660 51

63 (51-89)

Progression-free survival

103 48 31 17 14 13 11 9 4 1 1 0 0A+H

104 36 22 9 5 4 2 1 0 0 0 0 0A

CI, confidence intervalPFS = time from randomisation to date of progressive disease or death

Probability 1.0

0.8

0.6

0.4

0.2

0 5 10 15 20 25 30 35 40 45 50 55 60Months

95% CI

3.7, 7.02.0, 4.6

p value

0.0016

Median PFS

4.8 months2.4 months

Events

8799

0.0

No. at risk2.4 months

Patients(%)

0

10

20

30

40

50

60p=0.026

Clinical benefit

A+H (n=103)

A (n=104)

Clinical benefit rate in all patients

42.7

27.9

Overall survival

73 / 104 patients (70%) received H later during the course of disease

103 91 83 76 63 49 36 24 12 4 3 0 0A+H

104 96 87 73 58 42 34 22 5 2 1 1 0A

No. at risk

0 5 10 15 20 25 30 35 40 45 50 55 60Months

95% CI

22.8, 42.418.2, 37.4

p value

0.325

Median OS

28.5 months23.9 months

Events

5864

Probability 1.0

0.8

0.6

0.4

0.2

0.0

Most common AEs (>10%)

FatigueVomitingDiarrhoeaPyrexiaNasopharyngitisNauseaArthralgiaBack painChillsCoughHeadacheDyspnoeaConstipationBone pain

2121201717171515151414131211

1058725

107–66956

Patients, %

AE A+H (n=103) A (n=104)

Safety profile

Cardiac disorders

asymptomatic CHF (NYHA class I)

symptomatic CHF (NYHA class II)

myocardial infarction, ischaemia

dysrythmia

>1 AE

>1 SAE

Death due to AE

Grade 3/4 AEs

13

4a

1

2

7

87

23

0

25

2

0

0

1

1

65

6

2b

15

Patients, %

a1 patient had a myocardial infarction and subsequent CHF class I

b1 event occurred after crossover to A+H

A+H(n=103)

A(n=104)

CHF, congestive heart failure; NYHA, New York Heart Association

Conclusions

• Trastuzumab added to anastrozole significantly improves PFS for women with HER2 and HR co-positive MBC

• >15% of patients receiving A + H did not progress for at least 2 years; thus chemotherapy can be delayed

• Despite 70% of patients receiving H after progression on A alone OS seems to be improved

• Treatment with A + H was manageable, with no new or unexpected AEs

How does this affect clinical practice?

• In patients with HER-2/neu positive and hormone receptor positive advanced breast cancer, the combination of trastuzumab and anastrazole is well tolerated

• Small study (n=207), underpowered?• Does not address whether sequential

therapy may be optimal in this uncommon patient population

A Randomized Trial of CEF vs. Dose Dense EC followed by

Paclitaxel vs. AC followed by Paclitaxel in Women with Node

Positive or High Risk Node Negative Breast Cancer

NCIC CTG MA21

Results of an Interim Analysis

Background• Milan Cancer Institute: 15 yr DFS 42% (CMF) vs.

28% (no Rx)• NSABP B - 15: 3yr DFS 62% (4 cycles AC) vs. 68%

(AC delayed CMF) vs. 63% (6 cycles CMF) • NCIC CTG MA5: 5yr DFS 63% (CEF) vs. 53%

(CMF)• EORTC, NCIC CTG, SAKK: PFS 34m (CEF) vs.

34m (12 weeks dose dense EC) in LABC • CALGB 9344: 3 yr DFS 77% (AC/T) vs. 73% (AC)

Patient Population: Inclusion

• ≤ 60 years

• Histologically confirmed operable breast cancer

• Axillary node +ve, high risk node –ve (tumor ≥ 1cm, grade III or ER –ve, or LVI)

• Able to start protocol Rx within 12 weeks of surgery

NCIC CTG MA 21

ECF

AC → T

EC →T

Stratification: No. of nodes +ve (0,1-Stratification: No. of nodes +ve (0,1-3, 4-10, >10); Surgery (partial vs. 3, 4-10, >10); Surgery (partial vs. mastectomy), ER (+ vs. -) mastectomy), ER (+ vs. -)

Regimens

• CEF:6 cycles of C 75 mg/m2 po days 1-14, E 60mg/m2 and 5FU 500mg/m2 both iv Days 1 & 8 plus antibiotics (cotrimoxazole or cipro)

• Dose dense EC: 6 cycles every 2 weeks of E 120mg/m2 and C 830mg/m2 both iv, plus filgrastim and epoetin alfa followed by 4 cycles of T 175 mg/m2 every 3 weeks

• AC/T: 4 cycles of A 60mg/m2 and C 600mg/m2 both iv every 3 weeks followed by T 175 mg/m2 every 3 weeks

Other Therapy

• ER +ve or PR +ve: tamoxifen, and after 2004 aromatase inhibitors in postmenopausal women

• Radiation: post-lumpectomy breast radiation and post-mastectomy as per local institutional policy

• Trastuzumab: allowed after June 2005 if completed chemotherapy within previous 6 months

OUTCOMES• Primary: Relapse-free survival

(recurrence or death)

• Secondary: Overall survival

Toxicity

Quality of life

Statistics

• Sample size 2100• One planned interim analysis when 1/2

expected recurrences (227)• Stratified log rank test for RFS• The interim analysis (O’Brien-Fleming type

boundaries) would use global test of significance for 3-way comparison. If p<0.005, would then proceed to pair-wise comparisons

Baseline Characteristics

CEF %

n=701

EC/T %

n=701

AC/T %

n=702

Age: <50

≥50

60

40

61

39

62

38

Surgery: partial

total

51

49

50

50

50

50

ER: negative

positive

40

60

41

59

41

59

Menopause: pre

post

69

31

68

32

67

33

Baseline CharacteristicsCEF %

n=701

EC/T %

n=701

AC/T %

n=702

Axillary nodes: 0

1-3

4-10

> 10

28

43

22

7

28

43

22

6

28

44

23

6

T Status: T1

T2

T3

T4

34

56

9

1

34

54

10

2

36

55

8

1

Relapse-Free Survival: All Patients

P = 0.001 (stratified)

CEFCEF

EC-TEC-T

AC-TAC-T

CEFEC/TAC/T

701701702

451441405

125101113

2 yr 4 yr

Result: RFS Between Arms

Treatment Hazard Ratio (95% CI)

P Value

EC/T to CEF 0.89 (0.64, 1.22) 0.46

AC/T to CEF 1.49 (1.12, 1.99) 0.005

AC/T to EC/T 1.68 (1.25, 2.27) 0.0006

Test TypeTest Type Hazard Hazard P-valueP-value¹¹ Ratio (95% CI) Ratio (95% CI)

ER+ PatientsER+ PatientsEC/T to CEF EC/T to CEF 1.06 (0.65,1.72) 1.06 (0.65,1.72) 0.79 0.79AC/T to CEF AC/T to CEF 1.27 (0.80,2.01) 1.27 (0.80,2.01) 0.29 0.29 AC/T to EC/T AC/T to EC/T 1.20 (0.76,1.90) 1.20 (0.76,1.90)

0.39 0.39

ER- PatientsER- PatientsEC/T to CEF EC/T to CEF 0.78 (0.50,1.20) 0.78 (0.50,1.20) 0.23 0.23 AC/T to CEF AC/T to CEF 1.67 (1.15,2.42) 1.67 (1.15,2.42) 0.007 0.007 AC/T to EC/T AC/T to EC/T 2.15 (1.44,3.21) 2.15 (1.44,3.21)0.0002 0.0002

1Log-Rank Test, adjusted for stratification factors2Interaction Test for Treatment and ER p=0.23

Differences in RFS Between Treatment Arms

Toxicity

CEF EC/T AC/T

Febrile Neutropenia 22.9% 16.7% 4.8%

Cardiac Toxicity - delayed

Grade 1/2 34.9% 28.0% 21.5%

Grade 3/4 2.0% 0.7% 0.4%

Thromboembolic Events - acute 7.7% 7.8% 2.0%

ToxicityCEF EC/T AC/T

Leukemia/MDS 4 – AML

3 – AML

1 – ALL0

Sensory neuropathy - acute

Grade 1/2 25.7% 65.8% 64.1%

Grade 3/4 0.6% 5.9% 5.8%

Motor neuropathy - acute

Grade 1/2

Grade 3/43.9%

0.4%

7.5%

1.4%

6.3%

0.4%

Conclusion

• AC/T given every three weeks is significantly inferior to CEF or EC/T in terms of RFS in patients with high risk operable breast cancer.

• Taxane based chemotherapy may not be necessary in all women receiving adjuvant chemotherapy.

• The role of non-dose dense taxane based chemotherapy is unclear.

Conclusion

• A dose dense/dose intense approach with anthracyclines adds benefit in this setting.

• It is too early to detect any difference between CEF and dose dense EC/T.

How does this affect clinical practice?

• Adds thought-provoking data on the use of taxanes in the adjuvant setting and the benefits of therapy based on hormone-receptor status

• Unclear the role of dose-dense AC->T

EFECTEvaluation of Faslodex vs. Exemestane

Clinical Trial

William J Gradishar MDNorthwestern University Feinberg School of Medicine

Martine PiccartJules Bordet InstituteBrussels, Belgium

Stephen ChiaBritish Columbia Cancer Agency

Vancouver, Canada

Stephen ChiaBritish Columbia Cancer Agency

Vancouver, Canada

What are the options following adjuvant / What are the options following adjuvant / 1st-line non-steroidal AI?1st-line non-steroidal AI?

1st treatment1st treatment

2nd treatment2nd treatment

4th treatment4th treatment

3rd treatment3rd treatment

Non-steroidal AINon-steroidal AI

Fulvestrant?Fulvestrant?Exemestane?Exemestane?

ExemestaneExemestaneFulvestrantFulvestrant TamoxifenTamoxifen

TamoxifenTamoxifen TamoxifenTamoxifenExemestaneExemestaneor or

FulvestrantFulvestrant

Fulvestrant and exemestane after Fulvestrant and exemestane after progression on non-steroidal AIsprogression on non-steroidal AIs

Endocrine agentEndocrine agent

FulvestrantFulvestrant

ExemestaneExemestane

CBR (%)CBR (%)

35353030

2020

ReferenceReference

Ingle et al 2006Ingle et al 2006Perey et al 2006Perey et al 2006

LLøønning et al 2000nning et al 2000

Ingle et al. J Clin Oncol 2006; 24:1052Ingle et al. J Clin Oncol 2006; 24:1052––10561056Perey et al, Ann Oncol Advance Access published online on October 9, 2006Perey et al, Ann Oncol Advance Access published online on October 9, 2006

LLøønning et al. nning et al. Clin Oncol 2000; 18: 2234–44Clin Oncol 2000; 18: 2234–44

Progression

Fulvestrant loading dose + placebo for

exemestane (n=330)

Prior non-steroidal AI failure

Survival

Progression

Survival

Exemestane 25 mg orallydaily + placebo for

Fulvestrant (n=330)

Analysis after 580 events(progression or death)

500 mg Day 1, 250 mg Day 14 & 28,

and monthly

Endpoints in protocol

Primary: • Time to disease progression

Secondary: • Overall survival

• Objective response rate

• Clinical benefit rate (OR + SD ≥24weeks)

• Duration of response, time to response

• Tolerability

Key inclusion criteria• Postmenopausal women, ER+ and/or PgR+ positive

• Progression during NSAI treatment for ABC or recurrence on NSAI for adjuvant therapy or within 6 months of its discontinuation

• Measurable disease or bone lesions

• PS 0–2 and normal organ function

• No life-threatening visceral metastatic disease or any brain or leptomeningeal involvement

Demographic characteristicsDemographic characteristics

Median ageMedian age

RaceRaceCaucasianCaucasianBlackBlackOrientalOrientalOtherOther

Metastatic sitesMetastatic sitesBoneBoneLungLungLiverLiver

ER+ and/or PgR+ER+ and/or PgR+

FulvestrantFulvestrantn=351n=351

63 years63 years

ExemestaneExemestanen=342n=342

63 years63 years

89.2%89.2%3.1%3.1%1.1%1.1%6.6%6.6%

67.2%67.2%34.5%34.5%31.1%31.1%

99.7%99.7%

91.2%91.2%3.8%3.8%1.2%1.2%3.8%3.8%

66.4%66.4%36.3%36.3%32.2%32.2%

98.5%98.5%

Time to progression (ITT)Time to progression (ITT)Proportion Proportion of patients of patients progression-progression-freefree

MonthsMonthsAt risk:At risk:FulvestrantFulvestrantExemestaneExemestane

3.73.73.73.7Median (months)Median (months)

HR = 0.963, 95% CI (0.819, 1.133), p=0.6531HR = 0.963, 95% CI (0.819, 1.133), p=0.6531

Cox analysis, p=0.7021Cox analysis, p=0.7021

ExemestaneExemestaneFulvestrantFulvestrant

FulvestrantFulvestrant

ExemestaneExemestane

00 33 66 99 1212 1515 1818 2121 2424 2727

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

351351 195195 9696 5050 2525 1212 44 22

342342 190190 9898 4141 2121 1212 88 66

00

11

00

00

Objective response and clinical benefit rate Objective response and clinical benefit rate (evaluable for response population)(evaluable for response population)

* Analyses are not adjusted for baseline covariates* Analyses are not adjusted for baseline covariates

OR rateOR rate

(CR + PR)(CR + PR)

CB rateCB rate

(OR + SD (OR + SD ≥≥24 wks)24 wks)

FulvestrantFulvestrant

7.4%7.4%

(20/270)(20/270)

32.2%32.2%

(87/270)(87/270)

ExemestaneExemestane

6.7%6.7%

(18/270)(18/270)

31.5%31.5%

(85/270)(85/270)

Odds ratio*Odds ratio*(95% CI)(95% CI)

1.1201.120

(0.578, 2.186)(0.578, 2.186)

1.0351.035

(0.720, 1.487)(0.720, 1.487)

p-valuep-value

0.73640.7364

0.85340.8534

Proportion Proportion of patients of patients respondingresponding

MonthsMonths

At risk:At risk:FulvestrantFulvestrantExemestaneExemestane

FulvestrantFulvestrant

ExemestaneExemestane

00 33 66 99 1212 1515 1818 2121 2424 2727

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

2020 2020 1616 1111 88 33 00 00

1818 1818 1515 1010 55 44 33 33

FulvestrantFulvestrant

13.513.5

ExemestaneExemestane

9.89.8Median (months)Median (months)

Duration of ResponseDuration of Response (from randomisation)(from randomisation)

00 00

33 33

Duration of clinical benefitDuration of clinical benefit (Retrospective analysis)(Retrospective analysis)

Proportion Proportion of patients of patients progression-progression-freefree

FulvestrantFulvestrant

ExemestaneExemestane

MonthsMonthsAt risk:At risk:FulvestrantFulvestrantExemestaneExemestane

00 33 66 99 1212 1515 1818 2121 2424 2727

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0 FulvestrantFulvestrant

9.39.3

ExemestaneExemestane

8.38.3Median (months)Median (months)

8787 8787 7171 4040 2020 1010 33 11 11 00

8585 8585 6969 2828 1414 1010 66 55 11 00

Adverse eventsAdverse events

Patient had an AEPatient had an AE

Drug-related AEDrug-related AE

Withdrawal due to AEWithdrawal due to AE

AE of grade 3 or higherAE of grade 3 or higher

Serious AESerious AE

Drug-related SAEDrug-related SAE

Death due to AEDeath due to AE

Death due to drug-related AEDeath due to drug-related AE

FulvestrantFulvestrantn=351n=351

ExemestaneExemestanen=340n=340

88.9%88.9%

45.9%45.9%

2.0%2.0%

21.7%21.7%

11.4%11.4%

1.1%1.1%

0.9%0.9%

0%0%

88.8%88.8%

48.8%48.8%

2.6%2.6%

22.6%22.6%

12.4%12.4%

0.6%0.6%

0.9%0.9%

0%0%

Analysis of pre-specified AE categoriesAnalysis of pre-specified AE categories(2-sided Fisher’s exact test)(2-sided Fisher’s exact test)

Weight gainWeight gain

Increased appetiteIncreased appetite

Hot flushesHot flushes

Joint disordersJoint disorders

Nausea and / or vomitingNausea and / or vomiting

DiarrheaDiarrhea

Androgenic effectsAndrogenic effects

Injection-site reactionsInjection-site reactions

FulvestrantFulvestrantn=351n=351

ExemestaneExemestanen=340n=340

p-valuep-value

4 (1.1%)4 (1.1%)

2 (0.6%)2 (0.6%)

47 (13.4%)47 (13.4%)

93 (26.5%)93 (26.5%)

88 (25.1%)88 (25.1%)

46 (13.1%)46 (13.1%)

15 (4.3%)15 (4.3%)

56 (16.0%)56 (16.0%)

3 (0.9%)3 (0.9%)

1 (0.3%)1 (0.3%)

54 (15.9%)54 (15.9%)

99 (29.1%)99 (29.1%)

84 (24.7%)84 (24.7%)

46 (13.5%)46 (13.5%)

12 (3.5%)12 (3.5%)

46 (13.5%)46 (13.5%)

>0.999>0.999

>0.999>0.999

0.3890.389

0.4460.446

0.9300.930

0.9110.911

0.6960.696

0.3920.392

Summary

• The first phase III trial in this population• Confirmed efficacy of fulvestrant in patients who

have progressed on a NSAI • Similar efficacy seen on both treatment arms• No differences were seen in reported AEs between

fulvestrant and exemestane

How does this affect clinical practice?

• The steroidal aromatase inhibitor exemestane and the estrogen receptor downregulator fulvestrant are equivalent choices after progression on a nonsteroidal AI in metastatic breast cancer

• The loading dose of fulvestrant is well tolerated