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

Growth factor Estrogen IGFR HER2 Trastuzumab Plasma membrane P P P P Anastrozole PI3-K P P SOS RAS RAF Cell survival Akt P MEK P ER p90 RSK P MAPK P Cytoplasm Nucleus P P P ER P ER p160 CBP Basal transcription machinery ERE ER target gene transcription Cell growth Adapted from Johnston 2005

TAnDEM study design

HER2-positive, hormone receptor positive MBC (n=208 a ) 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

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

a One patient did not receive study drug and was excluded from analyses MBC, metastatic breast cancer

Primary efficacy • PFS Secondary efficacy • Clinical benefit rate • Overall response rate • TTP • Duration of response • OS • 2-year survival

End points

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

Age, years Time from initial diagnosis, months Duration of metastatic disease, months No. metastatic sites/patient No. lesions/patient Sites of metastases, % patients lung liver bone soft tissue other Previous therapy, % patients hormonal chemotherapy anthracycline LVEF, % A+H (n=103) 56 (31-85) 25.6 (0.6-419) 1.6 (0.3-67) 2 (1-5) 4 (1-14) 42 32 62 45 70 60 53 45 62 (50-82) A (n=104) 54 (27-77) 27.3 (0.6-154) 1.2 (0.3-19) 2 (1-5) 4 (1-13) 46 28 51 42 63 66 60 51 63 (51-89) All data are median (range) unless otherwise noted; A, anastrozole; H, trastuzumab

Probability 1.0

Progression-free survival

0.8

0.6

Events Median PFS 95% CI p value 87 99 4.8 months 2.4 months 3.7, 7.0

2.0, 4.6

0.0016

0.4

0.2

0.0

0 5 10 15 20 25 30 Months 35 40 45 2.4 months No. at risk A+H A 103 48 104 36 31 22 17 9 14 5 13 4 11 2 9 1 4 0 1 0 CI, confidence interval PFS = time from randomisation to date of progressive disease or death 50 1 0 55 60 0 0 0 0

Clinical benefit rate in all patients

Patients (%) 60 50 40 30 20 10 0 p=0.026

42.7

27.9

Clinical benefit A+H (n=103) A (n=104)

Probability 1.0

0.8

Overall survival

Events 58 64 Median OS 95% CI 28.5 months 23.9 months 22.8, 42.4

18.2, 37.4

p value 0.325

0.6

0.4

0.2

No. at risk A+H A 0.0

0 5 103 91 104 96 10 83 87 15 76 73 20 63 58 25 30 Months 35 49 42 36 34 24 22 40 12 5 45 50 55 60 4 2 3 1 0 1 0 0 73 / 104 patients (70%) received H later during the course of disease

Most common AEs (>10%)

AE Fatigue Vomiting Diarrhoea Pyrexia Nasopharyngitis Nausea Arthralgia Back pain Chills Cough Headache Dyspnoea Constipation Bone pain Patients, % A+H (n=103) A (n=104) 21 21 20 17 17 17 15 15 15 14 14 13 12 11 6 6 9 5 6 10 5 8 7 2 5 10 7 –

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 Patients, % A+H (n=103) A (n=104) 13 4 a 1 2 7 2 0 0 1 1 87 23 0 25 a 1 patient had a myocardial infarction and subsequent CHF class I b 1 event occurred after crossover to A+H CHF, congestive heart failure; NYHA, New York Heart Association 65 6 2 b 15

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

E C F EC →T AC → T Stratification: No. of nodes +ve (0,1-3, 4-10, >10); Surgery (partial vs. mastectomy), ER (+ vs. -)

Regimens

• CEF :6 cycles of C 75 mg/m 2 po days 1-14, E 60mg/m 2 and 5FU 500mg/m 2 both iv Days 1 & 8 plus antibiotics (cotrimoxazole or cipro) • Dose dense EC : 6 cycles every 2 weeks of E 120mg/m • AC/ T 2 and C 830mg/m filgrastim and epoetin alfa followed by 4 cycles of T 175 mg/m 2 2 every 3 weeks both iv, plus : 4 cycles of A 60mg/m 2 and C 600mg/m 2 both iv every 3 weeks followed by T 175 mg/m 2 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

Age: <50 ≥50 Surgery: partial total ER: negative positive Menopause: pre post

CEF

% n=701 60 40 51 49 40 60 69 31

EC/ T

% n=701 61 39 50 50 41 59 68 32

AC /T

% n=702 62 38 50 50 41 59 67 33

Baseline Characteristics

Axillary nodes: 0 1-3 4-10 > 10 T Status: T1 T2 T3 T4

CEF

% n=701 28 43 22 7 34 56 9 1

EC /T

% n=701 28 43 22 6 34 54 10 2

AC /T

% n=702 28 44 23 6 36 55 8 1

CEF EC/T AC/T 701 701 702

Relapse-Free Survival: All Patients

P = 0.001 (stratified) 2 yr 451 441 405 CEF EC-T AC-T 4 yr 125 101 113

Result: RFS Between Arms

Treatment

EC/T to CEF

Hazard Ratio (95% CI)

0.89 (0.64, 1.22)

P Value

0.46

AC/T to CEF 1.49 (1.12, 1.99) AC/T to EC/T 1.68 (1.25, 2.27) 0.005

0.0006

Test Type

Differences in RFS Between Treatment Arms

Hazard Ratio (95% CI) P-value¹ ER+ Patients EC/T to CEF AC/T to CEF AC/T to EC/T ER- Patients EC/T to CEF AC/T to CEF AC/T to EC/T 1.06 (0.65,1.72) 1.27 (0.80,2.01) 1.20 (0.76,1.90) 0.78 (0.50,1.20) 1.67 (1.15,2.42) 2.15 (1.44,3.21) 0.79

0.29 0.39 0.23 0.007 0.0002 1Log-Rank Test, adjusted for stratification factors 2Interaction Test for Treatment and ER p=0.23

Toxicity

CEF Febrile Neutropenia Cardiac Toxicity - delayed Grade 1/2 Grade 3/4 22.9% 34.9% 2.0% Thromboembolic Events - acute 7.7% EC/T 16.7% 28.0% 0.7% 7.8% AC/T 4.8% 21.5% 0.4% 2.0%

Leukemia/MDS

Toxicity

CEF 4 – AML Sensory neuropathy - acute Grade 1/2 Grade 3/4 25.7% 0.6% Motor neuropathy - acute Grade 1/2 Grade 3/4 3.9% 0.4% EC/T 3 – AML 1 – ALL AC/T 0 65.8% 5.9% 7.5% 1.4% 64.1% 5.8% 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

EFECT

Evaluation of Faslodex vs. Exemestane Clinical Trial William J Gradishar MD Northwestern University Feinberg School of Medicine Martine Piccart Jules Bordet Institute Brussels, Belgium Stephen Chia British Columbia Cancer Agency Vancouver, Canada

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

1st treatment 2nd treatment 3rd treatment 4th treatment Non-steroidal AI Exemestane?

Fulvestrant?

Fulvestrant Tamoxifen Exemestane Tamoxifen Exemestane or Fulvestrant Tamoxifen

Fulvestrant and exemestane after progression on non-steroidal AIs

Endocrine agent Fulvestrant Exemestane Reference Ingle et al 2006 Perey et al 2006 L ønning et al 2000 CBR (%) 35 30 20

Ingle et al. J Clin Oncol 2006; 24:1052 –1056 Perey et al, Ann Oncol Advance Access published online on October 9, 2006 L ønning et al. Clin Oncol 2000; 18: 2234–44

500 mg Day 1, 250 mg Day 14 & 28, and monthly Prior non-steroidal AI failure Fulvestrant loading dose + placebo for exemestane (n=330) Exemestane 25 mg orally daily + placebo for Fulvestrant (n=330) Progression Progression Survival Analysis after 580 events (progression or death) Survival

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 characteristics

Fulvestrant n=351 Exemestane n=342 63 years 63 years Median age Race Caucasian Black Oriental Other Metastatic sites Bone Lung Liver ER+ and/or PgR+ 89.2% 3.1% 1.1% 6.6% 67.2% 34.5% 31.1% 99.7% 91.2% 3.8% 1.2% 3.8% 66.4% 36.3% 32.2% 98.5%

Time to progression (ITT)

1.0

Proportion of patients progression free 0.8

Median (months) Fulvestrant 3.7

Exemestane 3.7

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

Cox analysis, p=0.7021

0.6

0.4

0.2

Fulvestrant Exemestane At risk: Fulvestrant Exemestane 0.0

0 3 6 351 342 195 190 96 98 9 50 41 12 15 Months 25 21 12 12 18 21 24 27 4 8 2 6 0 1 0 0

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

OR rate (CR + PR) CB rate (OR + SD ≥24 wks) Fulvestrant Exemestane 7.4% (20/270) 32.2% (87/270) 6.7% (18/270) 31.5% (85/270) * Analyses are not adjusted for baseline covariates Odds ratio* (95% CI) 1.120

(0.578, 2.186) 1.035

(0.720, 1.487) p-value 0.7364

0.8534

Duration of Response (from randomisation)

Proportion of patients responding 1.0

0.8

0.6

0.4

0.2

0.0

0 At risk: Fulvestrant Exemestane Median (months) Fulvestrant Exemestane Fulvestrant 13.5

Exemestane 9.8

20 18 3 20 18 6 16 15 9 11 10 12 15 Months 8 5 3 4 18 0 3 21 24 27 0 3 0 3 0 3

Duration of clinical benefit

Proportion of patients progression free 1.0

0.8

0.6

Median (months) 9.3

Exemestane 8.3

0.4

0.2

Fulvestrant Exemestane At risk: Fulvestrant Exemestane 0.0

0 87 85 3 87 85 6 71 69 9 40 28 12 15 Months 20 14 10 10 18 21 24 27 3 6 1 5 1 1 0 0

Adverse events

Patient had an AE Drug-related AE Withdrawal due to AE AE of grade 3 or higher Serious AE Drug-related SAE Death due to AE Death due to drug-related AE Fulvestrant n=351 88.9% 45.9% 2.0% 21.7% 11.4% 1.1% 0.9% 0% Exemestane n=340 88.8% 48.8% 2.6% 22.6% 12.4% 0.6% 0.9% 0%

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

Weight gain Increased appetite Hot flushes Joint disorders Nausea and / or vomiting Diarrhea Androgenic effects Injection-site reactions Fulvestrant n=351 4 (1.1%) 2 (0.6%) 47 (13.4%) 93 (26.5%) 88 (25.1%) 46 (13.1%) 15 (4.3%) 56 (16.0%) Exemestane n=340 3 (0.9%) 1 (0.3%) 54 (15.9%) 99 (29.1%) 84 (24.7%) 46 (13.5%) 12 (3.5%) 46 (13.5%) p-value >0.999

>0.999

0.389

0.446

0.930

0.911

0.696

0.392

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