Thursday, January 12, 2012 7:30 PM - 9:00 PM ET An Interactive Webcast Featuring Discussion of Key Presentations and Posters from the 2011 San Antonio

Thursday, January 12, 20127:30 PM - 9:00 PM ET

An Interactive Webcast Featuring Discussion of Key Presentations and Posters from the 2011 San Antonio Breast Cancer Symposium

Hope S Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials EducationUniversity of California, San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco, California

Antonio C Wolff, MDProfessor of OncologyBreast Cancer ProgramThe Johns Hopkins Kimmel Cancer CenterBaltimore, Maryland

Neil Love, MDResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abbott Laboratories, Allos Therapeutics, Amgen Inc, ArQule Inc, Astellas, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biodesix Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Medivation Inc, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Sanofi, Seattle Genetics and Teva Pharmaceuticals.

Disclosures for Hope S Rugo, MD

Paid Research

Genentech BioOncology, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche Laboratories Inc, Sanofi

Speakers Bureau Genomic Health Inc

Disclosures for Antonio C Wolff, MD

Paid Research Genentech BioOncology

Agenda

• Module 1: HER2-Positive Breast Cancer– CLEOPATRA, TEACH, APHINITY, others

• Module 2: Multigene/Biomarker Assays– Oncotype DX® in DCIS, RxPONDER study, PAM50, VeriStrat®

• Module 3: Advanced ER-Positive Disease– SWOG-S0226, BOLERO-2, others

• Module 4: HER2-Negative, BRCA1/2 Mutant– PARP inhibitors– Other chemotherapy ± biologics

• Module 5: Bone-Targeted Therapy– NSABP-B-34, ABCSG-12 update, denosumab, others

Module 1: HER2-Positive Breast Cancer

Baselga J et al. SABCS 2011;Abstract S5-5.

N Engl J Med 2012;366(2):109-19.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA)

Pertuzumab and Trastuzumab: Complementary Mechanisms of Action

HER1/3/4

Pertuzumab

HER2

Trastuzumab

Subdomain IV

Dimerization domain

Pertuzumab:• Inhibits ligand-dependent

HER2 dimerization and signaling

• Activates ADCC

Trastuzumab:• Inhibits ligand-independent

HER2 signaling• Activates ADCC• Prevents HER2 ECD

shedding

ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain

Adapted from Baselga J et al. SABCS 2011;Abstract S5-5.

CLEOPATRA Study Design


Centrally confirmed HER2-positive locally recurrent, unresectable or metastatic BC

≤1 hormonal regimen for mBC

(Neo)adjuvant systemic rx, incl trastuzumab and/or taxane if DFS ≥12 mos

Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after trastuzumab

Trastuzumab

Docetaxel (>6 cycles recommended)Docetaxel (>6 cycles recommended)

Study dosing q3wk:Trastuzumab: 8 mg/kg loading, 6 mg/kg maintPertuzumab: 840 mg loading, 420 mg maintDocetaxel: 75 mg/m2 (escalating to 100 mg/m2)

Trastuzumab

Docetaxel (>6 cycles recommended)Docetaxel (>6 cycles recommended)

PlaceboPlacebo

PertuzumabPertuzumab

1:1

N = 406

N = 402

R

Primary endpoint: Independently assessed progression-free survival

CLEOPATRA: Efficacy Endpoints

Docetaxel, Trastuzumab,Pertuzumab

(n = 402)

Docetaxel, Trastuzumab,

Placebo(n = 406)

Hazard Ratio

(95% CI) p-value

Median PFS (independently assessed)

18.5 mo 12.4 mo0.62

(0.51-0.75)<0.0001

Interim OS* Not reported Not reported 0.64(0.47-0.88) 0.005

Objective response rate** 80.2% 69.3% — 0.0011

* Interim analysis of OS did not cross O’Brien-Fleming stopping boundary; therefore, results are exploratory and nonsignificant (n = 165 OS events, 19.3 mo follow-up).

** Response evaluation prespecified to occur after OS; therefore, results are exploratory.


Prior Therapy for Breast Cancer


(n = 402)


Placebo(n = 406)

Prior (neo)adjuvant chemotherapy Yes No

45.8%54.2%

47.3%52.7%

Components of (neo)adjuvant therapy Anthracycline Taxane Trastuzumab Hormones

37.3%22.6%11.7%26.4%

40.4%23.2%10.1%23.9%


Primary Endpoint: Independently Assessed PFS (n = 433 PFS events)


• Median PFS, pertuzumab + trastuzumab + docetaxel: 18.5 mos

• Median PFS, placebo + trastuzumab + docetaxel: 12.4 mos

• Hazard ratio = 0.62• p < 0.0001

Overall Survival: Predefined Interim Analysis (Median Follow-Up: 19.3 Months, n = 165 OS Events)


Interim analysis of OS did not cross O’Brien-Fleming stopping boundary; therefore, results are exploratory and nonsignificant

• Pertuzumab + trastuzumab + docetaxel, 69 events

• Placebo + trastuzumab + docetaxel, 96 events

• Hazard ratio = 0.64

• p = 0.005

Adverse Events


(n = 402)


Placebo(n = 406)

Cardiac Symptomatic LVSD (independent assessment)* Fall in LVEF <50% and by ≥10% from baseline

1.0%

3.8%

1.0%

6.6%

≥Grade 3 AEs Neutropenia Febrile neutropenia Leukopenia Diarrhea

48.9%13.8%12.3%7.9%

45.8%7.6%

14.6%5.0%


von Minckwitz G et al. SABCS 2011;Abstract OT1-02-04.

Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer: APHINITY (BIG 4-11/BO25126/TOC4939g)

Jones S et al. SABCS 2011;Abstract PD07-03.

Phase II Trial of Adjuvant TC (Docetaxel/Cyclophosphamide) plus Trastuzumab (HER TC) in HER2 Positive Early Stage Breast Cancer Patients

Survival and Select Adverse Events (AEs)

Jones S et al. SABCS 2011;Abstract PD07-03.

AEs (n = 486) All Grades Grade 3/4

Neutropenia 51.4% 47.1%

Febrile neutropenia 7.0% 6.2%

Anemia 27.0% 1.0%

Thrombocytopenia 3.3% 0.2%

Fatigue 58.4% 4.3%

Diarrhea 38.3% 3.3%

Cardiac dysfunction 6.0% 0.4%

DFS, disease-free survival; OS, overall survival; ESBC, early-stage breast cancer

Survival

DFS OS

2-year 3-year 2-year 3-year

Overall safety population (n = 486) 97.8% 96.3% 99.4% 98.5%

Pts with node-positive ESBC (n = 101) 96.9% 91.9% 100% 96.5%

Pts with node-negative ESBC (n = 385) 98.1% 97.7% 99.2% 99.2%

Pts with node-negative tumor < 1.0 cm (n = 94) 100% 100% 100% 100%

Goss P et al. SABCS 2011;Abstract S4-7.

Results of the TEACH Trial. Lapatinib in Women with Early-Stage HER2-Overexpressing Breast Cancer: A Double-Blind, Placebo-Controlled, Phase III Trial

TEACH Study Design


Eligibility:

Stage I-IIIC HER2+ local ICH3+ or FISH+

No prior trastuzumab

Neo(adjuvant) CMF, anthracycline or taxane

Appropriate endocrine therapy

N = 3,147 from 33 countries

R

Lapatinib 1500 mg qd x 1 y

Placebo qd x 1 y

DiagnosisAdjuvantchemo

Median time sinceinitial diagnosis: 2.7 y

Primary endpoint: Disease-free survival

Survival Analysis: ITT and Centrally Confirmed FISH+ (Median F/U: 4 Years)

Endpoint Hazard ratio p-value

Disease-free survival ITT (N = 3,147) ER/PR+ ER/PR- Central HER2 (N = 2,490)

0.830.980.680.82

0.0530.8860.0060.04

Overall survival ITT 0.99 0.966


Common Adverse Events: Maximum NCI CTC Toxicity Grades


Lap Plac

Max Tox Grade, n (%)

Lapatinib (Lap)(n = 1,573)

Placebo (Plac)(n = 1,574)

Grade 1 414 (26) 558 (35)

Grade 2 674 (43) 505 (32)

Grade 3 333 (21) 104 (7)

Grade 4 21 (1) 15 (<1)

Diarrhea Rash Nausea Fatigue

Per

cen

tag

e o

f P

atie

nts

(%

)

Lap Plac Lap Plac Lap Plac

6

18

37

13

31 35

19

5

1

13

21

14

3

1

10

11

12

31

10

31

Yardley DA et al. SABCS 2011;Abstract P1-12-10.

Phase II Study Evaluating Lapatinib in Combination with nab®-Paclitaxel in Women Who Have Received ≤1 Chemotherapy Regimen for HER2-Overexpressing Metastatic Breast Cancer

Efficacy Analysis and Adverse Events

EndpointLapatinib + nab paclitaxel

(n = 60)

Overall response rate Complete response Partial response

53%7%

47%

Median progression-free survival 39.7 weeks

Serious Adverse Events

Diarrhea 5%

Anemia 3%

Febrile neutropenia 3%

Yardley DA et al. SABCS 2011;Abstract P1-12-10.

Gianni L et al. SABCS 2011;Abstract S4-8.

AVEREL, A Randomized Phase III Trial to Evaluate Bevacizumab in Combination with Trastuzumab + Docetaxel as First-Line Therapy for HER2-Positive Locally Recurrent/ Metastatic Breast Cancer

Efficacy Endpoints

Endpoint

Trastuzumab + Docetaxel(n = 208)

Trastuzumab + Docetaxel

+ Bevacizumab(n = 216)

Hazard Ratio p-value

Median PFS Investigator assessed* Independent review**

13.7 mo13.9 mo

16.5 mo16.8 mo

0.820.72

0.07750.0162

Median OS (interim) Unstratified Stratified

38.3 mo 38.5 mo1.010.94

0.95430.7078

Objective response rate Investigator assessed Independent review

69.9%65.9%

74.3%76.5%

——

0.34920.0265

Gianni L et al. SABCS 2011;Abstract S4-8.

* Unstratified** Stratified, censored for nonprotocol therapy

PFS According to Baseline Plasma VEGF-A

With permission from Gianni L et al. SABCS 2011;Abstract S4-8.

H + DOC low VEGF-A (n = 45)H + DOC high VEGF-A (n = 37)

H + DOC + BEV low VEGF-A (n = 36)H + DOC + BEV high VEGF-A (n = 43)

Plasma VEGF-A HR (95% CI)

H + DOC + BEV better

H + DOC better

≤ median 0.83 (0.50-1.36)

> median 0.70 (0.43-1.14)

Time (months)

Es

tim

ate

d p

rob

abili

ty

0.2 0.5 1 2 5

HR

16.616.5 13.68.5

A 42-year-old premenopausal woman presents 1 year after completing adjuvant TCH for ER-negative, HER2-positive IDC with asymptomatic lung mets. Your likely recommendation:

A 42-year-old premenopausal woman presents 1 year after completing adjuvant TCH for an ER-negative, HER2-positive IDC with asymptomatic lung mets. Your likely recommendation:

4%

31%

10%

10%

34%

4%

7%

0% 5% 10%15%

Other

Lapatinib/trastuzumab

Nanoparticle albumin-bound (nab) paclitaxel/T

Trastuzumab (T) alone

Paclitaxel/T

Lapatinib/capecitabine

Chemotherapy/trastuzumab/bevacizumab

20%25%30%35%

A 42-year-old premenopausal woman with an ER-positive, HER2-positive tumor presents 1 year after completing adjuvant TCH, on tamoxifen with asymptomatic lung mets. Your likely recommendation:

14%

12%

63%

6%

5%

0% 10% 20% 30% 40% 50% 60% 70%

Other

Chemotherapy/anti-HER2 treatment

E/anti-HER2treatment/chemotherapy

E/anti-HER2 treatment

Endocrine treatment (E)

A 42-year-old premenopausal woman with an ER-positive, HER2-positive tumor presents 1 year after completing adjuvant TCH, on tamoxifen with asymptomatic lung mets. Your likely recommendation:

Module 2: Multigene/Biomarker Assays

Solin LJ et al. SABCS 2011;Abstract S4-6.

A Quantitative Multigene RT-PCR Assay for Predicting Recurrence Risk after Surgical Excision Alone without Irradiation for Ductal Carcinoma in Situ (DCIS): A Prospective Validation Study of the DCIS Score from ECOG E5194

Methods for DCIS Score Validation Study

Patients with DCIS from ECOG-E5194 (n = 670)• Treated with surgical excision (≥3-mm negative margins) without irradiation• Some received tamoxifen (n = 96)• DCIS grade: low/intermediate ≤2.5 cm or high ≤1 cm

Patients with DCIS from ECOG-E5194 (n = 670)• Treated with surgical excision (≥3-mm negative margins) without irradiation• Some received tamoxifen (n = 96)• DCIS grade: low/intermediate ≤2.5 cm or high ≤1 cm

Oncotype DX assay by RT-PCR on formalin-fixed, paraffin-embedded tumors(n = 327)

Calculated: DCIS score, Recurrence Score®

• DCIS score based on an optimized gene expression algorithm• DCIS score calculated in 2 ways:

• Continuous variable• 3 prespecified risk groups: low (<39), intermediate (39-54), high (≥55)

Oncotype DX assay by RT-PCR on formalin-fixed, paraffin-embedded tumors(n = 327)

Calculated: DCIS score, Recurrence Score®

• DCIS score based on an optimized gene expression algorithm• DCIS score calculated in 2 ways:

• Continuous variable• 3 prespecified risk groups: low (<39), intermediate (39-54), high (≥55)



Primary Endpoint: Any IBE

DCIS Score Group N

10-Year Risk

High 36 27.3%

Intermediate 45 24.5%

Low 246 12.0%

Log rank p = 0.02 Log rank p = 0.01

DCIS Score Group N

10-Year Risk

High 36 19.1%

Intermediate 45 8.9%

Low 246 5.1%

Secondary Endpoint: Invasive IBE

10-Year IBE Outcomes with the New Oncotype DX DCIS Score

Gonzalez-Angulo AM et al. SABCS 2011;Abstract OT1-03-01.

SWOG S1007: A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with 1-3 Positive Nodes, Hormone Receptor (HR)-Positive and HER2-Negative Breast Cancer with Recurrence Score (RS) of 25 or Less

SWOG-S1007 (RxPONDER) Study Design

Gonzalez-Angulo AM et al. SABCS 2011;Abstract OT1-03-01.

HR-positive, HER2-negative, nodes 1-3+ early breast cancer with RS ≤ 25(N = 4,000)

R

No chemotherapy*;appropriate endocrine therapy**

No chemotherapy*;appropriate endocrine therapy**

Chemotherapy*;appropriate endocrine therapy**

Chemotherapy*;appropriate endocrine therapy**

Primary ObjectiveDetermine the effect of chemo in patients with node-positive BC who do not have high RS by Oncotype DX

1. DFS for patients treated with chemo compared to no chemo and dependence on the magnitude of RS2. Determine the optimal cut-point for recommending chemo or not

* Various 2nd- or 3rd-generation regimens (physician/patient choice)** Various options, dependent on menopausal status (physician/patient choice)

1:1

Rezai M et al. SABCS 2011;Abstract P2-12-26.

Impact of the Recurrence Score on Adjuvant Decision-Making in ER-Positive Early Breast Cancer — Results of a Large Prospective Multicentre Decision Impact Study in Node Negative and Node Positive Disease

Rezai M et al. SABCS 2011;Abstract P2-12-26.

Summary

• 366 evaluable German patients with N0 and N+ (1-3 positive nodes) early breast cancer and no contraindication to chemo.

• Physician recommendations assessed before and after Oncotype DX assay.

• Initial treatment recommendation changed in 33.1% of all cases:– 30.3% in N0 disease– 38.5% in N+ disease

• Treatment recommendations predominantly changed from chemoendocrine therapy to endocrine therapy alone:– 18.4% in N0 disease– 27.9% in N+ disease

About how many patients, if any, do you have in your practice with metastatic disease who had DCIS as their original diagnosis?

About how many patients, if any, do you have in your practice with metastatic disease who had DCIS as their original diagnosis?

0%

2%

9%

26%

63%

0%

0% 10% 20% 30% 40% 50% 60%

>10

6-10

3-5

2

1

None

70%

For how many patients with node-positive disease in your practice have you ordered an Oncotype DX assay?

For how many patients with node-positive disease in your practice have you ordered an Oncotype DX assay?

10%

27%

16%

11%

33%

3%

0% 5% 10% 15% 20% 25% 30% 35%

>10

6-10

3-5

2

1

None

Module 3: Advanced ER-Positive Breast Cancer

Mehta RS et al. SABCS 2011;Abstract S1-1.

A Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First-Line Therapy for Postmenopausal Women with Metastatic Breast Cancer: SWOG S0226.

SWOG-S0226 Study Design


Postmenopausal, ER/PR-positive metastatic breast cancer(N = 690)

R

Anastrozole - 1 mg PO dailyTreatment until progression; crossover

to fulvestrant strongly encouraged after progression

Anastrozole – 1 mg PO dailyFirst cycle of 28 days:

Subsequent cycles of 28 days:

Fulvestrant – 500 mg IM (2x5mL) Day 1Fulvestrant – 250 mg IM (1x5mL) Day 14Fulvestrant – 250 mg IM (1x5mL) Day 28

Fulvestrant – 250 mg IM (1x5mL) Day 28Treat until progression

Primary endpoint: Progression-free survival

Primary Endpoint: Progression-Free Survival

With permission from Mehta RS et al. SABCS 2011;Abstract S1-1.

Anastrozole + Fulvestrant (268 events)Anastrozole (297 events)Stratified log-rank p = 0.0070

Median PFSAnastrozole 13.5 mos (95% CI 12.1-15.1)Combination 15.0 mos (95% CI 13.2-18.4)

HR = 0.80 (95% CI 0.68-0.94)

Secondary Endpoint: Overall Survival

With permission from Mehta RS et al. SABCS 2011;Abstract S1-1.

Anastrozole + Fulvestrant (154 deaths)Anastrozole (176 events)Stratified log-rank p = 0.049

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)

SWOG-S0226 Study Design


Postmenopausal, ER/PR-positive metastatic breast cancer(N = 690)

R

Anastrozole - 1 mg PO dailyTreatment until progression; crossover

to fulvestrant strongly encouraged after progression

Anastrozole – 1 mg PO dailyFirst cycle of 28 days:

Subsequent cycles of 28 days:

Fulvestrant – 500 mg IM (2x5mL) Day 1Fulvestrant – 250 mg IM (1x5mL) Day 14Fulvestrant – 250 mg IM (1x5mL) Day 28

Fulvestrant – 250 mg IM (1x5mL) Day 28Treat until progression

Primary endpoint: Progression-free survival

Hortobagyi GN et al. SABCS 2011;Abstract S3.7.

Baselga J et al. N Engl J Med 2011;[Epub ahead of print].

Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial

Adapted from Atkins MB et al. Nat Rev Drug Discov 2009;8(7):535-6.

Mechanism of Action of mTOR Inhibitors

Crosstalk between ER and mTOR Signaling

Adapted from Di Cosimo S, Baselga J. Nat Rev Clin Oncol 2010;7(3):139-47.

Hortobagyi GN et al. SABCS 2011;Abstract S3-7.

Postmenopausal, ER-positive locally advanced or metastatic breast cancerProgression on letrozole or anastrozole(n = 724)

R

Everolimus – 10 mg daily+

Exemestane – 25 mg daily

(n = 485)

Placebo+


(n = 239)

Placebo+


(n = 239)

Stratification: Sensitivity to prior hormonal therapy and presence of visceral metastases

Endpoints:• Primary: Progression-free survival (PFS) by local assessment• Secondary: Overall survival, overall response rate, quality of life,

safety, bone markers, pharmacokinetics

BOLERO-2 Study Design

Primary Endpoint: PFS by Local Assessment


• Median PFS, everolimus plus exemestane: 7.4 mos

• Median PFS, placebo plus exemestane: 3.2 mos

• Hazard ratio = 0.44

• p-value <1 x 10-16

Response and Clinical Benefit


Everolimus + Exemestane

Placebo + Exemestane

Response Clinical Benefit

Per

cen

t

12.0%

1.3%

50.5%

25.5%

P < 0.0001

P < 0.0001

Common Adverse Events

Everolimus + Exemestane

(n = 482)

Placebo + Exemestane

(n = 238)

All Grades Grade 3/4 All Grades Grade 3/4

Stomatitis 59% 8% 11% <1%

Rash 39% 1% 6% 0

Fatigue 36% <5% 27% 1%

Diarrhea 33% <3% 19% <1%

Decreased appetite 30% 1% 12% <1%

Nausea 29% <2% 28% 1%

Noninfectious pneumonitis 15% 3% 0 0

Hyperglycemia 14% <6% 2% <1%


A 64-year-old woman has a 2-cm ER-positive, HER2-negative primary breast cancer and asymptomatic bone and nodal mets. What systemic treatment would you recommend (cost and reimbursement aside)?

A 64-year-old woman has a 2-cm ER-positive, HER2-negative primary breast cancer and asymptomatic bone and nodal mets. What systemic treatment would you recommend (cost and reimbursement aside)?

2%

2%

4%

21%

4%

66%

0%

1%

0% 10% 20% 30% 40% 50% 60%

Other

Chemotherapy

AI/everolimus/fulvestrant

AI/everolimus

AI/fulvestrant

Fulvestrant

AI

None

70%

A 64-year-old woman has ER-positive, HER2-negative asymptomatic bone and nodal mets during year 4 of adjuvant anastrozole. What would you recommend (cost and reimbursement aside)?

A 64-year-old woman has ER-positive, HER2-negative asymptomatic bone and nodal mets during year 4 of adjuvant anastrozole. What would you recommend (cost and reimbursement aside)?

4%

0%

35%

24%

23%

13%

1%

0% 5% 10%15%20%25% 35%

Other

Chemotherapy

Exemestane/everolimus/fulvestrant

Exemestane/everolimus

Exemestane/fulvestrant

Fulvestrant

Exemestane

30%

Module 4: HER2-Negative; BRCA1/2 Mutant Breast Cancer

Gradishar WJ et al. SABCS 2011;Abstract P5-19-03.

Nab-Paclitaxel Versus Docetaxel for the First-Line Treatment of Metastatic Breast Cancer: Overall Survival and Safety Analysis of a Randomized Phase 2 Trial

Final Overall Efficacy Analysis

Endpoint

Nab paclitaxel Docetaxel

300 mg/m2 q3w

(n = 76)

100 mg/m2 qw3/4

(n = 76)

150 mg/m2

qw3/4(n = 74)

100 mg/m2 q3w

(n = 74)

Overall response rate*

46% 63% 74% 39%

Median progression-free survival†

10.9 mo 7.5 mo 14.6 mo 7.8 mo

Median overall survival‡ 27.7 mo 22.2 mo 33.8 mo 26.6 mo

Gradishar WJ et al. SABCS 2011;Abstract P5-19-03.

* Investigator-assessed endpoint. Overall p-value among 4 treatment arms < 0.001.† Investigator-assessed endpoint. Overall p-value among 4 treatment arms = 0.008.‡ Overall p-value among 4 treatment arms = 0.047.

Miller KD et al. SABCS 2011;Abstract OT3-01-05.

PARP Inhibition After Preoperative Chemotherapy in Patients with Triple-Negative Breast Cancer (TNBC) or Known BRCA1/2 Mutations: Hoosier Oncology Group BRE09-146

BRE09-146 Study Design

Miller KD et al. SABCS 2011;Abstract OT3-01-05.

Stage I-III TNBC or BRCA1/2 mutant BC with residual disease after anthracycline and/or taxane neoadjuvant Rx (N = 128)

(Cisplatin 75 mg/m2 IV D1 q3wk +rucaparib 24 mg* IV D1,2,3 q3wk) x 4

*(30 mg IV cycles 2-4)

(Cisplatin 75 mg/m2 IV D1 q3wk +rucaparib 24 mg* IV D1,2,3 q3wk) x 4

*(30 mg IV cycles 2-4)

Cisplatin 75 mg/m2 IV D1 q3wk x 4Cisplatin 75 mg/m2 IV D1 q3wk x 4

Rucaparib 100 mg PO

x 24 wk

Rucaparib 100 mg PO

x 24 wk

Rucaparib is a potent IV and oral inhibitor of PARP1 and PARP2

Primary Objective: 2-year DFS

Secondary Objectives: Safety and tolerability, 1-year DFS, 5-year OS,

pharmacokinetics, correlatives of benefit from DNA damaging chemo and PARP inhibition

R

Andreopoulou E et al. SABCS 2011;Abstract OT3-01-17.

Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Low-Dose Metronomic Cyclophosphamide Alone or in Combination with Veliparib (ABT-888) in Chemotherapy-Resistant ER and/or PR-Positive, HER2/neu-Negative Metastatic Breast Cancer: New York Cancer Consortium Trial P8853

NYC Consortium P8853 Study Design

Andreopoulou E et al. SABCS 2011;Abstract OT3-01-17.

ER- and/or PR-positive, HER2-negative mBC progressing on ≥1 line of endocrine Rx and 2 lines of chemo (N = 62)

R

Cyclophosphamide 50 mg PO daily + veliparib 60 mg PO daily

Cyclophosphamide 50 mg PO daily + veliparib 60 mg PO daily

Cyclophosphamide 50 mg PO daily + placebo

Cyclophosphamide 50 mg PO daily + placebo

Primary Objective: PFSSecondary Objectives: ORR, clinical benefit rate, OS

A 55-year-old woman with a node-negative, triple-negative IDC receives adjuvant docetaxel/cyclophosphamide (TC) but then develops asymptomatic bone and nodal mets 18 months later. What is your preferred treatment?

A 55-year-old woman with a node-negative, triple-negative IDC receives adjuvant docetaxel/cyclophosphamide (TC) but then develops asymptomatic bone and nodal mets 18 months later. What is your preferred treatment?

4%

6%

6%

22%

21%

28%

13%

0% 5% 10% 15% 20% 25% 30%

Other

Platinum/paclitaxel/bevacizumab

Nab paclitaxel

Paclitaxel

Platinum/nabpaclitaxel/bevacizumab

Paclitaxel/bevacizumab

Nab paclitaxel/bevacizumab

When using nab paclitaxel, what dose and regimen do you use?

When using nab paclitaxel, what dose and regimen do you use?

80%

3%

17%

0% 10% 20% 30% 40% 50% 60%

150 mg/m2

qwkly 3/4

100 mg/m2

qwkly 3/4

300 mg/m2

q3wk

70% 80%

In the next 5 years, how likely is it that PARP inhibitors will become incorporated into the management of breast cancer?

In the next 5 years, how likely is it that PARP inhibitors will become incorporated into the management of breast cancer?

25%

44%

28%

3%

0% 10% 20% 30% 40% 50%

Very unlikely

Somewhat unlikely

Somewhat likely

Very likely

Module 5: Bone-Targeted Therapy

Paterson AHG et al. SABCS 2011;Abstract S2-3.

NSABP Protocol B-34: A Clinical Trial Comparing Adjuvant Clodronate vs Placebo in Early Stage Breast Cancer Patients Receiving Systemic Chemotherapy and/or Tamoxifen or No Therapy — Final Analysis

NSABP-B-34 Study Design


Stratification:Age (<50 vs ≥50)Number of positive nodes (0, 1-3, 4+)ER/PR status(N = 3,323)

Key Endpoints:Primary: Disease-free survival (DFS)Secondary: Incidence of skeletal metastases, overall survival, relapse-free survival, incidence of nonskeletal metastases and incidence of skeletal morbid events

Clodronate1,600 mg/day x 3 years

Clodronate1,600 mg/day x 3 years

Placebo* x 3 yearsPlacebo* x 3 years

* Alone or in addition to adjuvant chemotherapy or hormone therapy at the discretion of the investigator

R

Primary Endpoint: DFS


Treatment Arm N Events

Placebo 1,656 312

Clodronate 1,655 286

HR = 0.91 p = 0.27

Secondary Endpoints — Post-Hoc Analysis: Benefits Observed in Patients ≥50


Hazard Ratio p-value

Relapse-free interval 0.76 0.05

Bone metastasis-free interval 0.61 0.024

Nonbone metastasis-free interval 0.63 0.015

Overall survival 0.80 0.10

Gnant M et al. SABCS 2011;Abstract S1-2.

Long-Term Follow-Up in ABCSG-12: Significantly Improved Overall Survival with Adjuvant Zoledronic Acid in Premenopausal Patients with Endocrine-Receptor-Positive Early Breast Cancer

Anastrozole +zoledronic acidAnastrozole +zoledronic acid

ABCSG-12 Study Design


Premenopausal, Stage I and II ER/PR-positive breast cancer(N = 1,803)

Surgery (+RT)

Surgery (+RT)

Tamoxifen (Tam)Tamoxifen (Tam)

Tamoxifen +zoledronic acid (ZDA)

Tamoxifen +zoledronic acid (ZDA)

Anastrozole (A)Anastrozole (A)

Primary endpoint: Disease-free survival

Study dosing:Tamoxifen: 20 mg/dayZoledronic acid: 4 mg q6mAnastrozole: 1 mg/dayGoserelin: 3.6 mg q28d

GoserelinGoserelin R

OS: ZDA versus No ZDA


Univariate Multiple Cox Regression

No. of events

Hazard ratio (95% CI) p-value

Hazard ratio (95% CI) p-value

No ZDA 49/903 vs No ZDA (Mantel-Cox) vs No ZDA

ZDA 33/9000.63

(0.40-0.99)0.049

0.61 (0.39-0.96)

0.033

de Boer R et al. SABCS 2011;Abstract S1-3.

Long-Term Survival Outcomes among Postmenopausal Women with Hormone Receptor-Positive Early Breast Cancer Receiving Adjuvant Letrozole and Zoledronic Acid: 5-Year Follow-Up of ZO-FAST.

ZO-FAST Study Design


Postmenopausal Stage I, II and III ER/PR-positive breast cancerT-score ≥ -2.0(N = 1,065)

Key Endpoints:Primary: Bone mineral density (BMD) at 12 monthsSecondary: BMD at 36 and 60 months, disease recurrence, fractures, safety

Letrozole +immediate zoledronic acid (IM-ZDA)

Letrozole +immediate zoledronic acid (IM-ZDA)

Letrozole + delayed zoledronic acid (D-ZDA)

If 1 of the following occurs:• BMD T-score < -2.0• Clinical fracture• Asymptomatic fracture at 36 months

Letrozole + delayed zoledronic acid (D-ZDA)

If 1 of the following occurs:• BMD T-score < -2.0• Clinical fracture• Asymptomatic fracture at 36 months

Treatment duration = 5 years

R

DFS Comparison: ZO-FAST, AZURE and ABCSG-12


a Defined as naturally occurring menopause prior to diagnosis.

1 Data from Coleman RE, et al. N Engl J Med 2011;365(15):1396-1405; 2 Data from Gnant M, et al. Lancet Oncol 2011;12(7):631-641.

Trial n Hazard Ratio p-value

ZO-FAST Truly postmenopausala

888 0.71 0.0998

AZURE1

>5 y postmenopausal1,041 0.75 0.02

ABCSG-122

Rendered postmenopausal (overall population)

1,803 0.68 0.008

Osteonecrosis of the Jaw (ONJ)


• ZO-FAST (N = 1,065; 5-year follow-up)

– 3 confirmed cases (0.56%)a

• Other adjuvant ZDA trials

– Z-FAST (N = 601; 5-year follow-up)1

• No confirmed cases

– E-ZO-FAST (N = 527; 3-year follow-up)2

• 1 confirmed case (0.19%)

– ABCSG-12 (N = 1,803; >5-year follow-up)3

• No confirmed cases

– AZURE (N = 3,360; 5-year follow-up)4

• 17 confirmed cases (1.1%)

a A total of 9 potential ONJ events from 7 patients were reported and independently adjudicated by an external panel; 3 were confirmed, 2 had insufficient data, the remaining events were excluded.

1 Brufsky A, et al. SABCS 2009. Abstract 4083. 2 Llombart A, et al. ASCO-BC 2009. Abstract 213. 3 Gnant M, et al. ASCO 2011. Abstract 520. 4 Coleman RE, et al. N Engl J Med 2011;365:1396-1405.

A 42-year-old premenopausal woman has a node-negative, ER-positive, HER2-negative IDC with a low Recurrence Score (RS). The patient is receiving tamoxifen and has normal bone density. Would you add a bisphosphonate?

A 42-year-old premenopausal woman has a node-negative, ER-positive, HER2-negative IDC with a low Recurrence Score (RS). The patient is receiving tamoxifen and has normal bone density. Would you add a bisphosphonate?

9%

2%

84%

5%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

Possibly

Likely

Yes

No

A 62-year-old woman has a node-negative, ER-positive, HER2-negative IDC with a low RS. The patient is receiving an AI and has normal bone density. Would you add a bisphosphonate?

A 62-year-old woman has a node-negative, ER-positive, HER2-negative IDC with a low RS. The patient is receiving an AI and has normal bone density. Would you add a bisphosphonate?

7%

11%

72%

10%

0% 10% 20% 30% 40% 50% 60% 70% 80%

Possibly

Likely

Yes

No

Documents

Thursday, January 12, 2012 7:30 PM - 9:00 PM ET An Interactive Webcast Featuring Discussion of Key Presentations and Posters from the 2011 San Antonio