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Transcript of Thursday, January 12, 2012 7:30 PM - 9:00 PM ET An Interactive Webcast Featuring Discussion of Key...
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
Baselga J et al. SABCS 2011;Abstract S5-5.
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.
Baselga J et al. SABCS 2011;Abstract S5-5.
Prior Therapy for Breast Cancer
Docetaxel, Trastuzumab,Pertuzumab
(n = 402)
Docetaxel, Trastuzumab,
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%
Baselga J et al. SABCS 2011;Abstract S5-5.
Primary Endpoint: Independently Assessed PFS (n = 433 PFS events)
Baselga J et al. SABCS 2011;Abstract S5-5.
• 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)
Baselga J et al. SABCS 2011;Abstract S5-5.
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
Docetaxel, Trastuzumab,Pertuzumab
(n = 402)
Docetaxel, Trastuzumab,
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%
Baselga J et al. SABCS 2011;Abstract S5-5.
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
Goss P et al. SABCS 2011;Abstract S4-7.
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
Goss P et al. SABCS 2011;Abstract S4-7.
Common Adverse Events: Maximum NCI CTC Toxicity Grades
Goss P et al. SABCS 2011;Abstract S4-7.
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)
Solin LJ et al. SABCS 2011;Abstract S4-6.
Solin LJ et al. SABCS 2011;Abstract S4-6.
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
Mehta RS et al. SABCS 2011;Abstract S1-1.
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
Mehta RS et al. SABCS 2011;Abstract S1-1.
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+
Exemestane – 25 mg daily
(n = 239)
Placebo+
Exemestane – 25 mg daily
(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
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
• 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
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
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%
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
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
Paterson AHG et al. SABCS 2011;Abstract S2-3.
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
Paterson AHG et al. SABCS 2011;Abstract S2-3.
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
Paterson AHG et al. SABCS 2011;Abstract S2-3.
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
Gnant M et al. SABCS 2011;Abstract S1-2.
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
Gnant M et al. SABCS 2011;Abstract S1-2.
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
de Boer R et al. SABCS 2011;Abstract S1-3.
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
de Boer R et al. SABCS 2011;Abstract S1-3.
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)
de Boer R et al. SABCS 2011;Abstract S1-3.
• 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