Transcript Document

ASCO 2010: Metastatic Breast
Cancer
New Data & Expert Clinical Insights
Edith A. Perez, MD
Serene M. and Frances C. Durling Professor
of Medicine
Deputy Director, Mayo Clinic Cancer Center
Mayo Clinic
Mayo Clinic Today
 3 million patients a year from USA & 150 countries
 56,800 total personnel
Mayo Clinic in Minnesota
Mayo Clinic in Arizona
Mayo Clinic in Florida
Phase II/III Trials in Metastatic
Breast Cancer: What is New?
HER2 positive
Triple negative
General
A Phase Ib/II Trial of Trastuzumab-DM1
(T-DM1) with Pertuzumab
for Women with HER2+ MBC
Previously Treated with Trastuzumab
K. Miller, L. Gianni, F. Andre, V. Dieras, R. L.
Mahtani, N. Harbeck, J. E. Huang, T. Shih, Y.
Choi, H. A. Burris III
Miller K, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1012)
Study Design: HER2+ Locally
Advanced or Metastatic Breast Cancer
Cohort 2
Cohort 1
3-6 patients
T-DM1 3.0 mg/kg +
Pertuzumab*
T-DM1 3.6 mg/kg +
Pertuzumab*
0/3
or
1/6 DLTs
Yes†
Expand T-DM1
3.6 mg/kg* dose
level to 60
evaluable pts
Yes
0/3
or
1/6 DLTs
No
Expand T-DM1
3.0 mg/kg dose
level to 60
evaluable pts
No
T-DM1 2.4 mg/kg +
Pertuzumab*
0/3
or
1/6 DLTs
Yes
Expand T-DM1
2.4 mg/kg dose
level to 60
evaluable pts
No
No Further Enrollment
Dose-Escalation Phase
Expansion Phase‡
DLT=dose-limiting toxicity: T-DM1=trastuzumab-MCC-DM1.
* Full-dose pertuzumab=Cycle 1 loading dose (840 mg); 420 mg all subsequent cycles.
† Patients enrolled to the initial cohort may now receive 3.6 mg/kg T-DM1 in subsequent cycles along with full-dose pertuzumab.
‡ 20 first-line and 40 relapsed (second-line and beyond) patients were to be included in this phase.

58 patients added into expanded Phase II at established dose*
Miller K, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1012)
Preliminary Efficacy Promising
with T-DM1 + Pertuzumab


67 patients enrolled
– 44 evaluable relapsed pts (2nd line or beyond)
– 22 pts with newly diagnosed HER2+ MBC (first-line)
– 1 pt without safety data, excluded from analysis
– Median 5 doses T-DM1 received
ORR 35.7% (10/28 partial responses)
ORR data from 28 pts who received ≥4 cycles, or progressed or died
Cohort 1 (n=3)
Cohort 2 (n=25)
Total (N=28)
0
0
0
Partial response
2 (66.7)
8 (32.0)
10 (35.7)
Stable disease
1 (33.3)
12 (48.0)
13 (46.4)
Progressive disease
0
4 (16.0)
4 (14.3)
Missing
0
1 (4.0)
1 (3.6)
Complete response
Miller K, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1012)
HER2+ Breast Cancer:
what is next in MBC?
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TDM4550 1st-line trial --- ESMO Oct 2010 (Perez et al)
– T-DM1 vs (Docetaxel + Trastuzumab)
CLEOPATRA
– Docetaxel + Trastuzumab +/- Pertuzumab
COMPLETE (MA.31)
– 1st line: Taxane + (Trastuzumab or Lapatinib)
EMILIA study ongoing; refractory
– T-DM1 vs (Lapatinib + Capecitabine)
Phase III Capecitabine + Trastuzumab or Lapatinib; refractory
MARIANNE to be initiated; 1st-line
 Phase III of T-DM1 vs (T-DM1 + Pertuzumab) vs taxane+ Trastuzumab
Safety and Efficacy of the Oral PARP
Inhibitor Olaparib (AZD2281) +
Paclitaxel as 1st or 2nd-line Rx of
Metastatic Triple-negative Breast
Cancer: Results From the Safety
Cohort of A Phase I/II Multicenter Trial
R. A. Dent, G. J. Lindeman, M. Clemons, H.
Wildiers, A. Chan, N. J. McCarthy, C. F. Singer,
E. S. Lowe, K. Kemsley, J. Carmichael
Dent RA, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1018)
Olaparib + Paclitaxel Well Tolerated
Except for Dose-Limiting Neutropenia
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Olaparib 200 mg po BID continuous + paclitaxel
90mg/m2 IV weekly for 3/4 weeks
1st-line TN breast cancer
–

N=19, about 70% first-line
Toxicities
–
Neutropenia Grade 1/2 (26%), Grade ≥3 (32%)
Acceptable dose intensity not achieved due to neutropenia
 Protocol amended to allow treatment with GSCF as secondary
prophylaxis, additional cohort (n=10) added
Diarrhea Grade 1/2 (63%)
Nausea Grade 1/2 (58%)
Fatigue Grade 1/2 (47%), Grade 3 (5%)

–
–
–
Dent RA, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1018)
Response Data of Olaparib +
Paclitaxel in TNBC
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No complete responses, 33-40% partial
responses
Median PFS >5 months in both cohorts
–
–
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6.3 months (no GCSF)
5.2 months (GCSF)
Regimen will not be pursued due to neutropenia
Dent RA, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1018)
Triple Negative Breast Cancer:
What is next for MBC?
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Evaluate role of PARP expression on sensitivity
to PARP inhibitors
Pending data of the phase III gem/carbo +/iniparib
Evaluate role of platinum agents, antiangiogenic Rx, brostacillin Rx
A Phase III Study (EMBRACE) of
Eribulin Mesylate Versus Treatment of
Physician's Choice in Patients With
Locally Recurrent or Metastatic Breast
Cancer Previously Treated With an
Anthracycline and a Taxane
C. Twelves, D. Loesch, J. L. Blum, L. T. Vahdat,
K. Petrakova, P. J. Chollet, C. E. Akerele, S.
Seegobin, J. Wanders, J. Cortes
Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)
Eribulin in Heavily Pretreated
Metastatic Breast Cancer
Eribulin mesylate
Patients (N = 762)
• Locally recurrent or MBC
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
• 2-5 prior chemotherapies
– ≥2 for advanced disease
Randomization 2:1
– Prior anthracycline and
taxane
• Progression ≤6 months
of last chemotherapy
• Neuropathy ≤ grade 2
• ECOG ≤2


Treatment of Physician's
Choice (TPC)
Any monotherapy (chemotherapy,
hormonal, biological) or
supportive care only
Primary
endpoint
• Overall survival
Secondary
endpoints
• PFS
• ORR
• Safety
Global, randomized, open-label Phase III trial (Study 305, EMBRACE)
Final analysis after 422 deaths
– Median age 55.2 yrs, 16% HER2+, 19% TNBC, median 4 prior agents
Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)
EMBRACE: Treatments of
Physician’s Choice
96% of patients treated with chemotherapy
50
Total patients = 247
% of patients
40
30
20
n=61
n=46
n=44
n=38
n=24
10
n=25
n=9
0
No patient received best supportive care or "biological" therapies only
Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)
EMBRACE: Significant Improvement in
OS with Eribulin vs Physicians’ Choice
1.0
Eribulin (n=508)
TPC (n=254)
1 year survival
53.9%
43.7%
Survival Probability
0.8
Eribulin
Median 13.12 months
0.6
HR* 0.81 (95% Cl 0.66, 0.99)
p-value†=0.041
TPC
Median 10.65 months
0.4
0.2
2.47 months
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Overall Survival (months)
ITT population, *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata
† p value from stratified log-rank test (pre-defined primary analysis); TPC, treatment of physicians’ choice, HR, hazard ratio;
Cl, confidence intervals
Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)
EMBRACE: PFS by Independent
and Investigator Review
1.0
Proportion progression-free
Proportion progression-free
Investigator review (ITT)
Independent review (ITT)
1.0
Eribulin (n=508)
0.8
TPC (n=254)
0.6
0.4
0.2
0.0
Eribulin (n=508)
0.8
TPC (n=254)
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
18
20
0
2
Time (months)
4
6
8
10
14
16
18
Time (months)
Median (months)
Median (months)
Eribulin
3.7
Eribulin
3.6
TPC
2.2
TPC
2.2
HR 0.87 (95% CI 0.71, 1.05)
p-value=0.14
12
HR 0.76 (95% CI 0.64, 0.90)
p-value=0.002
TPC, treatment of physicians’ choice
Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)
20
EMBRACE: ORR and Safety
Independent
review
ORR (CR+PR), %
p-value
Eribulin
(n=468)
TPC
(n=214)
Eribulin
(n=468)
TPC
(n=214)
12.2
4.7
13.2
7.5
0.002
0.028
SD, %
44.4
44.9
46.8
44.9
PD %
40.6
49.1
37.6
45.3
NE, %
2.6
1.4
2.4
2.3
22.6
16.8
27.8
20.1
Clinical benefit rate
(CR+PR+SD ≥6 months), %

Investigator
review
AEs
–
Grade 3/4 asthenia/fatigue (7.6%), neutropenia (44%), peripheral
neuropathy (8.4%) with eribulin
–
10% of pts experienced SAEs (eribulin 12%, physician choice 7%)
Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)
Sunitinib (SU) in Combination With
Docetaxel (D) Versus D Alone For the
First-line Treatment of Advanced Breast
Cancer (ABC)
J. Bergh, R. Greil, N. Voytko, A. Makhson, J. Cortes, A.
Lortholary, X. Huang, C. Giorgetti, K. A. Kern, M. Lichinitser
Phase III Trial of Sunitinib (SU) in
Combination With Capecitabine (C)
Versus C in Previously Treated
Advanced Breast Cancer (ABC)
J. Crown, V. Dieras, E. Staroslawska, D. A. Yardley, N. Davidson, T.
D. Bachelot, V. R. Tassell, X. Huang, K. A. Kern, G. Romieu
Bergh J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1010)
Crown J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1011)
SUN 1064 and 1099 Study Designs
SUN 1064
R
A
N
D
O
M
I
Z
A
T
I
O
N
Docetaxel 75 mg/m2 IV
day 1 q3w
+
Sunitinib 37.5 mg po
days 2-15 q3w
N=296
Docetaxel 100 mg/m2 IV
q3w
N=297
• No prior chemotherapy
for ABC
• 17% no chemotherapy
• 28% <12 month DFI
• 20% TNBC
SUN 1099
R
A
N
D
O
M
I
Z
A
T
I
O
N
CAP 2,000 mg/m2
po days 1-14 q3w
+
Sunitinib 37.5 mg po CDD
N=221
CAP 2,500 mg/m2
po days 1-14 q3w
N=221
• 78% previous rx for ABC
• Prior anthracycline and
taxane
• 27% TNBC
Bergh J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1010)
Crown J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1011)
Sunitinib in Combination with Docetaxel
or Capecitabine Not Recommended for
Advanced Breast Cancer
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Trials did not meet endpoints of prolonging PFS or OS
– Bergh (N=593)
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–
Crown (N=442)
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Median PFS 8.6 mo for SU + D vs 8.3 mo with D alone
Median OS 24.8 mo for SU + D vs 25.5 mo with D alone
Median PFS 5.5 mo for SU + C vs 5.9 mo for C alone
Median OS 16.4 mo for SU + C vs 16.5 mo for C alone
Sunitinib + docetaxel or + capecitabine not
recommended as combination in advanced breast
cancer
Bergh J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1010)
Crown J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr LBA1011)
Progression-free Survival (PFS) in
Patient Subgroups in RIBBON-2,
a Phase III Trial of Chemotherapy +/Bevacizumab for 2nd-line Rx of HER2negative MBC
A. Brufsky, R. R. Rivera, S. A. Hurvitz, I. N.
Bondarenko, V. Smirnov, V. Valero, H. S. Rugo,
R. Swamy, H. Mu,
E. A. Perez
Brufsky A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1021)
RIBBON-2: BV in Combination Provides
PFS Benefit to HER2- Patients

Bevacizumab added to variety of chemo agents in 2nd line HER2- stage
IV breast cancer
–

684 patients randomized to chemo + placebo (n=225) or chemo + BV (n=459)
Addition of BV improved median PFS (5.1 mo with placebo vs 7.2 mo
with BV, P=0.0072)
PFS by subset
Variable
N
Chemo only
Chemo + Bev
HR
ER/PR+
494
6.0
7.4
0.89 (0.71-1.10)
ER/PR-
190
2.8
6.5
0.53 (0.37-0.75)
Triple negative
159
2.7
6.0
0.49 (0.33-0.74)
Other
498
6.0
7.4
0.89 (0.71-1.10)
N
Chemo only
Chemo + Bev
HR
Taxane
304
5.8
8.0
0.64 (0.49-0.84)
Gemcitabine
160
5.5
6.0
0.90 (0.61-1.32)
Capecitabine
144
4.1
6.9
0.73 (0.49-1.08)
Vinorelbine
76
7.0
5.7
1.42 (0.78-2.59)
Backbone
Brufsky A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1021)
A Meta-analysis of Overall Survival
Data From 3 Randomized Trials of
Bevacizumab (BV) and 1st-line
Chemotherapy as Treatment for
Patients with MBC
J. O'Shaughnessy, D. Miles, R. J. Gray, V.
Dieras, E. A. Perez, R. Zon, J. Cortes, X. Zhou,
S. Phan, K. Miller
O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)
1st-line Chemotherapy +/Bevacizumab Meta-analysis
Meta-analysis of OS in 2,447 patients from 3 trials
– Control (n=1,008); BV + chemo (n=1,439)
E2100
Paclitaxel
Previousl
y
Untreate
d MBC
AVADO
Docetaxel
RIBBON-1
Capecitabine,
Taxane,
or
Anthracycline
RANDOMIZE

Chemo
+
No BV
Chemo
+
BV
Treat
until
PD
Optional
Secondline
Chemo +
BV
(AVADO and
RIBBON-1
only)
O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)
ChemoRx +/- Bevacizumab Meta-analysis:
Progression-Free Survival (pooled analysis)
Non-BV
(n=1008)
BV
(n=1439)
Median, mo
6.7
9.2
HR (95% CI)
0.64 (0.57–0.71)
O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)
Chemotherapy +/- Bevacizumab Meta-analysis:
Overall Survival (pooled analysis)
Median, mo
HR (95% CI)
1-yr survival rate (%)
Non-BV
(n=1008)
26.4
BV
(n=1439)
26.7
0.97 (0.78–1.01)
77
82
Summary (PFS, ORR, 1 yr survival, OS) of
Meta-analysis with Bevacizumab as 1st-line

PFS
–
–
–

ORR
–


HR=0.64, 36% reduction in risk of PD or death
2.5 month improvement in median PFS (P<0.0001)
Improvements across key clinical subpopulations
17% increase vs controls
1-year survival rate greater in BV + chemo arms
(P=0.003)
OS
–
No statistically significant difference
O’Shaughnessy J, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 1005)
A Meta-analysis of Results from Two
Randomized, Double-blind Studies of
Denosumab vs Zoledronic Acid (ZA)
for Treatment of Bone Metastases
A. Lipton, A. Stopeck, R. von Moos, D.H. Henry,
G.E. Richardson, G.I. Rodriguez, H.P. Bourgeois,
C. Ke, S. Jun, R.D. Dansey
Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)
Denosumab vs Zoledronic Acid:
Meta-analysis of Two Pivotal Trials
Key Inclusion
 Adults with confirmed bone
metastases from advanced
cancer (except prostate)
and multiple myeloma
Key Exclusion
 Current or prior intravenous
bisphosphonate
administration
Primary Endpoint
■
Secondary Endpoints
■
Denosumab 120 mg SC and
Placebo IV every 4 weeks (N=1912)
Supplemental Calcium and Vitamin D
Zoledronic acid 4 mg IV and
Placebo SC every 4 weeks (N=1910)
Time to first on-study SRE (non-inferiority)
Time to first on-study SRE (superiority)
■ Time to first and subsequent on-study SRE (superiority)
Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)
Denosumab vs Zoledronic Acid:
Time to First On-Study SRE

Significantly longer for denosumab vs zoledronic acid
Separation between treatments begins around 3 months
1.0
Proportion of Patients
Without SRE

HR 0.83 (95% CI: 0.74, 0.92)
P < 0.001 (Superiority)
0.8
Risk
17% Reduction
0.6
0.4
Median Months
to 1st SRE
0.2
Zoledronic acid 21.1
Denosumab
Not reached
0
0
6
12
18
24
30
Study Month
Patients at risk:
Zoledronic acid:
1910
1052
692
382
114
4
Denosumab:
1912
1084
716
402
127
4
Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)
Denosumab Superior to Zoledronic
Acid in Delaying or Preventing SREs


Denosumab reduced mean skeletal morbidity rate (SREs/year)
(0.64 vs 0.80 for zoledronic acid, P=0.0006)
Similar rates in both groups for overall rates of
–
–
–
–

Disease progression (HR 1.00; 95% CI: 0.92, 1.08; P=0.90)
Survival (HR 0.95; 95% CI: 0.86, 1.05; P=0.35)
AEs (AEs; 96% denosumab, 97% ZA)
Serious AEs (53% denosumab, 56% ZA)
Increased rates with zoledronic acid
–
–
AEs potentially associated with renal toxicity (9.6% vs 6.5% with
denosumab)
Acute phase reactions at 3 days (21.4% vs 8.8% with denosumab)
Lipton A, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr 565)
Summary of MBC Data at ASCO 2010


Feasibility of T-DM1 + Pertuzumab
Eribulin
–

Sunitinib
–

No benefit when added to docetaxel or capecitabine
Bevacizumab
–
–

Improved overall survival vs. standard of care
Improvement in RR and PFS, not OS in 1st-line setting
PFS benefit of bevacizumab in 2nd line setting, efficacy
across subgroups
Denosumab for bone metastases
–
Improved bone events vs zoledronic acid
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