Transcript Up-to-Date Review Breast Cancer

Up-to-Date Review
A Review of 2007
Breast Cancer Highlights
Harold J. Burstein, MD, PhD
Assistant Professor of Medicine
Dana Farber Cancer Institute
Breast Oncology center
Harvard Medical School
Boston, MA
Highlights
• New agents for refractory disease
– Ixabepilone
– Lapatinib
• Chemotherapy in node-positive disease?
– CALGB 9344
– Oncotype DX®
Ixabepilone: Epothilone B Analog
S.cellulosum
Epothilone B
Ixabepilone
• A new class of antineoplastics: the epothilones
• Epothilones bind to microtubules resulting in polymerization and
apoptosis
• Novel microtubule-stabilizing agent with tubulin-binding mode
distinct from other agents
Lee JJ, Swain SM. Semin Oncol. 2005;32(suppl 7):S22-S26
Kamath K et al. J Biol Chem. 2005;280:12902-12907
Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.
Ixabepilone: Preclinical Activity
N=8
Median Tumor Weight (mg)
1000
100
Control
Paclitaxel
Paclitaxel Rx (36 mg/kg/inj)
Ixabepilone Rx (10 mg/kg/inj)
Ixabepilone
10
40
70
100
130
160
Days Post-Tumor Implant
Pat-21 Xenograft
Lee FY et al. Clin Cancer Res. 2001;7:1429-1437.
Ixabepilone: Combination Preclinical Activity
Control
Capecitabine
2500
Trastuzumab Synergy
10000
Ixabepilone
Combination
250 mg/kg (MTD)
2000
10 mg/kg (MTD)
1500
1000
500
Median tumor weight (mg)
Median tumor weight (mg)
Capecitabine Synergy
Ixabepilone 4 mg/kg
1000
Trastuzumab
Ixabepilone
Combined
Rx
10
1
20
0
30
Control
100
(P=0.0001)
10
Trastuzumab, 10 mg/kg
Trastuzumab, 10 mg/kg
+
Ixabepilone, 4 mg/kg
60
40
Days Post-Tumor Implant
HER2 receptor positive KPL4
Human breast Carcinoma Xenografts
50
Days post-tumor implant
GEO Human Colon Carcinoma
Bevacizumab Synergy
2500
control
2000
Ixabepilone, 6mg/kg
1500
bevacizumab, 4mg/kg
1000
Ixabepilone, 6mg/kg
+
bevacizumab, 4mg/kg
500
0
Median tumor weight (mg)
Median tumor weight (mg)
2500
bevacizumab
4mg/kg
2000
control
1500
paclitaxel
24mg/kg
paclitaxel 24mg/kg
+
bevacizumab 4mg/kg
1000
500
0
10
20
30
40
50
60
Days post-tumor implant
GEO Human Colon Carcinoma
70
10
20
30
40
50
60
Days post-tumor implant
GEO Human Colon Carcinoma
70
Data on file. Bristol Myers Squibb Company; Princeton, NJ
Ixabepilone in MBC: Summary of
Single-agent Phase II Trials
100
90
Percentage (%)
80
83
77
70
60
26
57
35
53
SD
RR
50
40
35
30
20
42
22
10
0
41
57
N=65
After Adjuvant
Anthracycline1
(40 mg/m2 q3w)
N=23
N=37
12
N=49
3
4
Taxane Naïve MBC2 Taxane Pretreated MBC Taxane Resistant MBC
2
2
(6 mg/m daily X 5)
(40 mg/m q3w)
(6 mg/m2 daily X 5)
1. Roche H et al. J Clin Oncol. 2007;23:3415-3420.
2. Denduluri N et al. J Clin Oncol. 2007;23:3421-3427.
3. Low et al. J Clin Oncol 2005;23:2726–2734
4. Thomas E et al. J Clin Oncol. 2007;23:3399-3406
Study Design: International, Randomized,
Open-label, Phase III Trial
Ixabepilone
(40 mg/m2 IV over 3 hr d1 q3wk)
+
Capecitabine
Metastatic or locally
advanced breast cancer
RESISTANT
to anthracyclines
and taxanes
N = 752
Stratification
• Visceral metastases
• Prior chemotherapy for MBC
(2000 mg/m2/day PO 2 divided doses
d1-d14 q3wk)
N = 375
Capecitabine
(2500 mg/m2/day PO 2 divided doses
d1-d14 q3wk)
N = 377
•Anthracycline resistance
•Study site
Resistance to Prior Therapy
Strict definition: patients whose tumors rapidly progressed in the adjuvant or
metastatic setting after receiving both anthracyclines and taxanes
Setting
Anthracycline
Taxane
Metastatic
≤3 months of last dose
≤4 months of last dose
Neo/adjuvant
≤6 months of last dose
≤12 months of last dose
Minimum cumulative dose
Any
Doxorubicin: 240 mg/m2
Epirubicin: 360 mg/m2
Phase III Study 046:
Key Baseline Patient Demographics
Patients, no. (%)
Characteristic
Ixabepilone + Capecitabine
(N=375)
Capecitabine
(N=377)
53 (25-76)
52 (25-79)
Visceral disease (liver and/or lung)
316 (84)
315 (84)
No. of disease sites: < 2 sites
≥ 2 sites
43 (11)
332 (89)
36 (10)
341 (90)
91 (24)
96 (26)
Prior neoadjuvant/adjuvant chemotherapy
282 (75)
285 (76)
No. of prior chemotherapy regimens for
metastatic disease
0
1
27 (7)
179 (48)
33 (9)
184 (49)
152 (41)
17 (5)
138 (37)
22 (6)
164 (44)
165 (44)
40 (11)
327 (87)
144 (38)
44 (12)
319 (85)
130 (35)
Median age (min-max) in years
ER-, PR-, HER2-
2
3
Anthracycline resistance
Taxane resistance
Neoadjuvant/adjuvant setting
Metastatic setting
PD as best response to prior taxanes
Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006; Data on file. Bristol Myers Squibb Company; Princeton, NJ;
(ixabepilone) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ; 2007.
Phase III Study 046: Progression-free Survival
1.0
Median
95% CI
Ixabepilone + Capecitabine
5.7 mo
(4.8–6.7)
Capecitabine
4.1 mo
(3.1–4.3)
PROPORTION NOT PROGRESSED
0.9
0.8
0.7
0.6
HR: 0.69 (0.58–0.83)
0.5
P<0.0001
0.4
0.3
0.2
0.1
0.0
0
4
8
12
16
20
24
28
32
MONTHS
(ixabepilone) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ; 2007.
Phase III Study 046:
Non-hematologic Toxicities
Adverse Events
Capecitabine, %
(N=368)
Ixabepilone + Capecitabine,
% (N=369)
Total
G3
G4
Total
G3
G4
Peripheral sensory
neuropathy a,b,c
65
20
<1
16
0
0
Hand-foot syndrome
64
18
0
63
17
0
Fatigue/asthenia
60
15
<1
29
4
<1
Diarrhea
44
6
0
39
8
0.5
Myalgia/arthralgia
39
8
0
5
<1
0
Stomatitis/mucositis
31
4
0.5
20
3
0
Non-Hematologic Toxicities
a Grade
3/4 Peripheral Neuropathy 23% (21% sensory and/or 5% motor)
time to improvement of Grade 3/4 neuropathy is 6.0 weeks
cImprovement was defined as a return of symptoms to baseline levels or to grade 1
bMedian
Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006
Data on file. Bristol Myers Squibb Company; Princeton, NJ; (ixabepilone) [package insert]. Bristol-Myers Squibb Company:
Princeton, NJ; 2007.
Grade 3/4 Neuropathy Rates (%)
Ixabepilone Grade 3/4 Neuropathy Rates
in Breast Cancer
25
21
20
20
14
15
12
10
5
3
3
0
0
Prior Therapy
Treatment
schedule
Median # of
cycles
Neoadjuvant
Taxane Naïve
MBC
Taxane
Pretreated
MBC
Anthracycline
Pretreated
MBC
Taxane
Resistant
MBC
Anthracycline
and Taxane
resistant MBC
Anthracycline, Taxane,
and Capecitabine
resistant MBC
40 mg/m2 q3w
x 4 cycles
6 mg/m2 daily
x5
6 mg/m2 daily
x5
40 mg/m2 q3w
40 mg/m2 q3w
40 mg/m2 q3w
40 mg/m2 q3w
4
8
4
6
+ capecitabine
3
5
4
Roche H et al. J Clin Oncol. 2007;23:3415-3420; Denduluri N et al. J Clin Oncol. 2007;23:3421-3427; Low et al. J Clin Oncol 2005;23:2726–2734; Thomas E et al. J Clin
Oncol. 2007;23:3399-3406; Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305; Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006; Perez E, et al.
J Clin Oncol. 2007;23: 3407-3414.
Phase III Study 046:
Hematologic Toxicities
Ixabepilone +
Capecitabine, % (N=369)
Capecitabine, %
(N=368)
Total
G3
G4
Total
G3
G4
Neutropenia
79
32
36
31
9
2
Febrile Neutropenia
5
4
1
1
0.5
0.5
Leukopenia
90
41
16
36
5
1
Anemia
84
8
2
6
4
1
Thrombocytopenia
44
5
3
6
2
2
Adverse Events
Hematologic Toxicities
Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006; Data on file. Bristol Myers Squibb Company; Princeton, NJ;
(ixabepilone) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ; 2007.
Highlights
• New agents for refractory disease
– Ixabepilone
– Lapatinib
• Chemotherapy in node-positive disease?
– CALGB 9344
– Oncotype DX®
Interactions Between Trastuzumab
and Tumor Cells
Burstein, H. J. N Engl J Med 2005;353:1652-1654
Lapatinib Targets HER2
Konecny et al, Cancer Res 2006; 66(3): 1630-9)
Phase I Results Summary
• Steady-state achieved in 6-7 days in cancer patients (Studies
EGF10003 and EGF10004)1,2
• Serum concentrations were 90% of the in vitro IC503
• Dose proportionality at steady state (500 – 1600 mg/day)1
– Tmax = 3 – 6 hours post-dose
– Cmax = 1.02 – 2.13 g/mL
– AUC = 13.9 – 29.4 g/mL-h
• Effective half-life = 24 hours, once-daily dosing should be possible1,2
1. Burris HA et al. Journal of Clinical Oncology. 2005;23(23):5305-5313.
2. Burris HA et al. Oncologist. 2004;(9 suppl 3):10-15.
3. Kim TE, Murren JR. Drugs. 2003;6:886-893.
Phase I Results Summary
• Clinical activity observed in heavily pretreated patients in
EGF10003 (43 patients)1
– 1 CR in head and neck cancer
– 1 minor response
– Stable disease for up to 13 months in remainder
• Clinical activity observed in heavily pretreated patients in
EGF100042
– 4 PR in trastuzumab-resistant breast cancer
– Prolonged SD in 10 patients
• Well tolerated: most common AEs were rash, diarrhea, nausea,
and fatigue1,2
1. Burris HA et al. Oncologist. 2004;(9 suppl 3):10-15.
2. Burris HA et al. Journal of Clinical Oncology. 2005;23(23):5305-5313.
EGF20002/EGF20008: Designs
Location
Planned Accrual
Status
Treatment
Tumor HER2 Status
EGF20002
EGF20008
North America
Global
80
200
A = 120, B = 80
Completed
Completed
1500 mg QD*
1500 mg QD
3+ or FISH
A: 3+ or FISH
B: negative
Prior Therapy
Trastuzumab
Chemo
Yes
Yes: cohort A
1-2 Prior
A, T, & C
*first 13 patients treated at 1250 mg QD
Phase II Trial of Lapatinib for Brain
Metastases in Patients with HER2-positive
Breast Cancer
NU Lin, LA Carey, MC Liu, J Younger, SE Come, M Ewend, E Bullitt, A van den
Abbeele, JT Yap, G Harris, X Li, R Gelman, A Crawford, E Kasparian, HJ Burstein, D
Kirsch, F Hochberg, EP Winer
Dana-Farber/Harvard Cancer Center, University of North Carolina at
Chapel Hill, Georgetown University
Best CNS Response (RECIST)
(N=39)
Complete Response (CR)
Partial Response (PR)
Baseline
0
1 (2.5%)
Week 8
Test of Principle:
Should Trastuzumab be Continued
After Disease Progression?
Vinorelbine
Taxane +
Trastuzumab
Disease
Progression
Caveat:
trastuzumab t1/2
1-4 weeks
Vinorelbine +
Trastuzumab
MD Anderson, 2001 SWOG, 2003
Study Design
• Progressive, HER2+ MBC
or LABC
• Previously treated with
anthracycline, taxane and
trastuzumab*
• No prior capecitabine
Stratification:
• Disease sites
• Stage of disease
R
A
N
D
O
M
I
Z
E
N=528
Lapatinib 1250 mg po qd
continuously +
Capecitabine 2000 mg/m2/d
po days 1-14 q 3 wk
Capecitabine 2500 mg/m2/d po days
1-14 q 3 wk
Patients on treatment until progression or
unacceptable toxicity, then followed for
survival
*Trastuzumab must have been administered for metastatic disease
Progression-free Survival
Independent Radiology Review
Investigator Reported Outcomes
Geyer CE et al. N Engl J Med 2006;355:2733-2743
Overall Survival
Geyer CE et al. N Engl J Med 2006;355:2733-2743
Efficacy End Points in the
Intention-to-Treat Population
Geyer CE et al. N Engl J Med 2006;355:2733-2743
Adverse Events
Geyer CE et al. N Engl J Med 2006;355:2733-2743
San Antonio Breast Cancer Symposium 2007
• German collaborative group study (Gunter von Minckwitz)
Trastuzumabtreated patients
R
A
N
D
O
M
I
Z
E
D
Capecitabine
Capecitabine
+
Trastuzumab
Higher response rate and longer TTP
resulted with ongoing anti-HER2 therapy
with trastuzumab
Highlights
• New agents for refractory disease
– Ixabepilone
– Lapatinib
• Chemotherapy in node-positive disease?
– CALGB 9344
– Oncotype DX®
Adjuvant Treatment for a 2 x 2 Marker Model
of Breast Cancer
ER +
trastuzumab
HER2+
HER2 -
chemo
endocrine
ER trastuzumab
chemo
endocrine
± chemo
chemo
In the Beginning, There Was AC
And Then There Was CALGB 9344
CALGB 9344
 A dose
DFS
OS
Sequential T
Meta-analysis of Disease-free Survival (DFS)
De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008
Meta-analysis of Disease-free Survival (DFS)
According To Estrogen Receptor (ER) Status
De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008
Meta-analysis of Disease-free Survival (DFS)
According to HER-2 Status
De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008
Pooled DFS (A) and OS (B) Curves for Studies
Included in the Meta-analysis
De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008
Disease-free Survival Among Patients Treated with or
without Paclitaxel According to Estrogen-Receptor
Status and HER2 Expression
Hayes D et al. N Engl J Med 2007;357:1496-1506
ER neg
ER pos
BasaloidHER2+
Sorlie, et al. PNAS 2001
Oncotype DX® Results:
Distribution of Quantitative ER and HER2
• First Cohort - n = 10,618
HER2 Expression (relative to ref genes; log2)
15
HER2+
14
13
12
11
10
Triple Neg*
9
8
7
ER+HER2(luminal?)
6
2
3
*>94% of these cases are PR-;
rarely strongly PR+
4
5
6
7
8
9
10
11
ER Expression (relative to ref genes; log2)
12
13
14
Current Recommendations for
Chemotherapy for ER+ Breast Cancer
• NIH Consensus Conference 2000
– LN+
– LN – if T > 1 cm
• NCCN 2006
– LN+
– LN – if T > 1cm
– Consider for LN – if 0.6 to 1.0 cm
• St. Gallen 2005 (endocrine responsive)
– LN + (> 4 LN if HER2 negative, any if HER2+)
– Consider for LN – if: T > 2 cm, or grade 2-3, or LVI+, or
HER2+, or age < 35 years
Candidate Gene Selection
From ~40,000 genes
384 cancer-related
genes*
*Sources include:
1) Sotiriou et al., Breast Cancer Res Treat 4:R3, 2002
2) Scherf et al., Nat Genetics 24:236-44, 2000
3) Lamendola et al., Cancer Res 63:2200-5, 2003
4) Chang et al., Lancet 362:362-9, 2003
5) Staunton et al., Proc Natl Acad Sci U S A 98:10787-92, 2001
16 Cancer and 5 Reference Genes
• Best RT-PCR performance
and most robust predictions
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GSTM1
CD68
HER2
GRB7
HER2
BAG1
ESTROGEN
ER
PR
Bcl2
SCUBE2
INVASION
Stromolysin 3
Cathepsin L2
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
Genomic Health-NSABP B-14 Prospective
Clinical Validation Study
• Objective
– Validate Recurrence Score as predictor of distant recurrence in
N-, ER+, Tamoxifen-treated patients
• Design
Placebo--Not Eligible
B-14
Randomized
Tamoxifen--Eligible
Registered
Tamoxifen--Eligible
– Pre-specified 21 gene assay, algorithm, endpoints, analysis
plan
– Blinded laboratory analysis of three 10 micron tumor block
sections
B14-Results
DRFS - All 668 Patients
100%
90%
80%
DRFS
70%
10 year DRFS = 85%
60%
50%
40%
30%
20%
10%
0%
0
2
4
6
8
Years
10
12
14
16
Oncotype DX®
Validation Study B-14
Paik et al. NEJM 2004;351:2817
Benefit from Tamoxifen in the NSABP B14
by Oncotype DX® Recurrence Score
1.0
1.0
0.8
0.4
DRFS
0.6
Low Risk (RS<18)
0.2
Placebo
Tamoxifen
N
171
142
0.0
0
2
4
6
0.6
0.4
Int Risk (RS 18-30)
N
85
Placebo
Tamoxifen 69
0.2
8
10
Years
12
14
0.0
16
0
2
4
1.0
6
8
Years
0.8
DRFS
DRFS
0.8
0.6
0.4
High Risk (RS≥31)
0.2
Placebo
Tamoxifen
N
99
79
0.0
0
2
4
6
8
10
12
14
16
10
12
14
16
Chemotherapy Response and Oncotype DX®
NSABP Study B-20
Tam + MF
Design
Randomized
Tam + CMF
Tam
Objective: Determine the magnitude of the chemotherapy
benefit as a function of 21 gene Recurrence Score assay
B-20 Results
• Tam vs Tam + Chemo – All
1.0
0.9
0.8
0.7
DRFS
0.6
0.5
All Patients
Tam + Chemo
Tam
0.4
0.3
N
424
227
Events
33
31
0.2
P = 0.02
0.1
0.0
0
2
4
6
Years
8
10
12
1.0
0.9
0.8
RS < 18 “low”
0.7
0.6
0.5
DRFS
0.4
1.0
0.3
0.9
0.2
Low Risk Patients (RS < 18)
Tam + Chemo
Tam
0.1
0.8
0.7
0.0
0
2
4
6
8
10
12
Years0.6
0.5
DRFS
0.4
0.3
RS 18-30 “int”
1.0
0.2
Int Risk (RS 18 - 30)
Tam + Chemo
Tam
0.1
0.9
0.8
0.0
0
2
4
6
8
0.7 10
Years
12
0.6
0.5
DRFS
0.4
0.3
RS > 30 “high”
0.2
High Risk Patients (RS  31)
Tam + Chemo
Tam
0.1
0.0
0
2
4
6
Years
8
10
12
Phase III SWOG 8814 (TBCI 0100)
Postmenopausal, N+, ER+
RANDOMIZE
N = 1477
tam x 5 yrs
(N = 361)
CAF x 6, then
tam
CAF x 6, with
concurrent tam
(N= 550)
(N = 566)
Superior Disease-Free Survival (DFS)
and Overall Survival (OS) over 10 Years
Albain, et al. Breast Cancer Res Treat 2005
Outcomes in RS Subset Mirror Those Reported
in Main Trial: Superiority of CAF-T
0.75
0.50
0.25
Stratified log-rank P-value = 0.054 at 10 years
(adjusted for nodal status)
Tamoxifen (N=148, 63 events)
CAF-T
(N=219, 74 events)
0.00
Disease-free survival
1.00
Disease-Free Survival
0
2
4
6
Years since registration
8
10
SWOG 8814/TBCI 0100
21-Gene Recurrence Score is Prognostic for DFS and
OS in Tamoxifen Arm
Overall Survival by Risk Group
Disease-Free Survival by Risk Group
2
4
6
1.00
8
Years since registration
10-yr: 60%, 49%, 43%
0.25
Stratified log-rank P = 0.003 at 10 years
Low RS <18 (N=55)
Intermediate RS 18-30 (N=46)
High RS ≥31 (N=47)
0.00
Low RS <18 (N=55)
Intermediate RS 18-30 (N=46)
High RS ≥31 (N=47)
0
(tamoxifen alone)
Overall Survival
0.50
0.75
0.75
0.50
0.25
Stratified log-rank P = 0.017 at 10 years
0.00
Disease-free survival
1.00
(tamoxifen alone)
10
0
2
4
6
8
Years since registration
10-yr: 77%, 68%, 51%
10
1.00
Disease-Free Survival by Treatment
Disease-free survival
0.25
0.50
0.75
No benefit to CAF over
time if low RS
Stratified log-rank P = 0.97 at 10 years
Tamoxifen (N=55, 15 events)
CAF-T
(N=91, 26 events)
0.00
Strong benefit if high RS
Low risk (RS < 18)
0
2
4
6
8
10
Disease-Free Survival by Treatment
Disease-Free Survival by Treatment
1.00
1.00
0.25
Stratified log-rank P = 0.033 at 10 years
0
2
4
6
Years since registration
8
0.75
0.50
Stratified log-rank P = 0.48 at 10 years
Tamoxifen
CAF-T
0.00
Tamoxifen (N=47, 26 events)
CAF-T
(N=71, 28 events)
Intermediate risk (RS 18-30)
0.25
0.50
0.75
Disease-free survival
High risk (RS ≥31)
0.00
Disease-free survival
Years since registration
10
0
2
4
(N=46, 22 events)
(N=57, 20 events)
6
Years since registration
8
10
Summary
• New treatment options available for refractory breast
cancer
– Ixabepilone
– Lapatinib
• Ongoing refinement for:
– Patients who need chemotherapy
– Which types of chemotherapy