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A Report from SABCS
Up-to-Date Review of the Treatment of
Advanced Breast Cancer
William J. Gradishar, MD
Director, Breast Medical Oncology
Professor of Medicine
Robert H. Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine
Chicago, IL
Chemotherapy for MBC
Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in
Anthracycline-Pretreated MBC (Phase III)
Efficacy Results
• 305 patients randomized
• GD: Gemcitabine 1000 mg/m2 d1,8 Docetaxel 75 mg/m2 d1 q 3 w
• CD: Capecitabine 1250 mg/m2 b.i.d. d1-14 Docetaxel 75 mg/m2 d1 q 3 w
GD
(N = 153)
CD
(N = 152)
P-value
32%
32%
.93
First-line
43%
29%
.051
Second-line
14%
36%
.008
Median PFS
8.05 mos
7.98 mos
.121
First-line
8.51 mos
7.69 mos
.499
Second-line
6.60 mos
8.51 mos
.073
19.29 mos
21.45 mos
.98
ORR
Median OS
Chan S, et al. SABCS 2007 Abstract 1078.
Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in
Anthracycline-Pretreated MBC (Phase III)
Toxicities
Grade 3/4 Adverse Events
(≥ 10% patients)
GD
CD
Grade 3
Grade 4
Grade 3
Grade 4
Neutropenia
36%
48%
26%
53%
Febrile Neutropenia/ Neutropenic
Sepsis
5%
3%
7%
7%
Leukopenia*
57%
20%
44%
22%
0
0
26%
0
Diarrhea*
7%
< 1%
17%
1%
Mucositis*
4%
0
12%
3%
Asthenia
7%
0
11%
0
Hand-foot syndrome*
* P < .05
Chan S, et al. SABCS 2007 Abstract 1078.
Study Design: International, Randomized,
Open-Label, Phase III Trial
Trial Design
Ixabepilone
(40 mg/m2 IV over 3 hr d1 q 3 wk)
Metastatic or locally
advanced breast cancer
RESISTANT
to anthracyclines
and taxanes
(N = 752)
Stratification:
• Visceral metastases
• Prior chemotherapy for MBC
• Anthracycline resistance
• Study site
+
Capecitabine
(2000 mg/m2/day PO 2 divided doses d1-d14 q 3 wk)
(N = 375)
Capecitabine
(2500 mg/m2/day PO 2 divided doses d1-d14 q 3 wk)
(N = 377)
Vadhat LT, et al, ASCO 2007 Abstract 1006.
Capecitabine ± Ixabepilone
Progression-free Survival by Independent Radiologic Review
Proportion Progression-Free
1.0
0.8
Median
95% CI
Ixabepilone + Capecitabine
5.8 mo
(5.5–7.0)
Capecitabine
4.2 mo
(3.8–4.5)
HR: 0.75 (0.64–0.88)
0.6
P = 0.0003
0.4
0.2
0
0
4
8
12
16
20
24
28
32
36
Months
Vadhat LT, et al, ASCO 2007 Abstract 1006.
Capecitabine ± Ixabepilone
Response
% Response
ORR (CR + PR)
Investigator
IRR
Capecitabine Ixabepilone Capecitabine
Ixabepilone
+
+
Capecitabine
Capecitabine
(N = 377)
(N = 375)
(N = 377)
(N = 375)
42
23
35
P < .0001
14
P < .0001
Stable disease
36
38
41
46
Progressive disease
14
29
15
27
Unable to determine
8
10
9
12
Vadhat LT, et al, ASCO 2007 Abstract 1006.
Capecitabine ± Ixabepilone
Toxicity
• All toxicity-related deaths in combination arm attributable to
neutropenia:
– Incidence with baseline ≥ grade 2 LFTs was 31% (5/16)
– Incidence post amendment with baseline ≤ grade 1 LFTs was 2% (7/353)
• Grade 3/4 hematologic:
– 4 versus < 1% FN (0.001)
– 8 versus 4% thrombocytopenia (0.011); 10 versus 4% anemia (0.005)
• Grade 3/4 nonhematologic:
– 23% peripheral neuropathy:
•
Primarily sensory
•
Cumulative
•
Reversible:
– Median time to resolution 6 weeks
Vadhat LT, et al, ASCO 2007 Abstract 1006.
Efficacy of Ixabepilone/Capecitabine in ER/PR/HER2Negative MBC Resistant to Anthracyclines and Taxanes
Receptor Subgroup
All Patients
ORR
Median
PFS
HR
ER/PR/HER2
Negative
Non-TripleNegative
HER2+
ER+
I+C
C
I+C
C
I+C
C
I+C
C
I+C
C
(N = 375)
(N = 377)
(N = 91)
(N = 96)
(N = 284)
(N = 281)
(N = 59)
(N = 53)
(N = 173)
(N = 178)
35%
14%
27%
9%
37%
16%
31%
8%
40%
19%
5.8 mo
4.2 mo
4.1 mo
2.1 mo
7.1 mo
5.0 mo
5.3 mo
4.1 mo
7.6 mo
5.7 mo
0.75
0.68
0.74
0.69
0.81
Rugo H, et al. SABCS 2007, Abstract 6069.
Hormonal Therapy for MBC
Fulvestrant vs. Exemestane Following Prior Nonsteroidal
AI Therapy: EFECT, a Phase III Trial in Postmenopausal
Women With Advanced Breast Cancer
Eligibility Criteria:
•
•
•
•
Postmenopausal women
HR+
Measurable disease
Prior nonsteroidal AI failure
for advanced breast
cancer or for adjuvant
therapy or within 6 months
of its discontinuation
(N = 693)
R
A
N
D
O
M
I
Z
E
Fulvestrant: loading dose 500 mg on
d 0, followed by 250 mg on d 14, 28
q 28 ± 3 days thereafter
(N = 351)
Exemestane: 25 mg orally daily +
placebo
(N = 342)
Primary Endpoint:
• Time to disease progression
Chia S, et al. SABCS 2007, Abstract 2091.
Fulvestrant vs. Exemestane Following Prior
Nonsteroidal AI Therapy: EFECT Trial
Efficacy
Previous Analysis
Median Follow-Up 13 months
Fulvestrant
Exemestane
HR
P-Value
3.7 mos
3.7 mos
0.963
0.6531
Objective Response Rate
7.4%
6.7%
1.120*
0.7364
Clinical Benefit Rate
32.2%
31.5%
1.035*
0.8534
Duration of Response
13.5 mos
9.8 mos
–
–
Duration of Clinical Benefit
9.3 mos
8.3 mos
–
–
Time to Progression
* Odds ratio
Gradishar WJ, et al. Breast Cancer Res Treat 2006; 100(suppl 1):S8 (abstract 12).
Fulvestrant vs. Exemestane Following Prior
Nonsteroidal AI Therapy: EFECT Trial
Efficacy
Current Analysis
Median Follow-Up 20.9 months
Fulvestrant
Exemestane
HR
P-Value
24.3 mos
23.1 mos
1.012
0.9072
ER+ and PgR+
24.4 mos
22.6 mos
0.992
0.9488
Not ER+ and PgR+
24.3 mos
23.7 mos
1.040
0.8044
Overall Survival
Adverse events (all grades) similar between arms:
• Injection site pain (F 9.7%; E 8.8%)
• Hot flashes (F 8.8%; E 11.5%)
• Fatigue (F 6.3%; E 10%)
Chia S, et al. SABCS 2007, Abstract 2091.
HER2-Targeted Therapy for MBC
Trastuzumab Beyond Progression Trial
Study Design
Eligibility Criteria:
• Progressive MBC or LABC
• HER2 overexpression
• Previous trastuzumab
• Trastuzumab-free interval <
6 wks
• LVEF ≥ 50
R
A
N
D
O
M
I
Z
E
Capecitabine 2,500 mg/m2 d1-14 q21 days
(N = 78)
Capecitabine 2,500 mg/m2 d1-14 q21 days
+
Continuation of Trastuzumab 6 mg/kg
every 3 weeks
(N = 78)
• Primary endpoint: time to progression
• Secondary endpoints: OS, ORR, safety
*Study closed at 156 patients due to slow accrual
following FDA registration of lapatinib for this indication
Von Minckwitz G, et al. SABCS 2007. Poster 4056.
Trastuzumab Beyond Progression Trial
Results
Capecitabine
(N = 78)
Capecitabine/
Trastuzumab
(N = 78)
Overall Response Rate
24.6%
48.9%
Stable Disease
49.1%
35.1%
Median PFS
5.6 mos
8.5 mos
Median OS
19.9 mos
20.3 mos
3.3%
5.3%
Vomiting
6%
1.6%
Diarrhea
20.9%
14.8%
Hand-foot syndrome
23.9%
31.1%
6%
4.9%
Grade 3/4 Adverse Events (> 5% of patients)
Neutropenia
Fatigue
• Severe cardiac events: 2.9% capecitabine; 4.9% capecitabine/trastuzumab
Von Minckwitz G, et al. SABCS 2007. Poster 4056.
RegistHER: CNS Metastases in Patients
with HER2-Postitive MBC
• Multicenter prospective, observational study
• 1023 patients enrolled, 768 included in present analysis
• 30.7% developed CNS metastases, 6.8% at time of initial diagnosis
• Median time to first CNS event: 12.1 mos
• Median survival following first CNS metastases: 13.9 mos
• Characteristics of patients who developed CNS metastases:
– Younger (< 50: 45.3% vs. 39.3% others; P = .0347)
– HR-negative (53.4% vs. 39.6% others; P = .0044)
– Greater tumor burden (2+ metastatic sites 61% vs. 51.6% others; P = .0356)
Yardley D, et al. SABCS 2007 Abstract 6049.
Lapatinib + Capecitabine for the Treatment of Brain
Metastases in Patients With HER2+ Breast Cancer
Trial Design and Parent Study Results
Parent Study
Extension Study
Lapatinib
monotherapy
750 mg BID
Lapatinib
1,250 mg/day continuously
+
Capecitabine
2,000 mg/m2/d po d1-14 q 3 wk
CNS PD*
• Parent Study Results:
–
(N = 242)
–
≥ 50% CNS volumetric tumor reduction 6%
–
≥ 20% CNS volumetric tumor reduction 17%
–
Median PFS: 9.3 weeks
Lin NU, et al. SABCS 2007. Poster 6076.
Lapatinib + Capecitabine for the Treatment of Brain
Metastases in Patients With HER2+ Breast Cancer
Extension Study Results
Extension Study Results
(N = 51)
Complete Response
0
Partial Response
20%
Stable Disease
39%
Median PFS (all patients)
15.8 weeks
Median PFS (Pts with ≥ 20% reduction in
tumor volume)*
20.0 weeks
Median PFS (Pts without ≥ 20% reduction
in tumor volume)
8.21 weeks
* HR 0.34 (Patients with ≥ 20% tumor volume reduction versus all others); P =.0013
• Most frequent grade 3/4 adverse events: palmoplantar erthrodysesthesia,
diarrhea, nausea, vomiting, and fatigue
Lin NU, et al. SABCS 2007. Poster 6076.
EGFR-Targeted Therapy for MBC
SABCS Abstract 307
TBCRC 001:
EGFR Inhibition with Cetuximab in
Metastatic Triple Negative Breast Cancer
Carey LA, Mayer E, Marcom PK, Rugo H, Liu M, Ma C, Rimawi M,
Storniolo A, Forero A, Esteva F, Wolff A, Ingle J, Ferraro M, Sawyer L,
Davidson N, Perou CM, Winer EP
Rationale for Combination Cetuximab/Carboplatin
in Basal-like Breast Cancer
• Basal-like breast cancer is characterized by high
expression of EGFR (one of the basal gene cluster)
• EGFR targeting is effective in basal-like preclinical
models.
• Basal-like are "triple negative" (ER-, PR-, and HER2negative) limiting options to chemotherapy.
• Association with BRCA1 mutation carriers raises
question of platinum sensitivity.
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IV
Triple Negative Breast Cancer
Study Design
Arm 1
Cetuximab
PD
Cetuximab + carboplatin
Randomized
Phase II
Arm 2 Cetuximab + carboplatin
Tissue, circulating tumor cells
Germline DNA
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IV
Triple Negative Breast Cancer
Objectives
• Primary Objectives:
– ORR single agent cetuximab in triple negative metastatic breast cancer
(MBC).
– ORR to combination cetuximab/carboplatin in triple negative MBC
• Secondary Objectives:
– Time to disease progression on single agent cetuximab
– Time to disease progression on combination cetuximab/carboplatin.
– Correlation of downstream effects of EGFR inhibitor on MAPK, AKT,
Ki67 and EGFR-dependent signaling, proliferation, and apoptosis with
toxicity and response (serial bx pts)
– Changes in biomarkers and gene expression in circulating tumor cell
– Overall survival
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IV
Triple Negative Breast Cancer
Patient Population and Treatment
•
Patient population
– 100 patients for 93 evaluable
– Stage IV, measurable disease
– ER, PR, and HER2-negative (HER2 0-1+ IHC or FISH-negative)
– 0-3 prior chemotherapy regimens
– Otherwise healthy
– Available archival tissue
•
Treatment
– Arm 1:
• Cetuximab 400 mg/m2 load then 250 mg/m2 iv q wk
• Upon progression – add carboplatin AUC 2 iv q wk (3 of 4 wks)
–
Arm 2:
• Cetuximab + carboplatin (same doses/schedule)
– Desired 20% of patients undergo serial biopsy
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IV
Triple Negative Breast Cancer
Study Status
Arm 1 closes
Spring 2006
Study opens
3/07
Interim analysis
Arm 1: 31 patients, 24 evaluable
Arm 2: 69 patients, 44 evaluable
10/07
Completed
accrual
Being reported SABCS 12/07
Data analysis in progress
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IV
Triple Negative Breast Cancer
Patient/Tumor Characteristics
Factor
Arm 1
Median age
51
Race: White
40 (61%)
Black
18 (27%)
Hispanic
5 (8%)
Other
3 (6%)
Post-menopause
49 (75%)
ECOG PS 0-1
59 (93%)
Visceral disease
32 (48%)
Prior chemotherapy
64 (97%)
Anthracycline
3 (80%)
Taxane
41 (62%)
1st line treatment
30 (45%)
2nd- 3rd line treatment
36 (55%)
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Toxicity
Toxicity
% pts any grade (Gr 3-4)
Arm 1a:
Cetuximab alone
(N = 31)
Rash
59% (6%)
Fatigue
33% (6%)
Arm 1b:
Cetuximab + carboplatin
(N = 22)
63% (23%)
63% (18%)
Pain
17% (3%)
Mucositis
17% (0)
9% (0)
17% (3%)
41% (0)
Other GI
13% (0)
18% (0)
Anorexia
10% (0)
9% (0)
Hypomagnesemia
7% (0)
23% (5%)
Neutropenia
0
14% (9%)
Anemia
0
9% (0)
Thrombocytopenia
0
5% (0)
Pneumonitis/bronchospasm
0
14% (9%)
Nausea/vomiting
9% (5%)
TBCRC 001: Cetuximab in Stage IV
Triple Negative Breast Cancer
Efficacy Arm 1 (ITT)
Arm 1a: Ct alone
Arm 1b: C → Ct + Cp
(N = 31)
(N = 22)
CR
0
0
PR
2 (6%)
4 (18%)
SD
5 (16%)
5 (23%)
EPD
2 (6%)
3 (14%)
PD
22 (71%)
10 (45%)
RR
6%
18%
CB
10%
27%
Response
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IV
Triple Negative Breast Cancer
Conclusions
• Single agent cetuximab is well tolerated, but only 2 RR of 31
evaluable patients were seen, prompting closure of Arm 1 according
to a priori stopping rules.
• Disease stabilization was seen in 16%, 1 durable
– Two patients are still in PR at 69 and 42 weeks, respectively
• Analysis of combination therapy on arm 1 reveals a 18% RR and
27% CB rate
– This is encouraging in a largely pretreated population
• Arm 2 analysis is in progress
• Early progression limited treatment in some, supporting the
biologically aggressive nature of triple negative breast cancer and
potentially complicating efforts to treat
Carey LA, et al. SABCS 2007. Abstract 307.
SABCS Abstract 308
Randomized Phase II Study of Weekly
Irinotecan/Carboplatin With or Without
Cetuximab in Patients With
Metastatic Breast Cancer
O’Shaughnessy J; Weckstein DJ; Vukelja SJ; McIntyre K;
Krekow L; Holmes FA; Asmar L; Blum JL
Weekly Irinotecan/Carboplatin With or
Without Cetuximab in Patients With MBC
Rationale
•
•
•
•
•
Irinotecan and carboplatin (ICb) is a synergistic antineoplastic
combination in several cancers
Weekly irinotecan is an active agent in MBC1
Epidermal growth factor receptor (EGFR) inhibition enhances antitumor
activity of both irinotecan and cisplatin in breast cancer preclinical
models2,3
EGFR is overexpressed in over 50% of triple negative breast cancers4
and may be involved in endocrine-therapy resistance as well5
It is hypothesized that the addition of cetuximab (E) to ICb will increase
the overall response rate of the ICb combination and will prolong the
median time to progression for patients with metastatic breast cancer
References:
1Perez EA, Hillman DW, Mailliard JA, et al. J Clin Oncol. 2004;22:2849-2855.
2Ciardiello F, Bianco R, Damiano V, et al. Clin Cancer Res. 2000;6:3739-3747.
3Ciardiello F, Tortora G. Expert Opin Investig Drugs. 2002;11:755-768.
4Nielsen TO, Hsu FD, Jensen K, et al. Clin Cancer Res. 2004; 10:5367-5374.
5Johnston SR, Head J, Pancholi S, et al. Clin Cancer Res. 2003; 9:524S-532S.
Weekly Irinotecan/Carboplatin With or
Without Cetuximab in Patients With MBC
Key Eligibility
• Metastatic breast cancer measurable by RECIST
• 0-1 chemotherapy regimens for metastatic disease
• No prior irinotecan or platinum agent
• If HER2-positive (HER2+), patients must have
progressed on trastuzumab
O’Shaughnessy J, et al. SABCS 2007. Abstract 308.
Weekly Irinotecan/Carboplatin With or
Without Cetuximab in Patients With MBC
Treatment Schema
STRATIFY
Triple negative
(ER-, PR-, HER2negative)
R
A
N
D
O
M
I
Z
E
*Irinotecan (I) 100 mg/m2
Carboplatin (Cb) AUC = 2.5
Day 1, 8 q 21 days
Cetuximab (E)
alone
at progression
*Irinotecan (I) 100 mg/m2, D1, 8 q 21d
Carboplatin (Cb) AUC = 2.5, D1, 8 q 21d
Cetuximab (E) 400 mg/m2, D1, then
250 mg/m2 weekly thereafter
*Starting ICb doses decreased to 90 mg/m2 and AUC = 2.0 midway
through enrollment due to diarrhea with ICb + E
O’Shaughnessy J, et al. SABCS 2007. Abstract 308.
ICb ± E: Patient Characteristics
Number of Patients Enrolled*
Median Age (Years)
ECOG Performance Status
0
1
2
Receptor Status
ER-/PR-/HER2- (Triple Negative)
HR+/HER2HER2+
Metastatic Sites
Bone
Brain
Liver
Lung
Lymph Node
Prior Treatment
Anthracycline
Trastuzumab**
Taxane
Prior Adjuvant Chemotherapy
Prior Metastatic Chemotherapy
Arm 1 (ICb)
Arm 2 (ICb+E)
75
79
53
55
Number and Percentage (%) of Patients
52
19
4
(69)
(25)
(5)
44
34
1
(56)
(43)
(1)
36
38
1
(48)
(51)
(1)
42
35
2
(53)
(44)
(3)
30
2
25
25
19
(40)
(3)
(33)
(33)
(25)
28
5
30
34
33
(35)
(6)
(38)
(43)
(42)
61
2
62
57
33
(81)
(3)
(83)
(70)
(40)
58
3
56
57
22
(73)
(4)
(71)
(70)
(27)
*154 patients received at least 1 dose of ICb±E
**All HER2+ patients received trastuzumab, however additional patients also received trastuzumab.
Therefore, numbers for trastuzumab are slightly larger than HER2+ patients.
Note: Percentage totals in this table & subsequent tables may not add up to 100%, due to rounding.
Weekly Irinotecan/Carboplatin With or
Without Cetuximab in Patients With MBC
Overall Efficacy by Subset
Pts Evaluable for Efficacy (N = 138)
Number of Patients
Overall Response Rate
CR
PR
SD
PD
Triple Negative Pts
Number of Patients
Overall Response Rate
CR
PR
SD
PD
HR+/HER2 Negative Pts
Number of Patients
Overall Response Rate
CR
PR
SD
PD
Arm 1 (ICb)
69
21
4
17
31
17
(31)
(6)
(25)
(45)
(25)
69
26
4
22
28
15
(38)
(6)
(32)
(40)
(22)
(30)
(9)
(21)
(52)
(18)
39
19
3
16
15
5
(49)
(8)
(41)
(39)
(13)
(29)
(3)
(26)
(40)
(31)
28
7
1
6
12
9
(25)
(4)
(21)
(43)
(32)
33
10
3
7
17
6
35
10
1
9
14
11
Arm 2 (ICb+E)
O’Shaughnessy J, et al. SABCS 2007. Abstract 308.
Weekly Irinotecan/Carboplatin With or
Without Cetuximab in Patients With MBC
Conclusions
•
Cetuximab did not improve the ORR, PFS and OS when added to
irinotecan/carboplatin in MBC patients
•
On subset analysis, starting dose irinotecan/carboplatin plus cetuximab
had a higher ORR than starting dose irinotecan/carboplatin alone
•
On subset analysis, the addition of cetuximab increased the ORR
associated with irinotecan/carboplatin in triple negative metastatic breast
cancer
•
Irinotecan/carboplatin is an active regimen for both HR+ and triple
negative breast cancer
•
Single-agent cetuximab was minimally active following progression on
irinotecan/carboplatin
•
Diarrhea is the primary toxicity associated with irinotecan/carboplatin and
this was exacerbated by the addition of cetuximab
O’Shaughnessy J, et al. SABCS 2007. Abstract 308.
Treatment of Advanced Breast Cancer
Closing Comments
William J. Gradishar, MD