A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer
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Transcript of A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer
A Report from SABCS
Up-to-Date Review of the Treatment of Advanced Breast Cancer
William J. Gradishar, MDDirector, Breast Medical Oncology
Professor of Medicine
Robert H. Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of MedicineChicago, 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
Chan S, et al. SABCS 2007 Abstract 1078.
GD(N = 153)
CD(N = 152)
P-value
ORR 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
Median OS 19.29 mos 21.45 mos .98
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%
Hand-foot syndrome* 0 0 26% 0
Diarrhea* 7% < 1% 17% 1%
Mucositis* 4% 0 12% 3%
Asthenia 7% 0 11% 0
* P < .05 Chan S, et al. SABCS 2007 Abstract 1078.
Vadhat LT, et al, ASCO 2007 Abstract 1006.
Study Design: International, Randomized, Open-Label, Phase III Trial
Trial Design
Ixabepilone(40 mg/m2 IV over 3 hr d1 q 3 wk)
+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)
Metastatic or locally advanced breast cancer
RESISTANT to anthracyclines
and taxanes(N = 752)
Stratification:• Visceral metastases• Prior chemotherapy for MBC• Anthracycline resistance• Study site
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)
P = 0.0003
Pro
port
ion
Pro
gres
sion
-Fre
e
1.0
0.8
0.6
0.4
0.2
00 4 8 12 16 20 24 28 32 36
Months
Capecitabine ± IxabepiloneProgression-free Survival by Independent Radiologic Review
Vadhat LT, et al, ASCO 2007 Abstract 1006.
Capecitabine ± IxabepiloneResponse
Vadhat LT, et al, ASCO 2007 Abstract 1006.
Unable to determine 129108
27152914Progressive disease
46413836Stable disease
P < .0001P < .0001
14352342ORR (CR + PR)
Capecitabine
(N = 377)
Ixabepilone +
Capecitabine (N = 375)
Capecitabine
(N = 377)
Ixabepilone +
Capecitabine(N = 375)
IRRInvestigator
% Response
Capecitabine ± IxabepiloneToxicity
• 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/HER2-Negative MBC Resistant to Anthracyclines and Taxanes
Rugo H, et al. SABCS 2007, Abstract 6069.
Receptor Subgroup
All PatientsER/PR/HER2
NegativeNon-Triple-Negative
HER2+ ER+
I + C
(N = 375)
C
(N = 377)
I + C
(N = 91)
C
(N = 96)
I + C
(N = 284)
C
(N = 281)
I + C
(N = 59)
C
(N = 53)
I + C
(N = 173)
C
(N = 178)
ORR35% 14% 27% 9% 37% 16% 31% 8% 40% 19%
Median PFS 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
HR0.75 0.68 0.74 0.69 0.81
Hormonal Therapy for MBC
Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT, a Phase III Trial in Postmenopausal
Women With Advanced Breast Cancer
Chia S, et al. SABCS 2007, Abstract 2091.
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)
Primary Endpoint: • Time to disease progression
Primary Endpoint: • Time to disease progression
RANDOMIZE
RANDOMIZE
Fulvestrant: loading dose 500 mg on d 0, followed by 250 mg on d 14, 28 q 28 ± 3 days thereafter(N = 351)
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)
Exemestane: 25 mg orally daily + placebo (N = 342)
Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT Trial
Efficacy
Previous Analysis
Median Follow-Up 13 months
Fulvestrant Exemestane HR P-Value
Time to Progression 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 – –
* 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 AnalysisMedian Follow-Up 20.9 months
Fulvestrant Exemestane HR P-Value
Overall Survival 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
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 TrialStudy Design
Eligibility Criteria:
• Progressive MBC or LABC
• HER2 overexpression
• Previous trastuzumab
• Trastuzumab-free interval < 6 wks
• LVEF ≥ 50
• Primary endpoint: time to progression• Secondary endpoints: OS, ORR, safety• Primary endpoint: time to progression• Secondary endpoints: OS, ORR, safety
RANDOMIZE
RANDOMIZE
*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.
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)
Trastuzumab Beyond Progression TrialResults
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
Grade 3/4 Adverse Events (> 5% of patients)
Neutropenia 3.3% 5.3%
Vomiting 6% 1.6%
Diarrhea 20.9% 14.8%
Hand-foot syndrome 23.9% 31.1%
Fatigue 6% 4.9%
• 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
Lapatinibmonotherapy750 mg BID
Lapatinib 1,250 mg/day continuously
+Capecitabine
2,000 mg/m2/d po d1-14 q 3 wk
CNS PD*
Parent Study Extension Study
Lin NU, et al. SABCS 2007. Poster 6076.
• Parent Study Results:
– (N = 242)
– ≥ 50% CNS volumetric tumor reduction 6%
– ≥ 20% CNS volumetric tumor reduction 17%
– Median PFS: 9.3 weeks
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 HER2-negative) 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 IVTriple Negative Breast Cancer
Study Design
Cetuximab PD Cetuximab + carboplatin
Cetuximab + carboplatin
Randomized Phase II
Tissue, circulating tumor cells
Germline DNA
Arm 1
Arm 2
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IVTriple 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 IVTriple 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 biopsyCarey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IVTriple Negative Breast Cancer
Study Status
Spring 2006Study opens
Arm 1 closes
3/07Interim analysis
10/07Completed
accrual
Arm 1: 31 patients, 24 evaluableArm 2: 69 patients, 44 evaluable
Being reported SABCS 12/07
Data analysis in progress
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IVTriple Negative Breast Cancer
Patient/Tumor CharacteristicsFactor 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)
Arm 1b: Cetuximab + carboplatin
(N = 22)
Rash 59% (6%) 63% (23%)
Fatigue 33% (6%) 63% (18%)
Pain 17% (3%) 9% (5%)
Mucositis 17% (0) 9% (0)
Nausea/vomiting 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%)
TBCRC 001: Cetuximab in Stage IVTriple Negative Breast Cancer
Efficacy Arm 1 (ITT)
ResponseArm 1a: Ct alone
(N = 31)
Arm 1b: C → Ct + Cp
(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%
Carey LA, et al. SABCS 2007. Abstract 307.
TBCRC 001: Cetuximab in Stage IVTriple 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
STRATIFYTriple negative
(ER-, PR-, HER2-negative)
*Irinotecan (I) 100 mg/m2
Carboplatin (Cb) AUC = 2.5
Day 1, 8 q 21 days
*Irinotecan (I) 100 mg/m2, D1, 8 q 21dCarboplatin (Cb) AUC = 2.5, D1, 8 q 21d
Cetuximab (E) 400 mg/m2, D1, then 250 mg/m2 weekly thereafter
Cetuximab (E) alone
at progression
*Starting ICb doses decreased to 90 mg/m2 and AUC = 2.0 midway through enrollment due to diarrhea with ICb + E
RANDOMIZE
O’Shaughnessy J, et al. SABCS 2007. Abstract 308.
ICb ± E: Patient Characteristics Arm 1 (ICb) Arm 2 (ICb+E) Number of Patients Enrolled* 75 79 Median Age (Years) 53 55 Number and Percentage (%) of Patients ECOG Performance Status
0 52 (69) 44 (56) 1 19 (25) 34 (43) 2 4 (5) 1 (1)
Receptor Status ER-/PR-/HER2- (Triple Negative) 36 (48) 42 (53) HR+/HER2- 38 (51) 35 (44) HER2+ 1 (1) 2 (3)
Metastatic Sites Bone 30 (40) 28 (35) Brain 2 (3) 5 (6) Liver 25 (33) 30 (38) Lung 25 (33) 34 (43) Lymph Node 19 (25) 33 (42)
Prior Treatment Anthracycline 61 (81) 58 (73) Trastuzumab** 2 (3) 3 (4) Taxane 62 (83) 56 (71)
Prior Adjuvant Chemotherapy 57 (70) 57 (70) Prior Metastatic Chemotherapy 33 (40) 22 (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.
Pts Evaluable for Efficacy (N = 138) Arm 1 (ICb) Arm 2 (ICb+E)
Number of Patients 69 69
Overall Response Rate 21 (31) 26 (38) CR 4 (6) 4 (6) PR 17 (25) 22 (32) SD 31 (45) 28 (40) PD 17 (25) 15 (22)
Triple Negative Pts Number of Patients 33 39 Overall Response Rate 10 (30) 19 (49) CR 3 (9) 3 (8) PR 7 (21) 16 (41) SD 17 (52) 15 (39) PD 6 (18) 5 (13)
HR+/HER2 Negative Pts Number of Patients 35 28 Overall Response Rate 10 (29) 7 (25) CR 1 (3) 1 (4) PR 9 (26) 6 (21) SD 14 (40) 12 (43) PD 11 (31) 9 (32)
Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC
Overall Efficacy by Subset
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