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A Report from ECCO 14 Oral Chemotherapy in 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. - PowerPoint PPT Presentation
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A Report from ECCO 14
Oral Chemotherapy in 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
Capecitabine in the Treatment of Breast Cancer
• ECCO 14 trials of capecitabine in breast cancer
– Neoadjuvant therapy
• Capecitabine + docetaxel ± trastuzumab
• p53 mutation as prognostic factor
– First-line metastatic breast cancer
• Capecitabine + ixabepilone: subgroup analysis for 1st-line setting
• Capecitabine + lapatinib: updated efficacy and gene-array data
ECCO 14 Abstract P#2129
An Open-Label Study of Capecitabine (C) and Docetaxel (D) as Neoadjuvant Treatment for Patients with Recently Diagnosed HER2-neu Negative (HER2-) Breast Cancer (BC) plus
Trastuzumab (T) for HER2-neu Positive (HER2+) BC
D. Tripathy, C. Moisa, S. Glück
Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Treatment Schedule
Tripathy D, et al. ECCO 14. Abstract P#2129.
Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Baseline CharacteristicsHER2-
(N = 122)HER2+(N = 34)
Median age, years (range) 51 (24-80) 55 (31-68)
Hormone receptor positive 69 (57%) 15 (44%)
Histology
Ductal 100 (82%) 33 (97%)
Lobular 12 (10%) 1 (3%)
Mixed 8 (7%) 0
Other 2 (2%) 0
Menopausal status
Premenopausal 62 (51%) 12 (35%)
Postmenopausal 56 (46%) 22 (65%)
Tripathy D, et al. ECCO 14. Abstract P#2129.
Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Tripathy D, et al. ECCO 14. Abstract P#2129.
Efficacy HER2- HER2+
Pathologic Response (N = 88) (N = 26)
pCR + npCR (up to T1a) 12 (14%) 12 (46%)
pCR 7 (8%) 9 (35%)
npCR 5 (6%) 3 (12%)
Missing 9 (10%) 2 (8%)
Clinical Response (N = 90) (N = 25)
Overall response rate 55 (61%) 19 (76%)
Complete response 17 (19%) 13 (52%)
Partial response 38 (42%) 6 (24%)
Stable Disease 15 (17%) 2 (8%)
Progressive disease 0 1 (4%)
Missing 20 (22%) 3 (12%)
Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Tripathy D, et al. ECCO 14. Abstract P#2129.
Grade 3 /4 adverse events in > 3% patients (related or unrelated to treatment)
Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Conclusions
• Interim data suggest that capecitabine + docetaxel ± trastuzumab is a highly active, well-tolerated, non-anthracycline-containing treatment option
– 46% rate of pCR + npCR in HER2+ disease
– 14% rate of pCR + npCR in HER2- disease
• Data consistent with findings from a Belgian study in patients with inoperable HER2+ BC (45% pCR, 100% CR)
• Final analysis will be presented in 2008
Tripathy D, et al. ECCO 14. Abstract P#2129.
ECCO 14 Abstract P#2060
An Open-Label Study of Neoadjuvant Capecitabine (C) and Docetaxel (D)
with/without Trastuzumab (T) to Determine the Role of p53 Mutations in Clinical and
Pathological Responses in Patients with Recently Diagnosed Breast Cancer (BC)
N. Patten, S. Truong, D. Tripathy, S. Glück, U. Dugan, L. Wu
Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 Mutation
Trial Design
Patten N, et al. ECCO 14. Abstract P#2060.
Stage II/III Breast Cancer
• No prior systemic or local therapy
Capecitabine 825 mg/m2 PO bid d1-14 q 21 days+Docetaxel 75 mg/m2 d1 q 21 days ±Trastuzumab 4 mg/kg d1 followed by 2 mg/kg weekly for 4-cycles prior to surgery
• Primary endpoint:
– pCR + npCR
• Secondary endpoint:
– p53 mutation status for predicting pathological response to treatment
Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 Mutation
Results
• A total of 82 p53 mutations were detected:
– 57 (70%) missense, 9 (11%) frameshift, 14 (17%) nonsense, 1 (1%) splice site, and 1 (1%) silent
– Mutations were widely distributed in exons 2, 4, 5, 6, 7, 8, 9, 10
– Highest number of mutations in exons 5, 6, and 8
• There appeared to be an association between p53 mutation and triple-negative (ER-, PR-, HER2-) disease
– 80% (24/30) of triple-negative samples
– 64% (14/22) of HER2+ samples vs. 47% (32/68) of HER2- samples
– 28% (13/46) of ER+ samples vs. 75% (33/44) of ER- samples
– 23% (7/31) of PR+ samples vs. 66% (39/59) of PR- samples
Patten N, et al. ECCO 14. Abstract P#2060.
Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 Mutation
Conclusions
• Interim findings suggest that p53 mutations occur in approximately 50% of patients recently diagnosed with infiltrating breast cancer compared with previous reports of 20%-40%
• Somatic mutations were distributed across different functional domains of p53 and were most common in exons 5, 6, and 8
• A higher frequency of p53 gene mutations was observed in ER-, HER2+, and triple-negative samples, consistent with previous reports
• Analysis of status, type, and location of p53 mutation in relation to clinical and pathological outcomes is ongoing
Patten N, et al. ECCO 14. Abstract P#2060.
ECCO 14 Abstract O#2101
Phase III Study of Ixabepilone Plus Capecitabine in Patients with Metastatic Breast
Cancer (MBC) Progressing after Anthracyclines and Taxanes:
Subgroup Analysis of Patients Receiving Ixabepilone in the First-Line Setting
J. Jassem, E. Thomas, H. Gomez, R.K. Li, H.C. Chung, L.E. Fein, V.F. Chan, R.A. Peck, P. Mukhopadhyay, H. Roché
Metastatic or locally advanced breast
cancer heavily treated
Ixabepilone 40 mg/m2 IV over 3 hrs Day 1 +Capecitabine 2,000 mg/m2 PO 2 divided doses
Days 1-14, every 3 wks(N = 375)
Capecitabine 2,500 mg/m2 PO 2 divided doses Days 1-14 every 3 wks
(N = 377)
Ixabepilone + Capecitabine vs. Capecitabine International, Randomized, Open-label, Phase III Trial
Jassem J, et al. ECCO 14. Abstract O#2101.
Median 95% CI
Ixabepilone + Capecitabine 5.8 mos. (5.5–7.0)
Capecitabine 4.2 mos. (3.8–4.5)
Ixabepilone + Capecitabine vs. Capecitabine Primary Endpoint: Progression-Free Survival
P = 0.0003
HR: 0.75 (0.64-0.88)
4 14 20 26
Pro
port
ion
Pro
gres
sion
-Fre
e
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 6 8 10 12 16 18 22 24 28 30 32 34 36 38
Months
Jassem J, et al. ECCO 14. Abstract O#2101.
Ixabepilone + Capecitabine vs. Capecitabine Selected Outcomes
OutcomesIxabepilone +Capecitabine
Capecitabine P-value
Number of Pts 375 377 -
CR + PR 35% 14% < .001
G 3/4 Neutropenia 68% 11% < .001
Febrile Neutropenia 4% < 1% .001
G 3/4 Anemia 10% 4% .005
G 3/4 Neuropathy 23% 0 ?
Jassem J, et al. ECCO 14. Abstract O#2101.
Hazard ratio (95% Cl)
Ixabepilone + Capecitabine vs. Capecitabine Alone in Previously Treated or Resistant Patients
FavorsIxabepilone + Capecitabine
FavorsCapecitabine
< 50≥ 50
70-8090-100
YesNo
YesNo
YesNo
YesNo
OtherPositive
PositiveOther
HER2 status
ER status
Prior chemo metastatic
Anthracycline resistance
Visceral disease
KPS
Age
ER/PR/HER2-
0.26
0.4 0.6 0.8 1.0 1.2
/ /
PFS in Pre-Specified Subsets
Jassem J, et al. ECCO 14. Abstract O#2101.
Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Hematologic Toxicities
(%)*Ixabepilone +Capecitabine
(N = 369)
Capecitabine(N = 368)
P-value
Leukopenia 57 6 < 0.0001
Anemia 10 4 0.005
Neutropenia 68 11 < 0.0001
Thrombocytopenia 8 4 0.011
Febrile neutropenia 4 < 1 0.001
*By worst CTC AE x 3 grade
Jassem J, et al. ECCO 14. Abstract O#2101.
Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Non-Hematologic Toxicities
80
60
40
20
0
Ixabepilone + Capecitabine (N = 369)Ixabepilone + Capecitabine (N = 369)
Capecitabine (N = 368) Capecitabine (N = 368)
2323
% o
f P
atie
nts
% o
f P
atie
nts
00
1818
99
1717
330.30.3
6699
44 22 33 33 22 3300
88
22
Fatig
ue
Fatig
ue
Mya
lgia
Mya
lgia
Vom
iting
Vom
iting
Nau
sea
Nau
sea
Dia
rrhe
a
Dia
rrhe
a
Muc
ositi
s
Muc
ositi
s
Art
hral
gias
Art
hral
gias
Han
d / F
oot
Han
d / F
oot
synd
rom
e
synd
rom
e
Per
iphe
ral
Per
iphe
ral
Neu
ropa
thy
Neu
ropa
thy
Jassem J, et al. ECCO 14. Abstract O#2101.
Ixabepilone + Capecitabine vs. Capecitabine Prospectively-Defined Subset Analysis
Total PopulationFirst-Line after Adjuvant A/T
Ixabepilone + Capecitabine
(N = 375)Capecitabine
(N = 377)
Ixabepilone + Capecitabine
(N = 25)Capecitabine
(N = 30)
PFS (mos.), median5.8
(5.5-7.0)4.2
(3.8-4.5)7.0
(4.5-8.8)2.1
(1.4-4.2)
HR (95.17% CI)0.75
(0.64-0.88)0.46
(0.25-0.85)
Response Rate (%) 35 14 44 10
Jassem J, et al. ECCO 14. Abstract O#2101.
Ixabepilone + Capecitabine vs. Capecitabine Conclusions
• Ixabepilone + capecitabine demonstrates superior efficacy to capecitabine alone in MBC resistant to anthracyclines and taxanes
– Improvement in PFS (HR 0.75)
– 2.5-fold increase in ORR (35% vs. 14%)
– Benefit was consistent across subgroups
• Manageable safety profile (normal or grade 1 LFTs)
• Benefit is also confirmed in first-line patients who progress after adjuvant anthracycline and taxane therapy
Jassem J, et al. ECCO 14. Abstract O#2101.
ECCO 14 Abstract O#2096
Lapatinib (L) plus Capecitabine (C) in HER2+ Advanced Breast Cancer (ABC): Report of
Updated Efficacy and Genearray Data
J. Crown, D. Cameron, A.M. Martin, B. Newstat, T. Pienkowski, A. Jagiello-Gruszfeld, B. Kaufman, M.A. Casey, S. Stein, C. Geyer
Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer
Lapatinib 1,250 mg po qd continuously +
Capecitabine 2,000 mg/m2/d po d1-14 q 3 wk
Capecitabine 2,000 mg/m2/d po d1-14 q 3 wk
RANDOMIZE
Crown J, et al. ECCO 14. Abstract O#2096.
Locally Advanced or Metastatic Breast Cancer
• Previously treated with anthracycline, taxane, and trastuzumab
• No prior capectiabine
Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer
Updated Efficacy Results
End PointLapatinib + Capecitabie(N = 163)
Capecitabine Alone
(N = 161)
Hazard Ratio(95% CI)
P-value
Median, TTP (wks) 27 190.57
(0.43-0.77)0.00013
Overall Response 24% 14% 0.017
Overall survival (L + C vs. C): HR = 0.78 [0.55-1.12]; P = 0.177
Crown J, et al. ECCO 14. Abstract O#2096.
Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer
Genearray Data
• 103/217 patient tumor blocks evaluable for gene expression by qRT-PCR
• Genearray analysis data
– 55 blocks in L + C arm
• 19 responders (PR = 19)
• 26 non-responders (SD = 20, PD = 6)
• 10 non-evaluable
– 35 blocks in C arm
• 5 responders (PR = 5)
• 22 non-responders (SD = 20, PD = 12)
• 8 non-evaluable Crown J, et al. ECCO 14. Abstract O#2096.
Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer
Genearray Data
• Genearray analysis
– Elevated baseline HER2 mRNA expression correlates with response to L + C (P < 0.01) and longer TTP (P < 0.0001)
– Patients with elevated baseline FOX3A mRNA levels and reduced baseline BCL-2 mRNA responded to L + C alone
• Consistent with preclinical response data in breast cancer cell lines
Crown J, et al. ECCO 14. Abstract O#2096.