1. 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

2. 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

3. D. Tripathy, C. Moisa, S. Glück
ECCO 14 Abstract P# 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

4. Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Treatment Schedule
Tripathy D, et al. ECCO 14. Abstract P#2129.

5. Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Baseline Characteristics
HER2-
(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%)
Other
2 (2%)
Menopausal status
Premenopausal
62 (51%)
12 (35%)
Postmenopausal
56 (46%)
22 (65%)
Tripathy D, et al. ECCO 14. Abstract P#2129.

6. Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
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%)
Progressive disease
1 (4%)
20 (22%)
Tripathy D, et al. ECCO 14. Abstract P#2129.

7. Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC
Grade 3 /4 adverse events in > 3% patients
(related or unrelated to treatment)
Tripathy D, et al. ECCO 14. Abstract P#2129.

8. 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.

9. N. Patten, S. Truong, D. Tripathy, S. Glück, U. Dugan, L. Wu
ECCO 14 Abstract P# 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

10. Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 Mutation Trial Design
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
Patten N, et al. ECCO 14. Abstract P#2060.

11. 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%) 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.

12. 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.

13. ECCO 14 Abstract O# 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

14. Metastatic or locally advanced breast cancer
Ixabepilone + Capecitabine vs. Capecitabine International, Randomized, Open-label, Phase III Trial
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)
Jassem J, et al. ECCO 14. Abstract O#2101.
References

15. Proportion Progression-Free
Ixabepilone + Capecitabine vs. Capecitabine Primary Endpoint: Progression-Free Survival 4 14 20 26
Proportion Progression-Free
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 2 6 8 10 12 16 18 22 24 28 30 32 34 36 38
Months
Median
95% CI
Ixabepilone + Capecitabine
5.8 mos.
(5.5–7.0)
Capecitabine
4.2 mos.
(3.8–4.5)
P =
HR: 0.75 ( )
Jassem J, et al. ECCO 14. Abstract O#2101.

16. Ixabepilone + Capecitabine vs. Capecitabine Selected Outcomes
P-value
Number of Pts
375
377 -
CR + PR
35%
14%
< .001
G 3/4 Neutropenia
68%
11%
Febrile Neutropenia 4%
< 1%
.001
G 3/4 Anemia
10%
.005
G 3/4 Neuropathy
23% ?
Jassem J, et al. ECCO 14. Abstract O#2101.

17. Ixabepilone + Capecitabine
Ixabepilone + Capecitabine vs. Capecitabine Alone in Previously Treated or Resistant Patients
Favors
Ixabepilone + Capecitabine
Capecitabine
< 50
≥ 50
70-80
90-100
Yes No
Other
Positive
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
Hazard ratio (95% Cl)
Jassem J, et al. ECCO 14. Abstract O#2101.

18. Ixabepilone + Capecitabine (N = 369)
Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Hematologic Toxicities
(%)*
Ixabepilone + Capecitabine (N = 369)
Capecitabine (N = 368)
P-value
Leukopenia 57 6
<
Anemia 10 4
0.005
Neutropenia 68 11
Thrombocytopenia 8
0.011
Febrile neutropenia
< 1
0.001
*By worst CTC AE x 3 grade
Jassem J, et al. ECCO 14. Abstract O#2101.

19. Ixabepilone + Capecitabine vs
Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Non-Hematologic Toxicities 80 60 40 20
Ixabepilone + Capecitabine (N = 369)
Capecitabine (N = 368) 23
% of Patients 18 9 17 3
0.3 6 4 2 8
Fatigue
Myalgia
Vomiting
Nausea
Diarrhea
Mucositis
Arthralgias
Hand / Foot
syndrome
Peripheral Neuropathy
Jassem J, et al. ECCO 14. Abstract O#2101.

20. Ixabepilone + Capecitabine
Ixabepilone + Capecitabine vs. Capecitabine Prospectively-Defined Subset Analysis
Total Population
First-Line after
Adjuvant A/T
Ixabepilone + Capecitabine
(N = 375)
Capecitabine
(N = 377)
(N = 25)
(N = 30)
PFS (mos.), median
5.8
( )
4.2
( )
7.0
( )
2.1
( )
HR (95.17% CI)
0.75
( )
0.46
( )
Response Rate (%) 35 14 44 10
Jassem J, et al. ECCO 14. Abstract O#2101.

21. 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.

22. ECCO 14 Abstract O# 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

23. 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
RANDOMIZE
Locally Advanced or Metastatic Breast Cancer
Previously treated with anthracycline, taxane, and trastuzumab
No prior capectiabine
Capecitabine 2,000 mg/m2/d po d1-14 q 3 wk
Crown J, et al. ECCO 14. Abstract O#2096.

24. Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer Updated Efficacy Results
End Point
Lapatinib + Capecitabie
(N = 163)
Capecitabine Alone
(N = 161)
Hazard Ratio
(95% CI)
P-value
Median, TTP (wks) 27 19
0.57
( )
Overall Response
24%
14%
0.017
Overall survival (L + C vs. C): HR = 0.78 [ ]; P = 0.177
Crown J, et al. ECCO 14. Abstract O#2096.

25. 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.

26. 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 < )
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.

27. Capecitabine in the Treatment of Breast Cancer Closing Comments
William J. Gradishar, MD