A Report from ECCO 14 Oral Chemotherapy in Breast Cancer

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.


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%)




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%)



Grade 3 /4 adverse events in > 3% patients (related or unrelated to treatment)


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


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


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



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


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


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 ?


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


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


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

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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


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


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


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



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.


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


Capecitabine in the Treatment of Breast Cancer

Closing Comments

William J. Gradishar, MD

Documents

A Report from ECCO 14 Oral Chemotherapy in Breast Cancer