Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Linda T. Vahdat, MD Medical Director,

Integration of Treatment Advances into Clinical Practice:

Novel Microtubule-Targeting Agents in Metastatic Breast Cancer

Linda T. Vahdat, MDMedical Director, Breast Cancer Research Program

Weill Cornell Medical College

New York Presbyterian Hospital

New York, NY

Program Goals

• Review data on new anti-microtubule agents (nab-paclitaxel and ixabepilone)

– Background

– Mechanism of action

– Pharmacology

– Pre-clinical data

– Clinical data

Why Target Microtubules?

• Perform multiple basic cellular functions

• Fill the area from nucleus to plasma membrane

• At least 3 distinct binding sites for tubulin-targeting drugs

• Disruption of microtubule cytoskeleton leads to mitotic arrest and cell death

Microtubule Structure and Assembly

-Slide courtesy of Dr. Paraskevi (Evi) Giannakakou

a

b

+

–

Mitosis and Microtubules

• Microtubules

– Make up the mitotic spindle

– Critical to separation of chromosomes in mitosis

Slide courtesy of Dr. Paraskevi (Evi) Giannakakou

Microtubule-Stabilizing Agents Derived From Natural Products

Agent Source Latin Name

Paclitaxel Pacific yew Taxus brevifolia

Epothilones Myxobacteria Sorangium cellulosum

Discodermolide Sponge Discodermia dissoluta

Eleutherobin Corals Eleutherobin aurea

Sarcodictyins Corals Sarcodictyon roseum

Taccalonolide Plant Tacca plantagine/chantrieri

Laulimalide SpongeFasciospongia rimosa

Cacospongia mycofijiensis

Partial Listing of Drugs That Target Microtubules

• Vinca alkaloids

• Taxanes

• Epothilones

nab-paclitaxel

nab-paclitaxel

• Paclitaxel bound to albumin

• Advantages:

– No premeds

– Cremophor free

– Shorter infusion time

• Might make use of gp60-albumin mediated receptor transport across endothelial cells

gp60 receptor Tumor endothelial cell Red Blood cell

Albumin-drug complex

Tumor cells

Internalized SPARC/Alb-drug complex

Surface SPARC bound to Alb-drug complex

Alb-drug complex transcytosed by gp60

TUMOR BLOOD VESSEL

gp60/Alb-drug complex

TUMOR INTERSTITIUM

SPARC on Tumor cell surface

gp60 receptor Tumor endothelial cell Red Blood cell

Albumin-drug complex

Tumor cells

Internalized SPARC/Alb-drug complex

Surface SPARC bound to Alb-drug complex

Alb-drug complex transcytosed by gp60

TUMOR BLOOD VESSEL

gp60/Alb-drug complex

TUMOR INTERSTITIUM

SPARC on Tumor cell surface

Caveolae

SPARC

Albumin-Drug Accumulation

Albumin-Bound Drug

Gp60 Receptor

nab-platform Utilizes Endogenous Albumin Pathways of Endothelial Transcytosis (gp60) and Intratumoral Binding of SPARC

A Pharmacokinetic Comparison of nab-paclitaxel and Paclitaxel

PK Comparison-linearityTotal Paclitaxel

nab-paclitaxel: 30 min infusion

Linear, predictable PK

Dose Cmax AUC CL

(mg/m2) % δ (ng/ml) % δ (ng*hr/ml) % δ (L/h/m2) % δ

135 ---- 3071 ---- 8604 ---- 15.9 ----

175 30 5202 70 15048 75 11.6 25

Paclitaxel: 3 hr infusion

Non-linear, less-predictable PK

Clinical PK Comparison of Total PaclitaxelStudy C008-0

nab-paclitaxel(dose-adjusted to 175 mg/m2)

paclitaxel (175 mg/m2)

Clinical Studies

nab-paclitaxel

Trial No. pts Setting Schedule RR (%)Med TTP

(wks)

Ibrahim1 63 No limit 300 mg/m2 Q3w 48 27

Mirtschung2 23 1st line125 mg/m2 QW (3 out of 4 wks)

57 NR

Gradishar3

nab-paclitaxel vs paclitaxel

460 1st line260 mg/m2 vs.

175 mg/m2 Q 3W33 vs 19 23 vs 17

Significant differences in Bold; RR= response rate, TTP= time to progression; NR= not reported

1Ibrahim, JCO 2005; 2Mirtschung Breast Ca Res Treat Suppl 2006; 3Gradishar JCO 2005

Phase II Study nab-paclitaxel vs. Docetaxel

Comparisons (N=300)Comparisons (N=300)

nabnab-paclitaxel vs. -paclitaxel vs. docetaxel docetaxel ((A, B, CA, B, C vs. vs. D D))

weekly vs. every-3-weekly vs. every-3-weeks weeks nabnab-paclitaxel -paclitaxel ((B, CB, C vs. vs. AA))

low vs. high dose low vs. high dose weekly weekly nabnab-paclitaxel -paclitaxel ( (BB vs. vs. C C) )

Arm A: nab-paclitaxel 300 mg/m2 q3w

Arm B: nab-paclitaxel 100 mg/m2

weekly 3 out of 4

Arm C: nab-paclitaxel 150 mg/m2

weekly 3 out of 4

Arm D: docetaxel 100 mg/m2 q3w

RR

AA

NN

DD

OO

MM

II

ZZ

EE

first-line metastatic breast cancer patients randomized to 4 arms:first-line metastatic breast cancer patients randomized to 4 arms:

Arms A, C and D administered at the MTDArms A, C and D administered at the MTDGradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.

Phase II Study nab-paclitaxel vs. Docetaxel

MBC and no previous chemotherapy for metastatic disease

(N = 300)

ABX ABX 300 mg/m300 mg/m22 every 3 wks every 3 wks(N = 76)(N = 76)

ABX ABX 100 mg/m100 mg/m22 wkly for 3 of 4 wks wkly for 3 of 4 wks(N = 76)(N = 76)

Docetaxel Docetaxel 100 mg/m100 mg/m22 every 3 wks every 3 wks(N = 74)(N = 74)

ABX ABX 150 mg/m150 mg/m22 wkly for 3 of 4 wks wkly for 3 of 4 wks(N = 74)(N = 74)

Gradishar W, et al. ASCO 2007. Abstract 1032.

Comparison of Investigator and Independent Radiology Review Response Assessments

43%

62%

70%

38%35%

45% 47%

28%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Investigator

IRR

Re

sp

on

se

Ra

te (

%)

Re

sp

on

se

Ra

te (

%)

300 mg/m300 mg/m22 100 mg/m100 mg/m22 150 mg/m150 mg/m22 docetaxeldocetaxelq3wq3w qw 3/4qw 3/4 qw 3/4qw 3/4 100 mg/m100 mg/m2 2 q3wq3w

((AA: N = 76): N = 76) ((BB: N = 76): N = 76) ((CC: N = 74): N = 74) ((DD: N = 74): N = 74)

nab-nab-paclitaxelpaclitaxel

Pearson Correlation Coefficient Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507(Investigator vs. IRR) = 0.507

Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.

Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d)

ABX 300 mg/m2 q3w ABX 100 mg/m2 qw3/4ABX 150 mg/m2 qw3/4Docetaxel 100 mg/m2 q3w

P = .016

P = .007P = .003

P = .002100

90

80

70

60

50

40

30

20

10

0

Res

po

nse

Rat

e (%

)

Treatment

43

62

n = 76 76 74 74

70

38


Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d)

Months

Progression-free SurvivalInvestigator Assessments

Pro

po

rtio

n N

ot

Imp

rove

d

30 6 9 12 15 180.0

0.25

0.50

1.0

75% of patients off-study

0.75

AB CD


• PFS statistically superior with 150 mg/m2 (P = .002) and 300 mg/m2 nab-paclitaxel (P = .046) compared with docetaxel in MBC

• PFS statistically superior with 150 mg/m2 nab-paclitaxel compared with 100 mg/m2 nab-paclitaxel (P = .009)

• Lower incidence of neutropenia and fatigue with all schedules of nab-paclitaxel compared with docetaxel

• Randomized phase III trial comparing weekly nab-paclitaxel 150 mg/m2 vs. docetaxel 100 mg/m2 in MBC planned

nab-paclitaxel: Grade 3/4 Toxicity in MBC

0

20

40

60

80

100

Neutro

penia

300mg/m2 Q3w

100mg/m2 QW

150mg/m2 QW

Grade 3/4 Neutropenia 19-37%

Docetaxel 100 mg/m2 q3w 21-74%


0

20

40

60

80

100

Neutro

penia FN

300mg/m2 Q3w

100mg/m2 QW

150mg/m2 QW

Febrile Neutropenia 1%

Docetaxel 100 mg/m2 q3w 7%


0

20

40

60

80

100

Neutro

penia FN PN

300mg/m2 Q3w

100mg/m2 QW

150mg/m2 QW

Peripheral neuropathy 7-14 %

100 mg/m² QW least neuropathy compared to two other nab-paclitaxel arms


Time to Improvement in Peripheral NeuropathyP

ropo

rtio

n N

ot Im

prov

ed

0.00

0.25

0.50

0.75

1.00

Days0 20 40 60 80 100

nab-paclitaxel 300 mg/m2 q3w (N = 13)

nab-paclitaxel 100 mg/m2 weekly (N = 7)

nab-paclitaxel 150 mg/m2 weekly (N = 12)

Docetaxel 100 mg/m2 ( N = 8)

A) Median, 16 days, 95% CI, 12 to 24B) Median, 22 days, 95% CI, 14 to 25C) Median, 23 days, 95% CI, 12 to 31D) Median, 41 days, 95% CI, 37 to 44

Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.


0

20

40

60

80

100

Neutro

penia FN PN

Fatig

ue

300mg/m2 Q3w

100mg/m2 QW

150mg/m2 QW

Fatigue 0-4 %

100 mg/m2 QW least neuropathy compared to two other nab-paclitaxel arms


Conclusions

• The response rates of q3w nab-paclitaxel and docetaxel were comparable

• For each regimen of nab-paclitaxel compared to docetaxel

– Grade 4 neutropenia, febrile neutropenia and mucositis were less frequent

– There were no statistical differences between the rates of peripheral neuropathy

Case: Taxane-naïve First-line Metastatic Breast Cancer

• 54 y.o. woman diagnosed with Stage II BC in 1999 (T= 2.5 cm N = 1/15, ER/PR pos. HER2neu = 0)

• AC Q3W x 4 followed by Tamoxifen

• 2006: increased abdominal fullness

• Mild elevation of transaminases EOD: liver metastases

• Biopsy: c/w prior BC ER/PR positive and HER2-neu non-amplified by FISH


Which treatment option would you recommend?

nab-paclitaxel

Docetaxel

Capecitabine

Vinorelbine



nab-paclitaxel Docetaxel Capecitabine Vinorelbine

Recommended Approach:

• nab-paclitaxel

Ixabepilone

• Derived from sorangium Cellulosum along the Zambezi River

• Myxobacteria

• Secondary metabolites (epothilones/fungicides)

Epothilones

Epothilones

• Macrolide lactones

– Epothilone A, B, E, F (epoxides)

– Epothilone C,D (olefins)

Goodin et al JCO 2004

Epothilones: Mechanism of Action

• Induce microtubule stabilization

– Bind to b-tubulin

– Compete with same binding site as paclitaxel and neuronal tau protein on b-tubulin

– Binding mode different from above

– Accumulate in G2/M

Effect of Epothilone B on Tumor Cells

Control cells displaying normal interphase microtubules .

Right: Cells treated with 10 nM epothilone B for 24 h displaying extensive microtubule

bundling.

Altmann et al Biochim Biophys Acta 2000

Microtubule bundling

Epothilones: Mechanism of Action

• Induces conformational changes in Bax (pro-apoptotic protein)

• Bcl-2- dependent

• Potential for synergism with Bcl-2 inhibitors

Pharmacologic Considerations

• Epothilone A and B

– High in vitro tumor activity

– Modest in vivo activity

– Metabolic instability

– Unfavorable PK

– Narrow therapeutic window

• Analogs developed to optimize product

Class-specific Advantages

• Low susceptibility to tumor resistance mechanisms

– MRP-1 and P-gp efflux pumps

– b (III) tubulin overexpression

– b-tubulin mutations

Pharmacology

ixabepilone

Ixabepilone: Pharmacology

• Excreted in the feces (75%) and urine (25%)

• Metabolized via P450 (CYP3A4)

• Linear (AUC increases with dose)

– Linear relationship between microtubule bundle formation in PBMC and plasma concentration

• T1/2: 39 hours (range:17-50 hrs)

Data: BMS data on file

Ixabepilone: Pharmacology

Daily x 5Q21d Daily x 3 Q21d Weekly Once Q21 d

Infusion duration (hr)

1 1 0.5-1 1

Dose (mg/m2/day)

Range 1.5 -8 8-10 1-30 32-65

MTD 6 8 25 50

DLT Neutropenia, neuropathy

MTD: maximum tolerated dose; DLT: dose-limiting toxicity; Q: every

Goodin et al, J Clin Oncol 22:2015, 2004

Pre-clinical Data

IC50 of Various Epothilones Against MCF-7 Cell Lines

3.26

2.04

0.29

2.31

6.9

0.7

0

1

2

3

4

5

6

7

Paclitaxel Epo A Epo B Epo D Epo F ZK-EPO

1Watkins EB et al, Current Phamaceutical Design, 2005; 2Hoffman J Breast Cancer Res Treat Abstract 1103, 2006

21 1 11 1

1

IC50 Values (nM) for Net Growth Inhibition of Human Carcinoma Cell Lines by Epothilones A and B in Comparison to Paclitaxel

Altmann et al Biochim Biophys Acta 2000

Ixabepilone: Phase II Data in Breast Cancer

1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol 2005;23:2726–34. 3. Conte P et al. J Clin Oncol 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol 2006;24(18S):abstr 660. 5. Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.

Roché1

After adjuvant anthra

OR

R (

%)

Low2

Taxane-pretreated MBC

Conte3

Taxane-resistant MBC

Thomas4

Multiresistant(anthra / tax / cape)

MBC

Baselga5

Neoadjuvant T2-4, N0-3,

M0

42

22

12

18 pCR19

0

15

30

45

Ixabepilone: Grade 3/4 Toxicity in MBC

Grade 3/4 neutropenia 35 to 58%

0

20

40

60

80

100

Neutro

penia

BMS 009NCI 0229BMS 010BMS 081BMS 031


0

20

40

60

80

100

Neutro

penia FN

BMS 009

NCI 0229

BMS 010

BMS 081

BMS 031

Febrile neutropenia 3-14% with 14 % on NCI0229


Sensory neuropathy ranged from 3-22%

0

20

40

60

80

100

Neutro

penia FN PN



Severe myalgias range from 3-26%

0

20

40

60

80

100

Neutro

penia FN PN

Mya

lgias



Fatigue variable at 6 to 34%

0

20

40

60

80

100

Neutro

penia

FN PN

Mya

lgias

Fatigu

e

BMS 009

NCI 0229

BMS 010

BMS 081

BMS 031


0

20

40

60

80

100

Neutro

peni

aFN PN

Mya

lgia

s

Fatigu

e

Diarrh

ea

BMS 009

NCI 0229

BMS 010

BMS 081

BMS 031

Diarrhea at 1 to 11%

Case: Early Relapse After Adjuvant ACT

• 53 y.o. woman with a h/o of a stage IIIB breast cancer

– Left lumpectomy and AND T= 3.5 cm N= 6/25 ER/PR= pos/neg and HER2-neu negative by FISH

– Received AC followed by paclitaxel Q2w

– Received chest wall RT followed by anastrozole

• Relapse in CW, lungs and liver 8 months after completing adjuvant therapy



nab-paclitaxel Docetaxel

Capecitabine

Vinorelbine

Ixabepilone



nab-paclitaxel

Docetaxel

Capecitabine

Vinorelbine

Ixabepilone


• Ixabepilone ± capecitabine

Phase III Data

A Multicenter Phase III Clinical Trial Comparing Ixabepilone plus Capecitabine

with Capecitabine Alone in Patients with Metastatic Breast Cancer Previously Treated with or Resistant to

Anthracycline and Resistant to Taxanes

Linda T. Vahdat, MD

Weill Cornell Medical College

New York, New York

On Behalf of the 046 Study Investigators

Ixabepilone(40 mg/m2 IV over 3 hr d1 q3wk)

+Capecitabine

(2000 mg/m2/day PO 2 divided doses d1-d14 q3wk)

N = 375

Capecitabine(2500 mg/m2/day PO 2 divided doses

d1-d14 q3wk)N = 377

Metastatic or locally advanced breast cancer

RESISTANT to anthracyclines

and taxanesN = 752

Stratification •Visceral metastases•Prior chemotherapy for MBC

Study Design: International, Randomized, Open-label, Phase III Trial

•Anthracycline resistance•Study site

Resistance to Prior Therapy

Strict definition: patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines and taxanes

Setting Anthracycline Taxane

Metastatic ≤3 months of last dose ≤4 months of last dose

Neo/adjuvant ≤6 months of last dose ≤12 months of last dose

Any

Minimum cumulative dose

Doxorubicin: 240 mg/m2

Epirubicin: 360 mg/m2

Patient Eligibility Criteria

Inclusion Criteria

• Women ≥18 years

• Locally advanced or MBC

• Anthracycline-resistant or minimum cumulative dose

• Taxane-resistant

• KPS 70–100

• Life expectancy ≥12 wk

Exclusion Criteria

• >3 prior chemo regimens (adjuvant and metastatic)

• ≥G2 motor/sensory neuropathy

• Reduced hematologic/renal function

• ≥G2 liver function tests*

• CNS metastases

*Protocol amendment excluded patients with ≥G2 liver function tests regardless of liver metastases; 377 patients (33 with ≥G2 liver function tests) had been enrolled before amendment

Median 95% CI

Ixabepilone + Capecitabine 5.8 mo (5.5–7.0)

Capecitabine 4.2 mo (3.8–4.5)

Progression-free Survival by Independent Radiologic Review

P=0.0003

HR: 0.75 (0.64–0.88)

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

Response Rate

% Response

Investigator IRR

Ixabepilone + Capecitabine

N=375

Capecitabine

N=377

Ixabepilone + Capecitabine

N=375

Capecitabine

N=377

ORR (CR + PR) 42 23 35 14

P<0.0001 P<0.0001

Stable disease 36 38 41 46

Progressive disease

14 29 15 27

Unable to determine

8 10 9 12

Grade 3/4 Non-hematologic ToxicitiesP

erip

hera

l

neur

opat

hy

23

0

Mya

lgia

8

0.3

Han

d-fo

ot

synd

rom

e

18 17D

iarr

hea

69

Muc

ositi

s

3 2

Vom

iting

4 2

Fatig

ue

9

3

Nau

sea

3 2

Art

hral

gia

30

0

% o

f Pa

tient

s

Ixabepilone + Capecitabine (N = 369)

Capecitabine (N = 368)

20

40

60

80

Epothilones in Development• Patupilone (epothilone B):

– Phase I trials in breast cancer in combination with other cytotoxics

– In preliminary efficacy data, toxicity included significant gastrointestinal effects

– New formulation appears to reduce toxicity

• KOS-862 (epothilone D):

– Phase II trial in anthracycline- and taxane-pretreated metastatic breast cancer

– Of the 41 evaluable patients, 5 achieved a PR and 3 had SD

– Grade 3 neurotoxicity in 43 evaluable patients: neuropathy (12%) and ataxia (9%)

– Phase I trial combined with trastuzumab:

• Unconfirmed response: 3/13

• Grade 3 neurotoxicity: 2/13

• ZK-EPO:

– First fully synthetic third-generation epothilone

– Not recognized by efflux pumps; efficacy in preclinical models in taxane-resistant disease

Cortes et al. J Clin Oncol 2006; 24(suppl):86s (abstract 2028).

Buzdar et al. Breast Cancer Res Treat 2005; 94(suppl 1):S69 (abstract 1087).Klar et al. Breast Cancer Res Treat 2005; 94(suppl 1):S64 (abstract 1072).

Case: Refractory Triple Negative Breast Cancer

• 46 y.o. woman with a h/o stage I BC (T = 1.8 cm N = 0 ER/PR/HER 2 neu: negative diagnosed in 2000

• RLE and SLNB

• AC x 4 Q3w followed by right breast RT

• Did well until 2005 when developed soft tissue mass adjacent to sternum

– Biopsy c/w recurrent BC ( ER/PR/HER2 neu negative)

• Capecitabine: Initial response followed by POD in bone

• Docetaxel: Initial response followed by POD in lungs and mediastinal LNs



nab-paclitaxel

Gemcitabine

Vinorelbine

Ixabepilone



nab-paclitaxel

Gemcitabine

Vinorelbine

Ixabepilone


• Ixabepilone

Integration of Treatment Advances into Clinical Practice:

Novel Microtubule-Targeting Agents in Metastatic Breast Cancer

Closing Remarks

Documents

Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Linda T. Vahdat, MD Medical Director,