Role of Novel Microtubule-Targeting Agents in Metastatic Breast Cancer

Andrew D. Seidman, MDProfessor of Medicine

Weill Medical College of Cornell UniversityAttending Physician

Memorial Sloan-Kettering Cancer CenterNew York, New York

Treatment of Metastatic Breast Cancer(MBC)

Case Studies

Case 1Taxane-naïve First-line MBC

• 48 y.o. woman was diagnosed with stage II BC in 2001

– T = 2.3 cm

– N = 0

– ER/PR: positive

– HER2: negative by FISH

• Adjuvant treatment: AC x 4 Q3w followed by right breast RT and tamoxifen x 2.5 years, then aromatase inhibitor x 2.5 years (after clearly menopausal)

• Did well until 2007 when she developed soft tissue mass adjacent to sternum and a right hilar mass

– Biopsy of parasternal mass c/w recurrent BC (ER/PR-positive, HER2-negative)

Case 1Taxane-naïve First-line MBC

• First-line treatment of metastatic breast cancer: fulvestrant, with POD after 3 months

• Second-line treatment of metastatic breast cancer: exemestane, with POD after 2 months

• Patient now has pain in parasternal area. CT scan shows 2 hepatic lesions “most compatible with metastases”. Normal LFT’s, no fatigue, no abdominal pain

Case 1Taxane-naïve First-line MBC

Which treatment option would you recommend?

Docetaxel

Paclitaxel

nab-paclitaxel

Paclitaxel + gemcitabine

Docetaxel + capecitabine

Capecitabine

Paclitaxel + bevacizumab

Ixabepilone ± capecitabine

Other

Case 2Early Relapse After Adjuvant AC→T

• 50 y.o. woman was diagnosed with stage IIIB breast cancer in 2006

– Received neoadjuvant AC followed by paclitaxel Q2w (dose-dense)

– Left lumpectomy

– T = 3.8 cm; N = 7/28; ER/PR: negative; HER2-negative by FISH

– Received chest wall RT

– 1-year after completing adjuvant therapy, relapse in chest wall, lungs, bone, and liver

Case 2Early Relapse After Adjuvant AC→T

Which treatment option would you recommend?

Docetaxel

nab-paclitaxel

Gemcitabine

Capecitabine

Vinorelbine

Ixabepilone ± capecitabine

Non-taxane combination (e.g. vinorelbine + capecitabine, gemcitabine + carboplatin)

Case 2Early Relapse After Adjuvant AC→T

Would you add bevacizumab to whatever first-line regimen that you recommend?

Yes

No

Case 3 Refractory MBC

• PH is a 55 y.o. woman who received adjuvant TAC and anastrozole for stage II ER+/PR-/HER2- breast cancer in 2004

• She relapsed in 2006 with numerous liver metastases, a moderate right pleural effusion, and innumerable bone metastases

• First-line treatment for MBC was paclitaxel/gemcitabine, with zolendronate– Patient responded well radiographically and symptomatically

– After 9 months, the disease progressed; a chest tube was placed for pleurodesis

• Second-line treatment was capecitabine– Stabilization of her disease for 6 months, then disease progressed

in liver and bone

Case 3Refractory MBC

Case 3Refractory MBC

Which treatment option would you recommend? nab-paclitaxel

Docetaxel

Vinorelbine

Ixabepilone

Irinotecan

Oral etoposide

Liposomal doxorubicin

Other

Treatment of MBC

5-Year Survival Rates by Stage

Stage 0 (95%)

Stage I (88%)

Stage II (66%)

Stage III (36%)

Stage IV (7%)

http://www.nlm.nih.gov/medlineplus/ency/article/000913.htm

Advances in Treatment

1980 1985 1990 1995 2000 2005

Capecitabine

Bevacizumab

Paclitaxel

CMF

Gemcitabine

Albumin-Bound Paclitaxel

Trastuzumab

Lapatinib

Doxorubicin

EpirubicinMitoxantrone

Vinorelbine

Docetaxel

HER2+

Aromatase Inhibitors

Tamoxifen

ER+ or PR+

Ixabepilone

Fulvestrant

Representative Single Agents

Chemotherapy Regimens for MBCChemotherapy Regimens for MBC2007 NCCN Recommendations2007 NCCN Recommendations

• Doxorubicin

• Epirubicin

• Pegylated liposomal doxorubicin

• Paclitaxel

• Docetaxel

• Capecitabine

• Vinorelbine

• Gemcitabine

• Albumin-bound paclitaxel

• CAF/FAC (cyclophosphamide/doxorubicin/ fluorouracil)

• FEC (fluorouracil/epirubicin/cyclophosphamide)

• AC (doxorubicin/cyclophosphamide)

• EC (epirubicin/cyclophosphamide)

• AT (doxorubicin/docetaxel; doxorubicin/paclitaxel)

• CMF (cyclophosphamide/methotrexate/fluorouracil)

• Docetaxel/capecitabine

• GT (gemcitabine/paclitaxel)

F = fluorouracil; A = doxorubicin; C = cyclophosphamide; E = epirubicin; T = paclitaxel; M = methotrexate.National Comprehensive Cancer Network. Breast Cancer. Clinical Practice Guidelines in Oncology – v.2.2007.

Combination Regimens

Taxanes as Adjuvant Therapy in BC

• Taxanes used in stage I-III BC significantly improves DFS

– Recurrence is still a substantial problem

• Emergence of molecular resistance to taxanes:

– Increases population requiring alternate therapy

– Decreases efficacy to other chemotherapies by cross-resistance

First-Line MBCSingle-Agent Response Rates

Treatment ORR (%)Docetaxel1 (75-100 mg/m2) 40-68Paclitaxel1 (175-250 mg/m2 3-24 h) 32-62Doxorubicin4 43Capecitabine3 30Vinorelbine2 35-53Gemcitabine2 18-37Cyclophosphamide4 36Fluorouracil4 28Methotrexate4 26Mitoxantrone4 27

1. Seidman AD, Clin Cancer Res 2.Vogel and Nabholtz. The Oncologist. 1999;4:17.3. O’Shaughnessy et al. Ann Oncol. 2001;12:1247.4. Sledge. Cancer Control. 1999;6:17.

Need for Better Therapies and Patient Need for Better Therapies and Patient Selection to Improve SurvivalSelection to Improve Survival

• Drug resistance is associated with >90% treatment failures in patients with metastatic cancer1

• 5-year survival of patients diagnosed with MBC is approximately 26%,2 despite considerable therapeutic advances over the past 20 years3

• Improved selection of patients for response to available therapies will result from genomic and proteomic analyses3

1. Longley and Johnson. J Pathol. 2005;205:275.2. American Cancer Society. Cancer Facts & Figures 2007. Atlanta: American Cancer Society; 2007.

3. Seidman. Oncology (Williston Park). 2006;30:983.

Clinical Challenges in the Management of MBC

• Individualizing treatment to specific cancer biology

• Reducing and managing toxicity of chemotherapies

• Understanding and then overcoming resistance to chemotherapy and hormone therapy

– Impact in metastatic and adjuvant settings

• Increasing disease control and survival

Rationale for New Agents

• MBC remains an important medical problem

• Anthracyclines and taxanes are the standard of care

– Increasing use in the adjuvant setting

– Drug resistance

• Need for new agents

– Capecitabine approved for use after failure of anthracyclines and/or taxanes

• ORRs 9% to 14% in phase III studies1,2

– Limited efficacy of other agents used in MBC

1. Miller et al. J Clin Oncol. 2005;23:792.2. Geyer et al. N Engl J Med. 2006;355:2733.

nab-Paclitaxel

Paclitaxel and

Docetaxel

C3C3 C10C10

PacPac Benzyl PhenylBenzyl Phenyl AcetylAcetyl

DocDoc terttert-Butoxy-Butoxy HydroxylHydroxyl

O

OH

NH

O

OH O

CH 3 CO O

O

O

O

OCOCH 3O

O

OH

NH

O

OH O

H O

O

O

OH

H13 2

B C

10

A

O

D

7

OCOCH 3O

2'213

7

3'

10

A

B C

OH

3'2'

H D

O

C3

C10

PACLITAXEL

DOCETAXEL

C3 C10

Limitations of Conventional, Solvent-based Taxane Therapy

• Taxanes, like many cancer drugs, are hydrophobic and require solvents

• Solvents cause hypersensitivity reactions that necessitate

– Corticosteroid premedication

– Prolonged infusion

• Solvents leach plasticizers, requiring specialized IV tubing

• Solvents alter the bioavailability of the active drug

van Zuylen L, et al. Invest New Drugs. 2001;19:125-141; van Tellingen O, et al. Clin Cancer Res. 1999;5:2918-2924; Ellis AG, et al. Cancer Chemother Pharmacol. 1996;38:81-87; LoRusso PM, Pilat MJ. ONS News. 2004;19:75-76.

Steroid-Associated Toxicities Dexamethasone Premedication for Taxanes

• Myalgias

• Hyperglycemia

• GI irritation

• Hypertension

• Edema

• Weight gain

• Immunosuppression

• Delayed wound healing

• Skin eruptions

• Insomnia

• Cardiac arrhythmias

• Nausea

• Vomiting

• Paresthesia

• Thromboembolism

• Muscle weakness

• Hypokalemia

• Osteoporosis

• Headache

• Vertigo

• Menstrual irregularities

• Cushingoid state

Dexamethasone prescribing information. Irvine, CA: Gensia Sicor Pharmaceuticals, Inc., 2001.

Alternative Approaches to Taxane Drug Development

Strategy Example Stage Reference

Pharmaceutical

Co-solvents HAS-Paclitaxel Pre-clinical Dosio (2001)

Emulsions Tocosol paclitaxel Clinical (Phase III) Spigel (2002)

Liposomes LEP-ETU Clinical (Phase I/II)Soepenberg

(2004)

Cyclodextrins PTX-CYD Pre-clinical Alcaro (2002)

Nanoparticles nab-paclitaxel Approved Gradishar (2005)

Microspheres Paclimer Clinical (Phase I) Armstrong (2006)

Chemical

Analogs BMS-184476; RPR 109881 Clinical (Phase II) Hildago (2001)

Prodrugs DHA-Paclitaxel Clinical (Phase II) Harries (2004)

Prodrugs Paclitaxel polyglumex Clinical (Phase III) Albain (2006)

Biological

Oral administration

Paclitaxel + cyclosporine Clinical (Phase II) Kruijtzer (2002)

Adapted from ten Tije AJ, et al. Clin Pharmacokinet. 2003;42:665-685.

Many Tumors Secrete Albumin-Binding Proteins

• SPARC:

Secreted Protein Acidic and Rich in Cysteine; also known as BM40 or osteonectin

• Expressed in ~50%-60% of breast cancers

• Shares sequence homology with C terminus of gp60 and binds albumin

• SPARC may be responsible for accumulation of albumin that is seen in some tumors

Increased Intratumoral Paclitaxel Concentration with nab-paclitaxel

Intratumoral paclitaxel Levels following Equal Doses of nab-paclitaxel and Taxol® in Nude Mice Bearing MX-1

Human Breast Cancer Xenografts

nab-paclitaxel = 1.33 x TAXOL®

120

100

80

60

400.01 0.1 1 10 100

140 nab-paclitaxel

Taxol®

Pac

litax

el (

nCi/g

)

Hours

Desai N, et al. Proc Am Soc Clin Oncol. 2002;21:116a; abstr 462.

nab-Paclitaxel Pharmacokinetics

0

5000

10,000

15,000

20,000

75 100 125 150 175 200 225 250 275 300

nab-Paclitaxel dose (mg/m2)

AU

C (

ng-

h/m

L)

N= 3 6 5 1 3 3 12 5

• Linear PK over relevant dose range, independent of infusion time (paclitaxel has non-linear PK)

• Faster clearance • Larger volume of distribution

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 line

260 mg/m2 vs. 175 mg/m2 *

Q 3W

33 vs.19 23 vs.17

•Cremophor-based paclitaxel

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

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

Randomized Comparison of Weekly or Every-3-Week nab-Paclitaxel vs. Every-3-Week

Docetaxel as First-Line Therapy in Patients with Metastatic Breast Cancer

William J. Gradishar1, Dimitry Krasnojon2, Sergei Cheporov3, Anatoly Makhson4, Georgiy Manikhas5, Alicia Clawson6, Michael J. Hawkins6

1 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

2 Leningrad Regional Oncology Center, St. Petersburg, Russia

3 Yaroslavl Regional Oncology Center, Yaroslavl, Russia

4 City Oncology Hospital, Moscow, Russia

5 St. Petersburg Oncology Center, St. Petersburg, Russia

6 Abraxis BioScience, Inc., Los Angeles, CA, USA

ASCO 2007

Study Design

Comparisons

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

weekly vs. every-3-weeks nab-paclitaxel (B, C vs. A)

low vs. high dose weekly nab-paclitaxel (B vs. 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

R

A

N

D

O

M

I

Z

E

D

300 First-line MBC patients randomized to 4 arms

Arms A, C and D administered at the MTD

Objective (RECIST) Investigator Confirmed Response Rates

43%

62%

70%

38%

0%

10%

20%

30%

40%

50%

60%

70%

P P = 0.002, B vs. D= 0.002, B vs. DP P == 0.003,.003, C vs. DC vs. D

P P == 0.016,.016, B vs. AB vs. AP P = 0.007= 0.007, C vs. A, C vs. A

Res

pons

e R

ate

(%)

300 mg/m2 100 mg/m2 150 mg/m2 docetaxelq3w qw 3/4 qw 3/4 100 mg/m2 q3w

(A: N = 76) (B: N = 76) (C: N = 74) (D: N = 74)

nab-paclitaxel

P P = 0.2, B vs. C= 0.2, B vs. C

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

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

nab-paclitaxel vs. docetaxel

• HR: 0.63, P = .046, nab-Paclitaxel 300 mg/m2 q3w vs. docetaxel

• HR: NS, P = NS , nab-Paclitaxel 100 mg/m2 qw vs. docetaxel

• HR = 0.46, P = .002, nab-Paclitaxel 150 mg/m2 qw vs. docetaxel

Higher vs. lower doses of nab paclitaxel

• HR = 0.55, P = .009, nab-Paclitaxel 150 mg/m2 vs. 100 mg/m2 qw

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

ABX 300 mg/m2 q3w

ABX 100 mg/m2 qw3/4

ABX 150 mg/m2 qw3/4

Docetaxel 100 mg/m2 q3w

NeutropeniaBased on Central Laboratory Data

Treatment ArmP vs.

docetaxelP vs.(B)

Grade (%)Febrile

Neutropenia(%)I II III IV

nab-paclitaxel 300 mg/m2 q3w (A; N = 76)

<0.001 0.007 20 29 39 5 1

nab-paclitaxel 100 mg/m2 weekly (B; N = 76)

<0.001 24 32 20 5 1

nab-paclitaxel 150 mg/m2 weekly (C; N = 74)

<0.001 0.004 15 34 34 9 1

Docetaxel 100 mg/m2

q3w (D; N = 74)3 3 19 75 8

P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity

Peripheral NeuropathyTreatment Related Adverse Events

Treatment ArmP vs.

docetaxelP vs.(B)

Grade (%)

I II III IV

nab-paclitaxel 300 mg/m2 q3w (A; N = 76)

0.140 0.006 34 21 17 0

nab-paclitaxel 100 mg/m2 weekly (B; N = 76)

0.190 33 11 9 0

nab-paclitaxel 150 mg/m2 weekly (C; N = 74)

0.345 0.027 30 20 16 0

Docetaxel 100 mg/m2

q3w (D; N = 74)32 19 11 0

P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity

FatigueTreatment Related Adverse Events

P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity

Treatment ArmP vs.

docetaxelP vs.(B)

Grade (%)

I II III IV

nab-paclitaxel 300 mg/m2 q3w (A; N = 76)

0.018 0.131 7 24 4 0

nab-paclitaxel 100 mg/m2 weekly (B; N = 76)

<0.001 18 13 0 0

nab-paclitaxel 150 mg/m2 weekly (C; N = 74)

0.015 0.103 20 19 3 0

Docetaxel 100 mg/m2

q3w (D; N = 74)22 15 19 0

ArthralgiasTreatment Related Adverse Events

P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity

Treatment ArmP vs.

docetaxelP vs.(B)

Grade (%)

I II III IV

nab-paclitaxel 300 mg/m2 q3w (A; N = 76)

0.021 0.003 7 25 1 0

nab-paclitaxel 100 mg/m2 weekly (B; N = 76)

0.551 11 7 0 0

nab-paclitaxel 150 mg/m2 weekly (C; N = 74)

0.048 0.008 16 19 0 0

Docetaxel 100 mg/m2

q3w (D; N = 74)5 12 0 0

Conclusions

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

• The response rates for both weekly nab-paclitaxel arms were superior to both q3w taxane arms

• TTP for weekly nab-paclitaxel at 150 mg/m2 appears superior to docetaxel

• 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

Ongoing Clinical Investigation with nab-Paclitaxel in MBC

• Combination Chemotherapy

– capecitabine, gemcitabine, vinorelbine, anthracycline, others

• Optimizing Dose and Schedule

• Combinations with “Biologics”

– trastuzumab, bevacizumab, RTKs, etc . . .

• Adjuvant and neoadjuvant therapy

• Molecular correlates of sensitivity and resistance

MSKCC IRB Protocol #04-018Schema

= nab-paclitaxel 100 mg/m2

= Carbo AUC 2 = Trastuzumab 2 mg/kg (after loading dose)

HER2+ MBC

Seidman AD et al. Proc ASCO 2008

MSKCC IRB Trial #04-018

• 32 patients enrolled

• Preliminary RR: 46%

• Preliminary median TTP: 16 mos.

• Well-tolerated

• 4 HSRs to weekly carboplatin

– Protocol amended for carboplatin to be dosed every 4 weeks

Seidman AD et al. Proc ASCO 2008

Proposed Trial First-line MBC with Biomarker Analysis

R

Paclitaxel 90 mg/mPaclitaxel 90 mg/m22 weekly* weekly*

nabnab-paclitaxel 150 mg/m-paclitaxel 150 mg/m22 weekly* weekly*

Ixabepilone 16 mg/mIxabepilone 16 mg/m22 weekly* weekly*Serum for Caveolin-1Serum for Caveolin-1

Tumor block for SPARC, aBTumor block for SPARC, aB crystallin, tubulin isoforms, luminal crystallin, tubulin isoforms, luminal

subtyping by IHC, subtyping by IHC, Circulating Tumor Cells (CTC) and Circulating Tumor Cells (CTC) and

Circ Endothelial Cells (CECCirc Endothelial Cells (CEC))

Serial serum measurement of caveolin-1Serial measurement of CTC and CEC

Tumor biopsy on accessible tissue

+Bevacizumab

10 mg/kg q 2 weeks* D 1, 8, 15 q 28 days

CALGB and NCCTG, PI: Hope Rugo; N=900

MSKCC Randomized Phase II Trial (CA-023) nab-Paclitaxel + Bevacizumab for MBC

RANDOMIZE

260 mg/m2 Q 3-weeks

260 mg/m2 Q 2-weeks with GCSF support

130 mg/m2 weekly

* Bevacizumab =

MSKCC IRB #06-025

(N = 165/225)

Adverse EventsIncidence (%)

MSKCC IRB Protocol 06-019Adjuvant Pilot Study

weeks

Dose-Dense Doxorubicin + Cyclophosphamide (60/600 mg/m2) followed by nab-paclitaxel (260 mg/m2) + Bevacizumab

1 3 5 7 9 11 13 15

B B B B B B B B B……

Bevacizumab q 3 wksfor 1 year

Dickler M et al. ASCO, SABCS 2007

Adjuvant Bevacizumab + Dose-Dense AC Followed by nab-Paclitaxel

Dickler M et al. Proc SABCS 2007

AC q2w x 4nab-paclitaxel 260

mg/m2 q2w x 4

Bevacizumab 10 mg/kg x q2w x 8 then 15 mg/kg q3w

Preliminary Results

N = 80

Median Baseline LVEF (N = 76) 68% (53% – 82%)

Median LVEF after 4 Cycles (N= 59) 68% (53% – 77%)

Median LVEF at 6 Months (N = 28) 63% (53% – 76%)

Asymptomatic LVEF Dysfunction 5

Symptomatic LVEF Dysfunction 0

NSABP Protocol FB-AX-003Neoadjuvant Treatment Regimen

Supportive therapyG-CSF: pegfilgrastim or filgrastim recommended

1 2 3 4 5 6 7 8 9 10

q 1 wk X 12 wks q 3 wks X 4

nab-paclitaxel 100 mg/m2

5-FU (500mg/m2) Epirubicin(100 mg/m2 or 75 mg/m2

if trastuzumab)Cyclophosphamide (500mg/m2)

11 12

14-21 days

Ixabepilone

• New antineoplastic class - natural epothilones and their analogs

Epothilones

• Low susceptibility to tumor resistance mechanisms

– MRP-1 and PGP efflux pumps

– b (III) tubulin overexpression

– b tubulin mutations

• Activity in multiple tumor models

• Demonstrated pre-clinical synergy with capecitabine

S.cellulosum Epothilone B Ixabepilone

Epothilones in Development for BC

Identifier Generic CompanyStage of

Development

BMS-247550 Ixabepilone Bristol-Myers Squibb Approved

KOS-862 Kosan/Roche Phase II

ZK219477 ZK-EPO Schering AG/Berlex Phase II

EPO906 Patupilone Novartis Phase I/II

BMS-310705 Bristol-Myers Squibb Phase I

KOS-1584 Kosan/Roche Phase I

Epothilones vs Taxanes

• Chemical structure unrelated to taxanes, but functionally similar– Competes for tubulin binding

• Ixabepilone: analog of epothilone B– Increased flexibility

• Unique tubulin binding site

• Prevents binding to ABC transporters

• Unaffected by most taxane-resistant tubulin mutations

O

O

O

OH

H O

O

OO

OCH3

CH3

CH3

OHOCCH3

CH3

R2O

NHR1

2’

OH

OH

CH3

CH3CH3CH3

CH3

CH3

O

O

O O

R

S

N

R1 R2

Paclitaxel: Phenyl AcetylDocetaxel: t-Butanol H

Epothilone A: R = HEpothilone B: R = CH3Goodin et al. J Clin Oncol. 2004;22:2015.

Giannakakou et al. PNAS. 2000;97:2904.

Pharmacologic Considerations

• Epothilones A and B

– High in vitro tumor activity

– Modest in vivo activity

– Metabolic instability

– Unfavorable pharmacokinetic characteristics

– Narrow therapeutic window

• Analogs developed to optimize product

Altmann et al., 2000.

IC50 Values (nM) for Net Growth Inhibition of Human Carcinoma Cell Lines by Epothilones A

and B in Comparison to Paclitaxel

3.26

2.04

0.29

2.31

6.9

0.7

0

1

2

3

4

5

6

7

Paclitaxel 1 Epo A1

Epo B 1 Epo D1

Epo F ZK-EPO 2

1 Watkins et al., 2005; 2 Hoffman, 2006.

1

IC50 of Epothilones Against MCF-7 Cell Lines

1

MDR = multidrug resistance; MTD = maximum tolerated

dose.

Modified from BMS data on file

PAT-7 MDR/MRP(Ovarian Cancer)

Log c

ell

kill

at

MTD

1.3

4.5

HCT/VM46 MDR(Colon Cancer)

0.4

3.1

0

1

2

3

4

5

6 Paclitaxel

Ixabepilone (epothilone B analog)

Epothilones Less Susceptible to MDR

• Poor substrates for MDR proteins

• MDR expression not altered in epothilone resistant cell lines

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).

Ixabepilone (BMS-247550)

• Semi-synthetic analog of epothilone B

• Low susceptibility in vitro to multiple tumor resistance mechanisms, including efflux transporters, such as P-gp and MRP-1

• Active in taxane-resistant disease

HN

OH

O

O O

S

NOH

ixabepilone

Isolated from the myxobacterium S. cellulosum

Ixabepilone Activity Demonstrated in Multiple in Vivo Tumor Models

Tum

or R

espo

nse

(log

cell k

ill)

Tumor Xenograft in Mice

0

1

2

3

4

5

A2780

sPat-

7

A2780

Tax

HCTVM46Pat-

21M50

76Pat-

26

Ixabepilone

Paclitaxel

Doxorubicin

A2780S cisplatin-sensitive human ovarian carcinoma; Pat-7 paclitaxel-resistant human ovarian carcinoma; A2780Tax human ovarian carcinoma with a tubulin mutation; HCTVM46 human colon carcinoma; Pat-21 paclitaxel-resistant human breast carcinoma; M5076 paclitaxel-refractory mouse fibrosarcoma; Pat-26 human pancreatic carcinoma

BMS data on file

BMS data on file

AUC = area under the curve.

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 peripheral blood mononuclear cells and plasma concentration

• T1/2: 39 hours (range 17–50 hours)

DLT = dose-limiting toxicity; Q = every.

Goodin et al., 2004.

IxabepiloneSchedules Studied

Daily x 5 q21dDaily x 3

q21dWeekly Once q21d

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

Summary of Phase II Trials of Ixabepilone for MBC

1. Low et al. J Clin Oncol. 2005;23:2726.2. Bunnell et al. J Clin Oncol. 2006;24(Suppl):10511.

3. Denduluri et al. J Clin Oncol. 2007; 25(23):3421.4. Thomas et al. J Clin Oncol. 2007; 25(23):3399.

5. Perez et al. J Clin Oncol. 2007;25(23):3407.6. Roche et al. J Clin Oncol. 2007; 25(23):3415.

*Registrational study

Study N Prior CT RR Dose/Schedule

Low 20051 37 Taxane 22% 6 mg/m2, d1-d5, q3w

Bunnell 20062 56Anthracycline

and taxane30%

40 mg/m2, d1 or d1-d3 + 2000 mg/m2 capecitabine

d1-d14, q3w

Denduluri 20073 23 No taxane therapy 57% 6 mg/m2, d1-d5, q3w

Thomas 20074 49Anthracycline

and taxane12% 40 mg/m2, d1, q3w

Perez 20075 113Anthracycline/

taxane/capecitabine18% 40 mg/m2, d1, q3w

Roche 20076 65 Anthracycline 42% 40 mg/m2, d1, q3w

Resistance CriteriaResistance to prior therapy:

• In patients with measurable disease, rapid tumor progression in the adjuvant or metastatic setting, after therapy with anthracyclines, taxanes and capecitabine

Perez et al. J Clin Oncol. 2007;25:3407.

Setting Anthracycline Taxane Capecitabine

Metastatic ≤8 weeks of last dose ≤8 weeks of last dose ≤8 weeks of last dose

Neoadjuvant/Adjuvant

≤6 months of last dose ≤6 months of last dose ≤6 months of last dose

Any

Minimum cumulative dose

Doxorubicin: 240 mg/m2

Epirubicin: 360 mg/m2

Any Progression during or after discontinuation of trastuzumab for HER2+ patients

Phase III Trial of Ixabepilone + Capecitabine in MBC Patients Previously Treated/Resistant

to Anthracyclines/Taxanes

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

+Capecitabine

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

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

d1-d14 q3wk)

Metastatic or locally advanced breast cancer

RESISTANT to anthracyclines

and taxanesN = 752

Stratification Visceral metastases Anthracycline resistancePrior chemotherapy for MBC Study site

Resistance Criteria

Resistance to prior therapy: • In 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

Neoadjuvant/Adjuvant

≤6 months of last dose ≤12 months of last dose

AnyMinimal cumulative dose:

doxorubicin 240 mg/m2 or epirubicin 360 mg/m2

Thomas et al. J Clin Oncol. 2007;25:5210.

Study Endpoints

• Primary

– Progression-free survival by blinded Independent Radiologic Review

• Secondary

– Response rate

– Time to response

– Duration of response

– Survival (pending 631 events)

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

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

MonthsThomas et al. J Clin Oncol. 2007;25:5210.

Response Rate

% Response

Investigator IRR

Ixabepilone + Capecitabine

N = 375

CapecitabineN = 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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28Weeks

Pro

po

rtio

n N

ot

Res

olv

ed

Grade 3/4 Peripheral Neuropathy

• Primarily sensory• Cumulative• Reversible

*Resolution = return to baseline or grade 1

Median time to resolution of 6 weeks*

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

Summary

• Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in metastatic breast cancer resistant to anthracyclines and taxanes

– Improvement of PFS (HR 0.75)

– 2.5-fold increase in ORR (35% vs 14%)

– Benefit was consistent across most subgroups

• Manageable safety profile (normal or Grade 1 LFTs)

Metastatic

≥3rd Line2nd Line1st Line

Adjuvant

Approved Use of Ixabepilone for Anthracycline/Taxane-Resistant Breast Cancer

Single agent• Taxanes (after A)• Capecitabine (X)

(after A + T)• Combination*• Capecitabine +

taxane (after A)• Gemcitabine +

taxane (after A)

• Capecitabine(after A + T)

• Taxanes(after A)

• Capecitabine (after A + T)

Adapted from NCCN Clinical Practice Guidelines in Oncology: Breast Cancer V.2.2007. Available at: www.nccn.org.Ixabepilone prescribing information.

Taxanes (T)

Anthracyclines (A)

• Ixabepilone +capecitabine(after A + T)

• Ixabepilone (after A + T + X)

• Combination• Ixabepilone +

capecitabine (after A + T)

• Ixabepilone (after A + T + X)

• Combination• Ixabepilone +

capecitabine (after A + T)

Overall Summary

• Taxanes are a key first-line component of BC therapy

• The majority of patients treated with a taxane develop resistance

• To date, most therapies developed to overcome resistance are inadequate

• Epothilones have shown activity against taxane-resistant tumors

– Poor substrates for P-gp

– May be unaffected by taxane-resistant tubulin mutations

– Positive results in clinical trials

Treatment of MBC

Case Studies

Case 1Taxane-naïve First-line MBC

• 45 y.o. woman was diagnosed with stage II BC in 2001

– T = 2.3 cm

– N = 0

– ER/PR: positive

– HER2: negative by FISH

• Adjuvant treatment: AC x 4 Q3w followed by right breast RT and tamoxifen

• Did well until 2007 when she developed soft tissue mass adjacent to sternum and a right hilar mass

– Biopsy of sternum c/w recurrent BC (ER/PR-positive, HER2-negative)

Case 1Taxane-naïve First-line MBC

Which treatment option would you recommend?

Docetaxel

Paclitaxel

nab-paclitaxel

Paclitaxel + gemcitabine

Docetaxel + capecitabine

Capecitabine

Paclitaxel + bevacizumab

Ixabepilone ± capecitabine

Other

Case 1Taxane-naïve First-line MBC

Which treatment option would you recommend?

Docetaxel

Paclitaxel

nab-paclitaxel

Paclitaxel + gemcitabine

Docetaxel + capecitabine

Capecitabine

Paclitaxel + bevacizumab

Ixabepilone ± capecitabine

• Recommended approach– nab-paclitaxel

Case 2Early Relapse After Adjuvant AC→T

• 50 y.o. woman was diagnosed with stage IIIB breast cancer in 2006

– Left lumpectomy

– T = 3.8 cm; N = 7/28; ER/PR: negative; HER2-negative by FISH

– Received AC followed by paclitaxel Q2w (dose-dense)

– Received chest wall RT

– 1-year after completing adjuvant therapy, relapse in chest wall, lungs, bone, and liver

Case 2Early Relapse After Adjuvant AC→T

Which treatment option would you recommend?

Docetaxel

nab-paclitaxel

Gemcitabine

Capecitabine

Vinorelbine

Ixabepilone ± capecitabine

Other non-taxane combination (e.g. vinorelbine + capecitabine, gemcitabine + carboplatin)

Case 2Early Relapse After Adjuvant AC→T

Which treatment option would you recommend?

Docetaxel

nab-paclitaxel

Gemcitabine

Capecitabine

Vinorelbine

Ixabepilone ± capecitabine

Other non-taxane combination

• Recommended approach

– Ixabepilone ± capecitabine

Case 3Refractory MBC

• PH is a 55 y.o. woman who received adjuvant TAC for stage II ER+/PR-/HER2- breast cancer in 2004

• She relapsed in 2006 with numerous liver metastases, a moderate right pleural effusion, and innumerable bone metastases

• First-line treatment for MBC was paclitaxel/gemcitabine, with zoledronate

– Patient responded well radiographically and symptomatically

– After 9 months, the disease progressed; a chest tube was placed for pleurodesis

• Second-line treatment was capecitabine

– Stabilization of her disease for 6 months, then disease progressed in liver and bone

Case 3Refractory MBC

Which treatment option would you recommend? nab-paclitaxel

Docetaxel

Vinorelbine

Ixabepilone

Irinotecan

Oral etoposide

Liposomal doxorubicin

Other

Case 3 Refractory MBC

Which treatment option would you recommend?

nab-paclitaxel

Docetaxel

Vinorelbine

Ixabepilone

Irinotecan

Oral etoposide

Liposomal doxorubicin

Other?

• Recommended approach

– Ixabepilone

Role of Novel Microtubule-Targeting Agents in Metastatic Breast Cancer

Closing Comments