role of novel microtubule-targeting agents in metastatic breast cancer andrew d. seidman, md...
Post on 22-Dec-2015
219 views
TRANSCRIPT
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