Transcript Challenges in the Treatment of Breast Cancer: Overcoming

Role of Novel Microtubule-Targeting
Agents in Metastatic Breast Cancer
Andrew D. Seidman, MD
Professor of Medicine
Weill Medical College of Cornell University
Attending Physician
Memorial Sloan-Kettering Cancer Center
New York, New York
Treatment of Metastatic Breast Cancer
(MBC)
Case Studies
Case 1
Taxane-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 1
Taxane-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 1
Taxane-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 2
Early 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 (dosedense)
– 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 2
Early 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 2
Early 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 3
Refractory MBC
Case 3
Refractory 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
Tamoxifen
CMF
Doxorubicin
Mitoxantrone
Epirubicin
Paclitaxel
Vinorelbine
Aromatase Inhibitors
ER+ or PR+
HER2+
Docetaxel
Gemcitabine
Capecitabine
Fulvestrant
Trastuzumab
Albumin-Bound Paclitaxel
Bevacizumab
Lapatinib
Ixabepilone
Chemotherapy Regimens for MBC
2007 NCCN Recommendations
Representative Single Agents
•
Doxorubicin
•
Epirubicin
•
Pegylated liposomal doxorubicin
•
Combination Regimens
•
CAF/FAC (cyclophosphamide/doxorubicin/
fluorouracil)
•
FEC
(fluorouracil/epirubicin/cyclophosphamide)
Paclitaxel
•
•
AC (doxorubicin/cyclophosphamide)
Docetaxel
•
•
EC (epirubicin/cyclophosphamide)
Capecitabine
•
•
Vinorelbine
AT (doxorubicin/docetaxel;
doxorubicin/paclitaxel)
•
Gemcitabine
•
CMF
•
Albumin-bound paclitaxel
(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.
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 MBC
Single-Agent Response Rates
Treatment
Docetaxel1 (75-100 mg/m2)
Paclitaxel1 (175-250 mg/m2 3-24 h)
Doxorubicin4
Capecitabine3
Vinorelbine2
Gemcitabine2
Cyclophosphamide4
Fluorouracil4
Methotrexate4
Mitoxantrone4
ORR (%)
40-68
32-62
43
30
35-53
18-37
36
28
26
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
Selection 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
Pac
C3
C10
CH
3 CO
O
O
10
NH
13
O
Benzyl Phenyl
Acetyl
C
2
A
OH
C10
7
B
O
2'
3'
C3
OH
O
D O
H
O
OH
O
OCOCH
3
PACLITAXEL
C3
Doc
tert-Butoxy
Hydroxyl
C10
HO
O
O
OH
O
10
NH
3'
7
B
O
13
2'
O
OH
DOCETAXEL
C
2
A
H
O
OH
O
D
OCOCH
O
3
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
• Nausea
• Hyperglycemia
• Vomiting
• GI irritation
• Paresthesia
• Hypertension
• Thromboembolism
• Edema
• Muscle weakness
• Weight gain
• Hypokalemia
• Immunosuppression
• Osteoporosis
• Delayed wound healing
• Headache
• Skin eruptions
• Vertigo
• Insomnia
• Menstrual irregularities
• Cardiac arrhythmias
• Cushingoid state
Dexamethasone prescribing information. Irvine, CA: Gensia Sicor Pharmaceuticals, Inc., 2001 .
Alternative Approaches to
Taxane Drug Development
Strategy
Example
Stage
Reference
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)
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)
Paclitaxel + cyclosporine
Clinical (Phase II)
Kruijtzer (2002)
Pharmaceutical
Co-solvents
Chemical
Biological
Oral
administration
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
140
nab-paclitaxel
Taxol®
Paclitaxel (nCi/g)
120
nab-paclitaxel = 1.33 x TAXOL®
100
80
60
40
0.01
0.1
1
10
100
Hours
Intratumoral paclitaxel Levels following Equal Doses of
nab-paclitaxel and Taxol® in Nude Mice Bearing MX-1
Human Breast Cancer Xenografts
Desai N, et al. Proc Am Soc Clin Oncol. 2002;21:116a; abstr 462.
nab-Paclitaxel Pharmacokinetics
• Linear PK over relevant dose range, independent of
infusion time (paclitaxel has non-linear PK)
• Faster clearance
• Larger volume of distribution
AUC (ng-h/mL)
20,000
15,000
10,000
5000
N=
3
6
5
1
3
3
12
5
0
75
100
125
150
175
200
225
nab-Paclitaxel dose (mg/m2)
250
275
300
nab-paclitaxel
Trial
No.pts
Setting
Schedule
RR (%)
Med TTP
(wks)
Ibrahim1
63
No limit
300 mg/m2 Q3w
48
27
Mirtschung2
23
1st line
125 mg/m2 QW
(3 out of 4 wks)
57
NR
33 vs.19
23 vs.17
Gradishar3
nab-paclitaxel
vs paclitaxel
460
1st line
260 mg/m2 vs.
175 mg/m2 *
Q 3W
•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-3Week 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
300 First-line MBC
patients
randomized to 4 arms
Comparisons
R
nab-paclitaxel vs.
docetaxel
(A, B, C vs. D)
A
N
D
weekly vs. every-3weeks nab-paclitaxel
(B, C vs. A)
O
Arm B: nab-paclitaxel 100 mg/m2
weekly 3 out of 4
M
I
low vs. high dose
weekly nab-paclitaxel
(B vs. C)
Arm A: nab-paclitaxel 300 mg/m2 q3w
Arm C: nab-paclitaxel 150 mg/m2
weekly 3 out of 4
Z
E
Arm D: docetaxel 100 mg/m2 q3w
D
Arms A, C and D administered at the MTD
Objective (RECIST)
Investigator Confirmed Response Rates
70%
P = 0.2, B vs. C
Response Rate (%)
60%
50%
40%
70%
62%
P = 0.016, B vs. A
P = 0.007, C vs. A
P = 0.002, B vs. D
P = 0.003, C vs. D
43%
38%
30%
20%
10%
0%
300 mg/m2
q3w
(A: N = 76)
100 mg/m2
qw 3/4
(B: N = 76)
nab-paclitaxel
150 mg/m2
qw 3/4
(C: N = 74)
docetaxel
100 mg/m2 q3w
(D: N = 74)
Phase II Study Evaluating Various Doses of
nab-Paclitaxel vs. Docetaxel (cont’d)
Higher vs. lower doses of nab
paclitaxel
• HR = 0.55, P = .009, nabPaclitaxel 150 mg/m2 vs. 100
mg/m2 qw
Proportion Not Improved
nab-paclitaxel vs. docetaxel
• HR: 0.63, P = .046, nabPaclitaxel 300 mg/m2 q3w vs.
docetaxel
• HR: NS, P = NS , nab-Paclitaxel
100 mg/m2 qw vs. docetaxel
• HR = 0.46, P = .002, nabPaclitaxel 150 mg/m2 qw vs.
docetaxel
Progression-free Survival
Investigator Assessments
1.0
ABX 300 mg/m2 q3w
ABX 100 mg/m2 qw3/4
ABX 150 mg/m2 qw3/4
Docetaxel 100 mg/m2 q3w
0.75
0.50
0.25
75% of patients off-study
0.0
0
3
6
9
12
Months
15
18
Gradishar W, et al. ASCO 2007. Abstract 1032.
Neutropenia
Based on Central Laboratory Data
Febrile
Neutropenia
(%)
Treatment Arm
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)
P vs.
(B)
Grade (%)
P vs.
docetaxel
I
3
II III IV
3 19 75
8
P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity
Peripheral Neuropathy
Treatment Related Adverse Events
Grade (%)
P vs.
docetaxel
P vs.
(B)
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
30
20
16
0
32
19
11
0
Treatment Arm
Docetaxel 100 mg/m2
q3w (D; N = 74)
0.027
P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity
Fatigue
Treatment Related Adverse Events
Grade (%)
P vs.
docetaxel
P vs.
(B)
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
20
19
3
0
22
15
19
0
Treatment Arm
Docetaxel 100 mg/m2
q3w (D; N = 74)
0.103
P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity
Arthralgias
Treatment Related Adverse Events
Grade (%)
P vs.
docetaxel
P vs.
(B)
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
16
19
0
0
5
12
0
0
Treatment Arm
Docetaxel 100 mg/m2
q3w (D; N = 74)
0.008
P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity
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 #04-018
Schema
HER2+ MBC
= nab-paclitaxel
100 mg/m2
= Carbo AUC 2
= Trastuzumab 2 mg/kg
(after loading dose)
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
CALGB and NCCTG, PI: Hope Rugo; N=900
Tumor biopsy on accessible tissue
Paclitaxel 90 mg/m2 weekly*
nab-paclitaxel 150 mg/m2 weekly*
R
* D 1, 8, 15 q 28 days
+
Bevacizumab
10 mg/kg
q 2 weeks
Ixabepilone 16 mg/m2 weekly*
Serum for Caveolin-1
Tumor block for SPARC, aB
crystallin, tubulin isoforms, luminal
subtyping by IHC,
Circulating Tumor Cells (CTC) and
Circ Endothelial Cells (CEC)
Serial serum measurement of caveolin-1
Serial measurement of CTC and CEC
MSKCC Randomized Phase II Trial (CA-023)
nab-Paclitaxel + Bevacizumab for MBC
(N = 165/225)
R
A
N
D
O
M
I
Z
E
* Bevacizumab =
260 mg/m2 Q 3-weeks
260 mg/m2 Q 2-weeks with GCSF support
130 mg/m2 weekly
MSKCC IRB #06-025
Adverse Events
Incidence (%)
MSKCC IRB Protocol 06-019
Adjuvant Pilot Study
Dose-Dense Doxorubicin + Cyclophosphamide (60/600 mg/m2)
followed by nab-paclitaxel (260 mg/m2) + Bevacizumab
Bevacizumab q 3 wks
for 1 year
B B B B B B
1
3
5
7
B B B……
9
11
13
15
weeks
Dickler M et al. ASCO, SABCS 2007
Adjuvant Bevacizumab + Dose-Dense AC
Followed by nab-Paclitaxel
AC q2w x 4
nab-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
Dickler M et al. Proc SABCS 2007
NSABP Protocol FB-AX-003
Neoadjuvant Treatment Regimen
1
2
3 4
5
6 7
8
q 1 wk X 12 wks
9 10 11 12
14-21 days
nab-paclitaxel
100 mg/m2
Supportive therapy
G-CSF: pegfilgrastim or filgrastim recommended
q 3 wks X 4
5-FU (500mg/m2) Epirubicin
(100 mg/m2 or 75 mg/m2
if trastuzumab)
Cyclophosphamide (500mg/m2)
Ixabepilone
Epothilones
• New antineoplastic class - natural epothilones and their
analogs
S.cellulosum
Epothilone B
Ixabepilone
• 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
Epothilones in Development for BC
Identifier
Generic
Company
Stage of
Development
BMS-247550
Ixabepilone
Bristol-Myers Squibb
Approved
Kosan/Roche
Phase II
KOS-862
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
R2O
O
• Chemical structure unrelated to
taxanes, but functionally similar
R1
– Increased flexibility
•
Unique tubulin binding site
•
Prevents binding to ABC transporters
• Unaffected by most taxaneresistant tubulin mutations
CH3
O
2’
– Competes for tubulin binding
• Ixabepilone: analog of
epothilone B
CH3
NH
CH3
O
O
H
OH
O O
OH
OCCH3
O
R1
R2
Phenyl
Acetyl
t-Butanol H
Paclitaxel:
Docetaxel:
R
O
S
CH3
CH3
CH3
CH3 CH3
N
O
O
Goodin et al. J Clin Oncol. 2004;22:2015.
Giannakakou et al. PNAS. 2000;97:2904.
O
CH3
Epothilone A:
Epothilone B:
OH
O
OH
CH3
R=H
R = CH3
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
IC50 Values (nM) for Net Growth Inhibition of
Human Carcinoma Cell Lines by Epothilones A
and B in Comparison to Paclitaxel
Altmann et al., 2000.
IC50 of Epothilones
Against MCF-7 Cell Lines
6.9
7
6
5
4
3.26
3
2.31
2.04
2
0.7
1
0.29
0
Paclitaxel 1
Epo A1
Epo B 1
Epo D1
1
Epo F
1
ZK-EPO 2
1 Watkins
et al., 2005; 2 Hoffman, 2006.
Epothilones Less Susceptible to MDR
• MDR expression not altered in
epothilone resistant cell lines
MDR = multidrug resistance;
MTD = maximum tolerated dose.
Modified from BMS data on file
Log cell kill at MTD
• Poor substrates for MDR
proteins
6
Paclitaxel
5
Ixabepilone
(epothilone B analog)
4.5
4
3.1
3
2
1.3
1
0.4
0
PAT-7 MDR/MRP
(Ovarian Cancer)
HCT/VM46 MDR
(Colon Cancer)
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
Isolated from the
myxobacterium
S. cellulosum
O
S
OH
N
HN
O
OH O
ixabepilone
• Low susceptibility in vitro
to multiple tumor
resistance mechanisms,
including efflux
transporters, such as
P-gp and MRP-1
• Active in taxane-resistant
disease
Ixabepilone
Tumor Response
(log cell kill)
Activity Demonstrated in Multiple in Vivo Tumor Models
5
Ixabepilone
4
Paclitaxel
Doxorubicin
3
2
1
0
Tumor Xenograft in Mice
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
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)
AUC = area under the curve.
BMS data on file
Ixabepilone
Schedules Studied
Daily x 5 q21d
Daily x 3
q21d
Weekly
Once q21d
1
1
0.5-1
1
Range
1.5-8
8-10
1-30
32-65
MTD
6
8
25
50
Infusion
duration (hr)
Dose
(mg/m2/day)
DLT
Neutropenia, neuropathy
DLT = dose-limiting toxicity; Q = every.
Goodin et al., 2004.
Summary of Phase II Trials of
Ixabepilone for MBC
Study
N
Prior CT
RR
Dose/Schedule
Low 20051
37
Taxane
22%
6 mg/m2, d1-d5, q3w
30%
40 mg/m2, d1 or d1-d3 +
2000 mg/m2 capecitabine
d1-d14, q3w
57%
6 mg/m2, d1-d5, q3w
12%
40 mg/m2, d1, q3w
Anthracycline
Bunnell 20062
56
Denduluri 20073
23
Thomas 20074
49
Perez 20075
113
Anthracycline/
taxane/capecitabine
18%
40 mg/m2, d1, q3w
Roche 20076
65
Anthracycline
42%
40 mg/m2, d1, q3w
*Registrational study
and taxane
No taxane therapy
Anthracycline
and taxane
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.
Resistance Criteria
Resistance to prior therapy:
• In patients with measurable disease, rapid tumor progression in the adjuvant or
metastatic setting, after therapy with anthracyclines, taxanes and capecitabine
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
Minimum cumulative dose
Any
Doxorubicin: 240 mg/m2
Epirubicin: 360 mg/m2
Any
Progression during or after discontinuation of trastuzumab for HER2+ patients
Perez et al. J Clin Oncol. 2007;25:3407.
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)
Metastatic or locally
advanced breast cancer
RESISTANT
to anthracyclines
and taxanes
N = 752
Capecitabine
(2500 mg/m2/day PO 2 divided doses
d1-d14 q3wk)
Stratification
Visceral metastases
Prior chemotherapy for MBC
Anthracycline resistance
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
Any
Minimal 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)
Progression-free Survival
by Independent Radiologic Review
Proportion Progression Free
1.0
0.8
Median
95% CI
Ixabepilone +
Capecitabine
5.8 mo
(5.5–7.0)
Capecitabine
4.2 mo
(3.8–4.5)
0.6
HR: 0.75 (0.64–0.88)
P = 0.0003
0.4
0.2
0
0
4
8
12
16
20
24
28
32
36
Months
Thomas et al. J Clin Oncol. 2007;25:5210.
Response Rate
Investigator
IRR
% Response
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 Toxicities
80
Ixabepilone + Capecitabine (N = 369)
% of Patients
Capecitabine (N = 368)
60
40
23
18 17
20
9
0
0
8
3
6
0.3
9
4
2
3
2
3
2
3
0
Grade 3/4 Peripheral Neuropathy
• Primarily sensory
• Cumulative
• Reversible
Proportion Not Resolved
1.0
0.9
0.8
0.7
0.6
Median time to resolution of 6 weeks*
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
Weeks
10
12
14
16
18
20
22
24
26
28
*Resolution = return to baseline or grade 1
Efficacy of Ixabepilone/Capecitabine in ER/PR/HER2Negative MBC Resistant to Anthracyclines and Taxanes
Receptor Subgroup
All Patients
ORR
Median
PFS
HR
ER/PR/HER2
Negative
Non-TripleNegative
HER2+
ER+
I+C
C
I+C
C
I+C
C
I+C
C
I+C
C
N = 375
N = 377
N = 91
N = 96
N = 284
N = 281
N = 59
N = 53
N = 173
N = 178
35%
14%
27%
9%
37%
16%
31%
8%
40%
19%
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
0.75
0.68
0.74
0.69
0.81
Rugo H, et al. SABCS 2007, Abstract 6069.
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)
Approved Use of Ixabepilone for
Anthracycline/Taxane-Resistant Breast Cancer
Adjuvant
Anthracyclines (A)
Taxanes (T)
Metastatic
1st Line
2nd Line
≥3rd Line
Single agent
• Taxanes (after A)
• Capecitabine (X)
(after A + T)
• Combination*
• Capecitabine +
taxane (after A)
• Gemcitabine +
taxane (after A)
• Taxanes
(after A)
• Capecitabine
(after A + T)
• Capecitabine
(after A + T)
• 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)
Adapted from NCCN Clinical Practice Guidelines in Oncology: Breast Cancer V.2.2007. Available at: www.nccn.org.
Ixabepilone prescribing information.
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 taxaneresistant 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 1
Taxane-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, HER2negative)
Case 1
Taxane-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 1
Taxane-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 2
Early 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 2
Early 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 2
Early 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 3
Refractory 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 3
Refractory 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