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Clinical Updates
Tubulin Inhibition in Breast Cancer:
A Therapeutic Target Critical to
Improving Outcomes
William J. Gradishar, MD
Professor of Medicine
Robert H. Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine
Chicago, IL
Role of Microtubule in Cellular Physiology
 Microtubules, a key component of cell cytoskeleton
• comprise filamentous polymers
• dynamic structures that depolymerize and rearrange
to form mitotic spindle which is essential to cell division
 Microtubules
• through mitotic spindle, align and separate chromosomes
• transport cellular material
• engage in intracellular signalling
• play integral role in cell growth and mitosis
• re-organized in cell invasion and migration, processes essential
to tumor metastasis
 Biological function of microtubules regulated by polymerization dynamics
McIntosh et al, Microtubules. Wiley-Liss: New York 1994; 413–34;
Oakley et al, Microtubules. Wiley-Liss: New York 1994; 33–45
Wordeman et al, Microtubules. Wiley-Liss: New York 1994; 287–301
Structure of a Microtubule
Jordan & Kamath, Curr Cancer Drug Targets 2007; 7: 730–42
Microtubule Involvement in Mitosis
Jackson et al, Nat Rev Cancer 2007; 7: 107–17
Reprinted by permission from Macmillan Publishers Ltd.
Effects of Tubulin-binding Drugs
on Microtubules
Jordan et al, Mol Cancer Ther 2005; 4: 1086–95
Verrills & Kavallaris, Curr Pharm Des 2005; 11: 1719–33
Taxane-based Therapy
 Active against a wide spectrum of malignancies
– Standard component of breast, ovarian, and NSCLC therapy
 Limitations with traditional taxanes
– Hydrophobic and require solvents
• Cremophor® with paclitaxel
• Tween 80 with docetaxel
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.
Solvent-based Taxane Toxicities
Reaction
Docetaxel
Paclitaxel
Hypersensitivity reaction (grade 3/4)
2.6%*
2%
Neutropenia (<500 mm3)
85.9%
52%
Leukopenia (<1000 mm3)
43.7%
17%
Thrombocytopenia (<100,000/mm3)
9.2%
20%
Anemia (<11 g/dL)
93.6%
78%
Peripheral neuropathy (grade 3/4)
5.5%
3%
Arthralgia/myalgia (grade 3/4)
10%
8%
Mucositis
7.4%
31%
Cardiovascular events
8.1%
16%
*Regardless of premedication.
Adapted from product inserts of paclitaxel (BMS, n=812)
and docetaxel (Aventis, n=2045).
Appropriate Clinical Utilization of
Novel Taxane Formulations
Improved Taxane Formulations
 Rationale
– Decrease hypersensitivity reactions
– Avoid solvent toxicities
– Improve side effect profiles
– Favorable PK
– Decrease infusion times
 Agents
– nab paclitaxel
– Paclitaxel poliglumex
– Milataxel
– DHA-paclitaxel
– Paclitaxel tocopherol-based emulsion formulation
Nanoparticle Albumin Bound
(nab) Platform
Albumin
IV/IA
Protein
Oral
Active
drug
Human
albumin
Topical
Proprietary
process
Insoluble drug
Inhalational
Stable nanoparticles
~0.1-0.2 µm, negatively charged
Mechanisms of Transport
of nab Paclitaxel to Tumors
Leaky junction
Tumor
interstitium
(A) Enhanced permeation
and retention (EPR) effect
Lumen of
tumor
microvessel
Endothelial cell
(EC)
Tumor
cell
(C) Tumor uptake
Caveolae and vesicles
Tumor
cell
(B) Receptor mediated
EC membrane
nab Paclitaxel
 First clinical application of albumin-bound nanoparticle (nab)
technology (FDA approved: Jan 2005)
 Paclitaxel bound to albumin in a nanoparticle
– Increases drug selectivity for tumor cells (albumin intake mechanisms)
 No routine steroid or antihistamine premedication required, no toxic
solvents
 In a phase III trial, demonstrated superior efficacy vs paclitaxel in
MBC
– RR doubled
– Prolonged TTP
– Improved grade 4 neutropenia/sensory neuropathy
Gradishar WJ, et al, J Clin Oncol. 2005;23:7794-7803.
Phase III Trial of nab Paclitaxel in MBC
Nab paclitaxel 260 mg/m2
i.v. over 30 min q 3 wk
No standard premedication
• Women with measurable
stage IV breast cancer
• No prior taxane therapy
• N = 460
or
Cremophor paclitaxel 175 mg/m2
i.v. over 3 hours q 3 wk
Standard premedication with
dexamethasone and antihistamines
Gradishar et al. J Clin Oncol. 2005;23:7794-7803.
Phase III Trial
Albumin-Bound Paclitaxel vs. Paclitaxel in MBC
Albumin-bound paclitaxel: 260 mg/m2 q3w; Paclitaxel:175 mg/m2 q3w
Albumin-Bound
Paclitaxel
N=229
Overall Response Rate
Paclitaxel
N=225
P-Value
33%
19%
.001
Time to Progression
23.0 wk
16.9 wk
.006
Grade 4 Neutropenia
9%
22%
<.001
10%*
2%
<.001
Grade 3 Sensory Neuropathy
* Median time to improvement: 22 days
Gradishar et al. JCO 23: 7794; 2005
Phase III
Every 3w Hematologic Toxicities
nab Paclitaxel
Paclitaxel
n=229
n=225
Hematologic toxicity
P-Value*
Grade 3
Grade 4
Grade 3
Grade 4
Neutropenia
25%
9%
31%
22%
<0.001
Thrombocytopenia
<1%
0%
<1%
0%
0.387
Anemia
<1%
<1%
0%
0%
0.192
Febrile neutropenia
<1%
<1%
<1%
0%
0.491
Septic deaths
0
0
--
*Cochran-Mantel-Haenszel test based upon all grades.
Gradishar et al. JCO 23: 7794; 2005
Randomized Study Comparing
nab-Paclitaxel with Solvent-based
Paclitaxel in Chinese Patients with
Metastatic Breast Cancer
Zhong-Zhen Guan, M.D.1; Fengyi Feng, M.D.2, Qing Li Li, M.D.3, Zefei Jiang,
M.D.4, Zhenzhou Shen, M.D.5, Shiying Yu, M.D.6, Jifeng Fen, M.D.7, Jianjin
Huang, M.D.8, Zhiwen Yao, M.D.9, Michael. J. Hawkins, M.D.9
1Sun
Yat Sen University Cancer Centre, Guangdong, China; 2Cancer Center of CAMS,
Beijing, China; 3Tianjin Tumor Hospital, Tianjin, China; 4PLA 307 Hospital, Beijing, China;
5Fudan University Cancer Center, Shanghai, China; 6Tonghi Hospital, Wuhan, China;
7Jiansu Tumor Hospital, Jiansu, China, 8No. 2 Hospital of Medical College, Zhejiang
University, Hangzhou, China, 9Abraxis BioScience, Inc., Los Angeles, CA.
Response Rate, Time To Progression,
Progression-free Survival, and Overall Survival
nab-paclitaxel
(n =104)
Overall Response Rate
(Complete Response + Partial Response)
Median Time To Progression (months)
95% CI
Median Progression-free Survival (months)
95% CI
•
•
SBpaclitaxel
P-value
(n = 106)
56 (54%)
31 (29%)
<0.001*
7.6
6.2
0.078**
6.7 to 8.6
4.7 to 8.0
7.6
6.2
6.7 to 8.5
4.7 to 8.0
For time to progression, 51% of events have occurred
For progression-free survival, 52% of events have occurred
P-value based on CMH test stratified by study site and line of therapy
** P-value based on log rank test
0.118**
Overall Response Rate
By Line of Metastatic Study Drug Therapy and By Prior Anthracycline Therapy
100
Overall Response Rate (%)
90
80
70
P< .001
60
P = .001
P = .181
P = .132
50
P-value based
on CMH test
stratified by
study site and
line of therapy
40
30
20
10
0
Line of Metastatic
Therapy
1st Line
>1st Line
Prior Adjuvant or Metastatic
Anthracycline Therapy
Yes
No
N
nab-Paclitaxel
61
43
60
44
SB-paclitaxel
64
42
72
34
Comparison of
nab Paclitaxel and Docetaxel
1st line MBC patients
(N=300)
R
Comparisons
N
• nab paclitaxel vs
docetaxel
(A, B, C vs D)
• Weekly vs every-3weeks nab paclitaxel
(B, C vs A)
• Low vs high dose
weekly nab paclitaxel
(B vs C)
Arm A: nab paclitaxel 300 mg/m2 q3w
A
D
Arm B: nab paclitaxel 100 mg/m2
weekly 3 out of 4
O
M
I
Arm C: nab paclitaxel 150 mg/m2
weekly 3 out of 4
Z
E
Arm D: docetaxel 100 mg/m2 q3w
Gradishar W, et al. ASCO 2007. Abstract 1032.
Response Rates for
nab Paclitaxel vs. Docetaxel
70%
70%
Response rate (%)
60%
62%
50%
40%
43%
38%
30%
20%
10%
0%
300 mg/m2
q3w
(A: n=76)
100 mg/m2
qw 3/4
(B: n=76)
150 mg/m2
qw 3/4
(C: n=74)
Docetaxel
100 mg/m2 q3w
(D: n=74)
nab paclitaxel
Gradishar W, et al. ASCO 2007. Abstract 1032.
Comparison of Investigator and Independent
Radiology Review Response Assessments
Response Rate (%)
Pearson Correlation Coefficient
(Investigator vs. IRR) = 0.507
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)
Neutropenia
(Based Upon Central Laboratory Data)
I
II
III
Febrile
neutropenia
P vs
IV
(%)
docetaxel
nab paclitaxel
300 mg/m2 q3w (A)
20
29
39
5
1
<0.001
nab paclitaxel
100 mg/m2 weekly
(B)
24
32
20
5
1
<0.001
nab paclitaxel
150 mg/m2 weekly
(C)
15
34
34
9
1
<0.001
Docetaxel
100 mg/m2 q3w (D)
3
3
19
75
7
Grade (%)
Treatment arm
P vs (B)
0.007
0.004
P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity.
Gradishar W, et al. ASCO 2007. Abstract 1032.
Treatment-related Adverse Events
Peripheral Neuropathy
Grade (%)
IV
P vs
docetaxel P vs (B)
Treatment arm
I
II
III
nab paclitaxel
300 mg/m2 q3w (A)
34
21
17
0.140
nab paclitaxel
100 mg/m2 weekly (B)
33
11
9
0.190
nab paclitaxel
150 mg/m2 weekly (C)
30
20
16
0.345
Docetaxel
100 mg/m2 q3w (D)
32
19
11
0.006
0.027
P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity.
Gradishar W, et al. ASCO 2007. Abstract 1032.
Treatment-related Adverse Events
Fatigue
Grade (%)
IV
P vs
docetaxel
P vs (B)
Treatment Arm
I
II
III
nab paclitaxel
300 mg/m2 q3w (A)
7
24
4
0.131
0.018
nab paclitaxel
100 mg/m2 weekly (B)
18
13
nab paclitaxel
150 mg/m2 weekly (C)
20
19
3
0.103
0.015
Docetaxel
100 mg/m2q3w (D)
22
15
19
P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity.
Gradishar W, et al. ASCO 2007. Abstract 1032.
nab Paclitaxel vs Docetaxel in
Taxane-naïve MBC
 Higher overall response rates with weekly nab paclitaxel
100 mg/m2 and 150 mg/m2 compared with docetaxel
 nab paclitaxel 150 mg/m2 weekly and 300 mg/m2 every 3
weeks increased PFS compared to docetaxel with an
improved safety profile
 nab paclitaxel 100 mg/m2 weekly was well tolerated and
resulted in PFS comparable to docetaxel
 nab paclitaxel 150 mg/m2 weekly produced a longer PFS
than nab paclitaxel 100 mg/m2 weekly
Gradishar W, et al. ASCO 2007. Abstract 1032.
Clinical Response to
nab Paclitaxel + Capecitabine
 More than 50% of patients achieved at least a partial response
Patient Best Response
Evaluable Patients
(n = 34)
Complete
3 (9%)
Partial
15 (44%)
Stable disease
11 (32%)
Disease progression
5 (15%)
Conclusion: First-line therapy with weekly nanoparticle albumin-bound
paclitaxel plus daily capecitabine is active and well tolerated
Schwartzberg LS, et al. SABCS 2006. Abstract 1096.
nab Paclitaxel + Capecitabine
Time to Progression (TTP)
25% Quartile for Time to Progression:
133 days Progression-free Survival
Survival distribution function
1
0.75
Product limited
estimate curve
0.5
Censored
observations
0.25
0
0
50
100
150
200
250
300
350
Days from first chemo date
•
Preliminary data demonstrates prolonged TTP with this combination
Schwartzberg LS, et al. SABCS 2006. Abstract 1096.
Case #1
 A 42-year old woman was diagnosed with stage II, left
sided breast cancer in 2005.
 Initial therapy included BCS. T= 3 cm; SLNB-negative;
ER, PR, HER2- negative.
 Adjuvant therapy was TC x 4
(docetaxel, cyclophosphamide) and radiation therapy.
Case #1 (cont.)
 3 ½ years later she presents with left rib pain. PE
reveals a 1 cm left supraclavicular node.
 Restaging demonstrates multiple lytic bone lesions and
several small lung nodules.
 FNA of SCN is positive for adenocarcinoma and
appears similar to the original breast cancer.
Case #1 (cont.)
Which systemic therapy would you recommend in
addition to bisphosphonate (BP) therapy?
 Paclitaxel / Bevacizumab
 Capecitabine
 Paclitaxel / Gemcitabine
 nab-Paclitaxel
 Doxorubicin
Case 1 (cont.)
Which systemic therapy would you recommend in addition to
bisphosphonate (BP) therapy?

Paclitaxel / Bevacizumab

Capecitabine

Paclitaxel / Gemcitabine

nab-Paclitaxel

Doxorubicin
Recommended Approach:
All options are reasonable.
Overcoming Breast Cancer
Resistance to Taxanes
New Strategies for
Resistant Breast Cancer
 Taxanes, alone or in combination with anthracyclines,
form the mainstay of adjuvant and metastatic breast
cancer therapy
 Taxane pre-treated recurrent breast cancer is an
increasingly important clinical issue
 A number of complex mechanisms may generate
resistance to established chemotherapies, including
taxanes
New Strategies for
Resistant Breast Cancer
 Clinically, taxane cross-resistance and an absence of
guidance regarding re-treatment increases the need for
novel chemotherapies with differing mechanisms of action
 Randomized controlled data demonstrating the activity of
the epothilone, ixabepilone, in taxane-resistant and pretreated patients supports its use in clinical practice
Taxane Re-treatment Following Previous
Taxane Therapy for MBC
 Modest clinical efficacy when taxanes re-introduced in taxanepre-treated / resistant MBC
- Single-agent taxane, ORR varies between 17- 44%
 Disease-free interval believed important
 In studies, there is significant variability in DFI criteria and little
correlation between interval and observed response rate
Valero et al, J Clin Oncol 1998; 16: 3362–8
Nishimura et al, Chemotherapy 2005; 51: 126–31
Seidman et al, J Clin Oncol 1996; 14: 1877–84
Taguchi et al, Breast J 2004; 10: 509–13
Yonemori et al, Breast Cancer Res Treat 2005; 89: 237–41
Perez et al, J Clin Oncol 2001; 19: 4216–23
Sawaki et al, Tumori 2004; 90: 36–9
Response Rates: MBC
Re-exposure to Single-agent Taxanes
Valero et al, J Clin Oncol 1998; 16: 3362–8
Seidman et al, J Clin Oncol 1996; 14: 1877–84
Nishimura et al, Chemotherapy 2005; 51: 126–31
Yonemori et al, Breast Cancer Res Treat 2005; 89: 237–41
Taguchi et al, Breast J 2004; 10: 509–13
Sawaki et al, Tumori 2004; 90: 36–9
Perez et al, J Clin Oncol 2001; 19: 4216–23
Time to Progression: MBC
Re-exposure to Single-agent Taxanes
Valero et al, J Clin Oncol 1998; 16: 3362–8
Seidman et al, J Clin Oncol 1996; 14: 1877–84
Yonemori et al, Breast Cancer Res Treat 2005; 89:
237–41Sawaki et al, Tumori 2004; 90: 36–9
Nishimura et al, Chemotherapy 2005; 51: 126–31
Taguchi et al, Breast J 2004; 10: 509–13
Perez et al, J Clin Oncol 2001; 19: 4216–23
Epothilones as Anticancer Agents
 Epothilones are tubulin-binding agents
 Ixabepilone is currently the only FDA-approved
epothilone
• in combination with capecitabine for the treatment
of patients with metastatic or locally advanced breast cancer
resistant to treatment with an anthracycline
and a taxane
• as monotherapy for the treatment of metastatic or
locally advanced breast cancer in patients whose
tumors are resistant or refractory to anthracyclines,
taxanes, and capecitabine
www.fda.gov
Phase II Study of Ixabepilone
in Taxane-refractory MBC
*5/6 responders had not responded to prior taxane therapy
Thomas et al, J Clin Oncol 2007; 25: 3399–406
Phase II Study of Ixabepilone in Taxane
Pre-treated Locally Advanced or MBC
Low et al, J Clin Oncol 2005; 23: 2726–34
Ixabepilone Efficacy in Heavily Pre-treated MBC
Study Design
Perez et al, J Clin Oncol 2007; 25: 3407–14
Ixabepilone in Heavily Pre-treated MBC
Response
Perez et al, J Clin Oncol 2007; 25: 3407–14
Ixabepilone in Heavily Pre-treated MBC
Survival
Perez et al, J Clin Oncol 2007; 25: 3407–14
Capecitabine ± Ixabepilone in Anthracyclineand Taxane-resistant, Locally Advanced or MBC
Response
Thomas et al, J Clin Oncol 2007; 25: 5210–7
Capecitabine ± Ixabepilone in Anthracyclineand Taxane-resistant, Locally Advanced or MBC
Grade 3/4 Adverse Events
*70/79 treated cases resolved after treatment discontinuation, median time to event
resolution 6 weeks
Most common grade 3/4 events
Thomas et al, J Clin Oncol 2007; 25: 5210–7
Phase II Study of Ixabepilone
in Taxane-naïve, Second-line MBC
Denduluri et al, J Clin Oncol 2007; 25: 3421–7
Ixabepilone as First-line Therapy in
MBC Patients Following Adjuvant Anthracyclines
Study Design
Roché et al, J Clin Oncol 2007; 25: 3415–20
Ixabepilone as First-line Therapy in MBC
Patients Following Adjuvant Anthracyclines
Efficacy
Roché et al, J Clin Oncol 2007; 25: 3415–20
Ixabepilone Studies
in Taxane-naïve or Pre-treated MBC
Response Rate
1Thomas
et al, J Clin Oncol 2007; 25: 3399–406
Low et al, J Clin Oncol 2005; 23: 2726–34
Perez et al, J Clin Oncol 2007; 25: 3407–14
2Thomas et al, J Clin Oncol 2007; 25: 5210–7
3Roché
et al, ASCO 2002; Abstract 223
Denduluri et al, J Clin Oncol 2007; 25: 3421–7
4Roché et al, J Clin Oncol 2007; 25: 3415–20
Moulder et al, SABCS 2007; Abstract 152
Ixabepilone Efficacy by Disease Stage
and Degree of Resistance
A/T=anthracycline- / taxane-resistant, Multi=multi-resistant, T=taxane-resistant, T-naïve=taxane-naïve
Adapted from, Fumoleau et al, ECCO 2007; Abstract 2119
Case #2
 47-year old female presents with recurrent metastatic BC
involving the liver (3 lesions) and bone. Bx confirmed
IDC – (ER, PR, HER2-negative)
 2 years earlier the patient was diagnosed with Stage II
IDC of the right breast (T = 3 cm; N = 3 of 12 positive
axillary nodes); ER, PR, HER2-negative
 Treatment included BCS followed by RT and dose-dense
AC followed by T
Case #2 (cont.)
At this time what systemic treatment would you
recommend?
 Paclitaxel and bevacizumab
 Capecitabine
 Capecitabine and docetaxel
 Gemcitabine and paclitaxel
 nab-paclitaxel
Case #2 (cont.)
At this time what systemic treatment would you
recommend?
 Paclitaxel and bevacizumab
 Capecitabine
 Capecitabine and docetaxel
 Gemcitabine and paclitaxel
 nab-paclitaxel
Recommended Approach:
The use of Capecitabine as a single agent is a reasonable option.
• Most patients tolerate the drug well.
• It has become very useful as an oral medication
Case #2 (cont.)
• The patient receives capecitabine as a single agent
• Repeat scans after 3 cycles confirm a partial response
in the liver and stable bone lesions
• Capecitabine is continued for 7 months at which time
disease progression is documented in the liver
• PS-1, LFT remain normal
Case #2 (cont.)
At this time you would recommend:
 Docetaxel and bevacizumab
 Paclitaxel and bevacizumab
 Ixabepilone
 Gemcitabine
 Navelbine
Case #2 (cont.)
Recommended Approach:
 Eliminate Gemcitabine and Navelbine as first choices.
 Clinical data supports Docetaxel + Bevacizumab, Paclitaxel +
Bevacizumab and Ixabepilone
Conclusions
 The tolerability profiles of classic solvent-based taxanes
are not optimal, warranting the advent of new tubulin
inhibitor formulations
 nab paclitaxel has demonstrated favorable efficacy
versus solvent-based taxanes, while decreasing the
severity of neutropenia and shortening the resolution of
neuropathy
 Many patients with progressive MBC, following prior
treatment with anthracyclines and taxanes ( and
capecitabine), remain good candidates for additional
systemic therapy
Conclusions (cont.)
 Identifying optimal treatment choices in this population
is a challenge
 Ixabepilone represents the first FDA-approved
epothilone for treatment of advanced breast cancer
 Ixabepilone has significant antitumor activity in heavily
pretreated patients with a manageable toxicity profile
 Ongoing clinical trials will establish the role of
ixabepilone in chemo-naïve patients and in combination
with biologic agents
Clinical Updates
Tubulin Inhibition in Breast Cancer:
A Therapeutic Target Critical to
Improving Outcomes