Tubulin Inhibition in Breast Cancer: A Therapeutic Target Critical to Improving Outcomes

1
Tubulin Inhibition in Breast CancerA
Therapeutic Target Critical to Improving Outcomes
Clinical Updates
William J. Gradishar, MD Professor of
Medicine Robert H. Lurie Comprehensive Cancer
Center Northwestern University Feinberg School of
Medicine Chicago, IL
2
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 essentialto tumor metastasis
• Biological function of microtubules regulated by
  polymerization dynamics

• McIntosh et al, Microtubules. Wiley-Liss New
  York 1994 41334
• Oakley et al, Microtubules. Wiley-Liss New York
  1994 3345
• Wordeman et al, Microtubules. Wiley-Liss New
  York 1994 287301

3
Structure of a Microtubule

• Jordan Kamath, Curr Cancer Drug Targets 2007
  7 73042

4
Microtubule Involvement in Mitosis

• Jackson et al, Nat Rev Cancer 2007 7
  10717Reprinted by permission from Macmillan
  Publishers Ltd.

5
Effects of Tubulin-binding Drugs on Microtubules

• Jordan et al, Mol Cancer Ther 2005 4 108695
• Verrills Kavallaris, Curr Pharm Des 2005 11
  171933

6
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.
200119125-141 van Tellingen O, et al. Clin
Cancer Res. 199952918-2924 Ellis AG, et al.
Cancer Chemother Pharmacol. 19963881-87
LoRusso PM, Pilat MJ. ONS News. 20041975-76.
7
Solvent-based Taxane Toxicities
Reaction Docetaxel Paclitaxel
Hypersensitivity reaction (grade 3/4) 2.6 2
Neutropenia (lt500 mm3) 85.9 52
Leukopenia (lt1000 mm3) 43.7 17
Thrombocytopenia (lt100,000/mm3) 9.2 20
Anemia (lt11 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,
n812) and docetaxel (Aventis, n2045).
8
Appropriate Clinical Utilization of Novel Taxane
Formulations
9
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

10
Nanoparticle Albumin Bound (nab) Platform
Albumin
IV/IA
Protein
Oral
Human albumin
Active drug
Topical
Proprietary process
Inhalational
Insoluble drug
Stable nanoparticles 0.1-0.2 µm, negatively
charged
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Mechanisms of Transport of nab Paclitaxel to
Tumors
Leaky junction
Tumor interstitium
Tumor cell
(A) Enhanced permeation and retention (EPR)
effect
Lumen of tumor microvessel
(C) Tumor uptake
Endothelial cell (EC)
Caveolae and vesicles
Tumor cell
(B) Receptor mediated
EC membrane
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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.
2005237794-7803.
13
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. 2005237794-7803.
14
Phase III TrialAlbumin-Bound Paclitaxel vs.
Paclitaxel in MBC
Albumin-bound paclitaxel 260 mg/m2 q3w
Paclitaxel175 mg/m2 q3w
Albumin-Bound Paclitaxel N229 Paclitaxel N225 P-Value
Overall Response Rate 33 19 .001
Time to Progression 23.0 wk 16.9 wk .006
Grade 4 Neutropenia 9 22 lt.001
Grade 3 Sensory Neuropathy 10 2 lt.001
Median time to improvement 22 days
Gradishar et al. JCO 23 7794 2005
15
Phase III Every 3w Hematologic Toxicities
Hematologic toxicity nab Paclitaxel n229 nab Paclitaxel n229 Paclitaxel n225 Paclitaxel n225 P-Value
Hematologic toxicity Grade 3 Grade 4 Grade 3 Grade 4 P-Value
Neutropenia 25 9 31 22 lt0.001
Thrombocytopenia lt1 0 lt1 0 0.387
Anemia lt1 lt1 0 0 0.192
Febrile neutropenia lt1 lt1 lt1 0 0.491
Septic deaths 0 0 0 0 --
Cochran-Mantel-Haenszel test based upon all
grades.
Gradishar et al. JCO 23 7794 2005
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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.91Sun 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.
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Response Rate, Time To Progression,
Progression-free Survival, and Overall Survival
nab-paclitaxel (n 104) SB-paclitaxel (n 106) P-value
Overall Response Rate (Complete Response Partial Response) 56 (54) 31 (29) lt0.001
Median Time To Progression (months) 7.6 6.2 0.078
95 CI 6.7 to 8.6 4.7 to 8.0
Median Progression-free Survival (months) 7.6 6.2 0.118
95 CI 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
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Overall Response Rate By Line of Metastatic
Study Drug Therapy and By Prior Anthracycline
Therapy
P-value based on CMH test stratified by study
site and line of therapy
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Comparison of nab Paclitaxel and Docetaxel
R A N D O M I Z E

• 1st line MBC patients
• (N300)
• 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/m2weekly 3 out of 4
Arm C nab paclitaxel 150 mg/m2weekly 3 out of 4
Arm D docetaxel 100 mg/m2 q3w
Gradishar W, et al. ASCO 2007. Abstract 1032.
20
Response Rates for nab Paclitaxel vs. Docetaxel
70
70
60
62
50
40
43
Response rate ()
38
30
20
10
0
300 mg/m2 100 mg/m2 150 mg/m2 Docetaxel q3w qw
3/4 qw 3/4 100 mg/m2 q3w (A n76) (B n76) (C
n74) (D n74)
nab paclitaxel
Gradishar W, et al. ASCO 2007. Abstract 1032.
21
Comparison of Investigator and Independent
Radiology Review Response Assessments
Pearson Correlation Coefficient (Investigator vs.
IRR) 0.507
Response Rate ()
300 mg/m2 100 mg/m2 150 mg/m2 docetaxel q3w qw
3/4 qw 3/4 100 mg/m2 q3w (A n 76) (B n
76) (C n 74) (D n 74)
nab paclitaxel
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Neutropenia (Based Upon Central Laboratory Data)
Treatment arm Grade () Grade () Grade () Grade () Febrile neutropenia () P vs docetaxel P vs (B)
Treatment arm I II III IV Febrile neutropenia () P vs docetaxel P vs (B)
nab paclitaxel 300 mg/m2 q3w (A) 20 29 39 5 1 lt0.001 0.007
nab paclitaxel 100 mg/m2 weekly (B) 24 32 20 5 1 lt0.001
nab paclitaxel 150 mg/m2 weekly (C) 15 34 34 9 1 lt0.001 0.004
Docetaxel 100 mg/m2 q3w (D) 3 3 19 75 7
P-values by Cochran-Mantel-Haenszel includes all
grades of toxicity.
Gradishar W, et al. ASCO 2007. Abstract 1032.
23
Treatment-related Adverse Events Peripheral
Neuropathy
Treatment arm Grade () Grade () Grade () Grade ()
Treatment arm I II III IV P vs docetaxel P vs (B)
nab paclitaxel 300 mg/m2 q3w (A) 34 21 17 0.140 0.006
nab paclitaxel 100 mg/m2 weekly (B) 33 11 9 0.190
nab paclitaxel 150 mg/m2 weekly (C) 30 20 16 0.345 0.027
Docetaxel 100 mg/m2 q3w (D) 32 19 11
P-values by Cochran-Mantel-Haenszel includes all
grades of toxicity.
Gradishar W, et al. ASCO 2007. Abstract 1032.
24
Treatment-related Adverse Events Fatigue
Treatment Arm Grade () Grade () Grade () Grade ()
Treatment Arm I II III IV P vs docetaxel P vs (B)
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.
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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.
26
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.
27
nab Paclitaxel Capecitabine Time to
Progression (TTP)
25 Quartile for Time to Progression 133 days
Progression-free Survival

• Preliminary data demonstrates prolonged TTP with
  this combination

Schwartzberg LS, et al. SABCS 2006. Abstract 1096.
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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.

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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.

30
Case 1 (cont.)
Which systemic therapy would you recommend in
addition to bisphosphonate (BP) therapy?

• Paclitaxel / Bevacizumab
• Capecitabine
• Paclitaxel / Gemcitabine
• nab-Paclitaxel
• Doxorubicin

31
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.

32
Overcoming Breast Cancer Resistance to Taxanes
33
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

34
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 pre-treated patients
  supports its use in clinical practice

35
Taxane Re-treatment Following Previous Taxane
Therapy for MBC

• Modest clinical efficacy when taxanes
  re-introduced in taxane-pre-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 33628
Seidman et al, J Clin Oncol 1996 14 187784
Yonemori et al, Breast Cancer Res Treat 2005
89 23741 Sawaki et al, Tumori 2004 90 369

• Nishimura et al, Chemotherapy 2005 51 12631
  Taguchi et al, Breast J 2004 10 50913 Perez
  et al, J Clin Oncol 2001 19 421623

36
Response Rates MBC Re-exposure to
Single-agent Taxanes
Valero et al, J Clin Oncol 1998 16
33628Seidman et al, J Clin Oncol 1996 14
187784 Yonemori et al, Breast Cancer Res Treat
2005 89 23741 Sawaki et al, Tumori 2004 90
369

• Nishimura et al, Chemotherapy 2005 51 12631
  Taguchi et al, Breast J 2004 10 50913 Perez
  et al, J Clin Oncol 2001 19 421623

37
Time to Progression MBC Re-exposure to
Single-agent Taxanes

• Nishimura et al, Chemotherapy 2005 51 12631
  Taguchi et al, Breast J 2004 10 50913 Perez
  et al, J Clin Oncol 2001 19 421623

Valero et al, J Clin Oncol 1998 16
33628Seidman et al, J Clin Oncol 1996 14
187784Yonemori et al, Breast Cancer Res Treat
2005 89 23741Sawaki et al, Tumori 2004 90
369
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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

39
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 3399406

40
Phase II Study of Ixabepilone in Taxane
Pre-treated Locally Advanced or MBC

• Low et al, J Clin Oncol 2005 23 272634

41
Ixabepilone Efficacy in Heavily Pre-treated MBC
Study Design

• Perez et al, J Clin Oncol 2007 25 340714

42
Ixabepilone in Heavily Pre-treated MBC Response

• Perez et al, J Clin Oncol 2007 25 340714

43
Ixabepilone in Heavily Pre-treated MBC Survival

• Perez et al, J Clin Oncol 2007 25 340714

44
Capecitabine Ixabepilone in Anthracycline- and
Taxane-resistant, Locally Advanced or MBC
Response

• Thomas et al, J Clin Oncol 2007 25 52107

45
Capecitabine Ixabepilone in Anthracycline- and
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 52107

46
Phase II Study of Ixabepilone in Taxane-naïve,
Second-line MBC

• Denduluri et al, J Clin Oncol 2007 25 34217

47
Ixabepilone as First-line Therapy in MBC
Patients Following Adjuvant AnthracyclinesStudy
Design

• Roché et al, J Clin Oncol 2007 25 341520

48
Ixabepilone as First-line Therapy in MBC Patients
Following Adjuvant Anthracyclines Efficacy

• Roché et al, J Clin Oncol 2007 25 341520

49
Ixabepilone Studies in Taxane-naïve or
Pre-treated MBCResponse Rate
1Thomas et al, J Clin Oncol 2007 25
3399406 Low et al, J Clin Oncol 2005 23
272634 Perez et al, J Clin Oncol 2007 25
340714 2Thomas et al, J Clin Oncol 2007 25
52107

• 3Roché et al, ASCO 2002 Abstract 223 Denduluri
  et al, J Clin Oncol 2007 25 342174Roché et
  al, J Clin Oncol 2007 25 341520Moulder et al,
  SABCS 2007 Abstract 152

50
Ixabepilone Efficacy by Disease Stageand Degree
of Resistance
A/Tanthracycline- / taxane-resistant,
Multimulti-resistant, Ttaxane-resistant,
T-naïvetaxane-naïve

• Adapted from, Fumoleau et al, ECCO 2007 Abstract
  2119

51
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

52
Case 2 (cont.)

• At this time what systemic treatment would you
  recommend?
• Paclitaxel and bevacizumab
• Capecitabine
• Capecitabine and docetaxel
• Gemcitabine and paclitaxel
• nab-paclitaxel

53
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

54
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

55
Case 2 (cont.)

• At this time you would recommend
• Docetaxel and bevacizumab
• Paclitaxel and bevacizumab
• Ixabepilone
• Gemcitabine
• Navelbine

56
Case 2 (cont.)

• At this time you would recommend
• Docetaxel and bevacizumab
• Paclitaxel and bevacizumab
• Ixabepilone
• Gemcitabine
• Navelbine

• Recommended Approach
• Eliminate Gemcitabine and Navelbine as first
  choices.
• Clinical data supports Docetaxel Bevacizumab,
  Paclitaxel Bevacizumab and Ixabepilone

57
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

58
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

59
Clinical Updates
Tubulin Inhibition in Breast CancerA
Therapeutic Target Critical to Improving
Outcomes