tubulin inhibition in breast cancer: a therapeutic target critical to improving outcomes william j....

Tubulin Inhibition in Breast Cancer:A Therapeutic Target Critical to

Improving Outcomes

William J. Gradishar, MDProfessor of Medicine

Robert H. Lurie Comprehensive Cancer Center

Northwestern University Feinberg School of Medicine

Chicago, IL

Clinical Updates

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; 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: 107–17Reprinted 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%

Adapted from product inserts of paclitaxel (BMS, n=812) and docetaxel (Aventis, n=2045).

*Regardless of premedication.

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

TopicalTopical

OralOral

InhalationalInhalational

IV/IAIV/IAProtein

Insoluble drug

Stable nanoparticles~0.1-0.2 µm, negatively charged

Proprietary process

Albumin

Human albumin

Active drug

Endothelial cell

(EC)

Tumor cell

EC membrane

Caveolae and vesicles

Leaky junctionTumor interstitium

(B) Receptor mediated

(C) Tumor uptake

Mechanisms of Transport of nab Paclitaxel to Tumors

Tumor cell

Lumen of tumor

microvessel

(A) Enhanced permeation and retention (EPR) effect

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

Gradishar et al. J Clin Oncol. 2005;23:7794-7803.

Nab paclitaxel 260 mg/m2

i.v. over 30 min q 3 wk

No standard premedication

Cremophor paclitaxel 175 mg/m2

i.v. over 3 hours q 3 wk

Standard premedication with dexamethasone and antihistamines

or

• Women with measurable stage IV breast cancer

• No prior taxane therapy

• N = 460

Phase III TrialAlbumin-Bound Paclitaxel vs. Paclitaxel in MBC

Albumin-Bound Paclitaxel

N=229

Paclitaxel

N=225P-Value

Overall Response Rate 33% 19% .001

Time to Progression 23.0 wk 16.9 wk .006

Grade 4 Neutropenia 9% 22% <.001

Grade 3 Sensory Neuropathy 10%* 2% <.001

Albumin-bound paclitaxel: 260 mg/m2 q3w; Paclitaxel:175 mg/m2 q3w

* Median time to improvement: 22 days

Gradishar et al. JCO 23: 7794; 2005

Phase III Every 3w Hematologic Toxicities

Hematologic toxicity

nab Paclitaxel

n=229

Paclitaxel

n=225

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.

• For time to progression, 51% of events have occurred

• For progression-free survival, 52% of events have occurred

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%) <0.001*

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

P-value based on CMH test stratified by study site and line of therapy ** P-value based on log rank test

Overall Response Rate By Line of Metastatic Study Drug Therapy and By Prior Anthracycline Therapy

0

10

20

30

40

50

60

70

80

90

100

Ove

rall

Res

pons

e R

ate

(%)

P = .132

P = .001P< .001

Prior Adjuvant or Metastatic Anthracycline Therapy

Line of Metastatic Therapy

Yes1st Line No>1st Line

P = .181

P-value based on CMH test stratified by study site and line of therapy

nab-Paclitaxel 61 43 60 44

SB-paclitaxel 64 42 72 34

N

Comparison of nab Paclitaxel and Docetaxel

Arm A: nab paclitaxel 300 mg/m2 q3w1st line MBC patients

(N=300)

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 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

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

Response Rates for nab Paclitaxel vs. Docetaxel


Res

pons

e ra

te (

%)

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

43%

62%

70%

38%

0%

10%

20%

30%

40%

50%

60%

70%

Comparison of Investigator and Independent Radiology Review Response Assessments

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

Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507

Neutropenia (Based Upon Central Laboratory Data)

Treatment arm

Grade (%)

Febrile

neutropenia

(%)P vs

docetaxel P vs (B)I II III IV

nab paclitaxel

300 mg/m2 q3w (A)20 29 39 5 1 <0.001 0.007

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 0.004

Docetaxel

100 mg/m2 q3w (D)3 3 19 75 7

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


Treatment-related Adverse Events Peripheral Neuropathy

Treatment arm

Grade (%)

I II III IVP 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.

Treatment-related Adverse Events Fatigue

Treatment Arm

Grade (%)

I II III IVP 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.

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

Clinical Response to nab Paclitaxel + Capecitabine

More than 50% of patients achieved at least a partial response

Patient Best ResponseEvaluable Patients

(n = 34)

Complete 3 (9%)

Partial 15 (44%)

Stable disease 11 (32%)

Disease progression 5 (15%)

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

Conclusion: First-line therapy with weekly nanoparticle albumin-bound paclitaxel plus daily capecitabine is active and well tolerated

nab Paclitaxel + Capecitabine Time to Progression (TTP)

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

• Preliminary data demonstrates prolonged TTP with this combination

Product limited estimate curve

Censored observations

25% Quartile for Time to Progression: 133 days Progression-free Survival

0

0.25

0.5

0.75

1

0 50 100 150 200 250 300 350

Days from first chemo date

Sur

viva

l dis

trib

utio

n fu

nctio

n

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.)

Paclitaxel / Bevacizumab

Capecitabine

Paclitaxel / Gemcitabine

nab-Paclitaxel

Doxorubicin

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?

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 pre-treated patients supports its use in clinical practice

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

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

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 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

Response Rates: MBC Re-exposure to Single-agent Taxanes



Valero et al, J Clin Oncol 1998; 16: 3362–8Seidman 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

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

Valero et al, J Clin Oncol 1998; 16: 3362–8Seidman et al, J Clin Oncol 1996; 14: 1877–84Yonemori et al, Breast Cancer Res Treat 2005; 89: 237–41Sawaki et al, Tumori 2004; 90: 36–9



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

Thomas et al, J Clin Oncol 2007; 25: 3399–406

*5/6 responders had not responded to prior taxane therapy

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


Ixabepilone in Heavily Pre-treated MBC Response


Ixabepilone in Heavily Pre-treated MBC Survival


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

Response


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

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

3Roché et al, ASCO 2002; Abstract 223

Denduluri et al, J Clin Oncol 2007; 25: 3421–74Roché et al, J Clin Oncol 2007; 25: 3415–20

Moulder et al, SABCS 2007; Abstract 152

1Thomas et al, J Clin Oncol 2007; 25: 3399–406Low et al, J Clin Oncol 2005; 23: 2726–34 Perez et al, J Clin Oncol 2007; 25: 3407–142Thomas et al, J Clin Oncol 2007; 25: 5210–7

Ixabepilone Efficacy by Disease Stageand Degree of Resistance

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

A/T=anthracycline- / taxane-resistant, Multi=multi-resistant, T=taxane-resistant, T-naïve=taxane-naïve

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

• 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.)

Case #2 (cont.)

At this time you would recommend: Docetaxel and bevacizumab


Ixabepilone

Gemcitabine

Navelbine

Case #2 (cont.)

At this time you would recommend: Docetaxel and bevacizumab


Ixabepilone

Gemcitabine

Navelbine

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

Tubulin Inhibition in Breast Cancer:A Therapeutic Target Critical to

Improving Outcomes

Clinical Updates

tubulin inhibition in breast cancer: a therapeutic target critical to improving outcomes william j....

Documents

microtubules jordan

breast cancer

cell division microtubules

clin cancer

new york

mol cancer ther

nat rev cancer

cancer chemother pharmacol