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Tubulin Inhibition in Breast Cancer: A Therapeutic Target Critical to Improving Outcomes William J. Gradishar, MD Professor of Medicine Robert H. Lurie.

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Presentation on theme: "Tubulin Inhibition in Breast Cancer: A Therapeutic Target Critical to Improving Outcomes William J. Gradishar, MD Professor of Medicine Robert H. Lurie."— Presentation transcript:

1 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 Clinical Updates

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 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

3 Structure of a Microtubule Jordan & Kamath, Curr Cancer Drug Targets 2007; 7: 730–42

4 Microtubule Involvement in Mitosis Jackson et al, Nat Rev Cancer 2007; 7: 107–17 Reprinted by permission from Macmillan Publishers Ltd.

5 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

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. 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.

7 Solvent-based Taxane Toxicities ReactionDocetaxelPaclitaxel Hypersensitivity reaction (grade 3/4)2.6%*2% Neutropenia (<500 mm 3 )85.9%52% Leukopenia (<1000 mm 3 )43.7%17% Thrombocytopenia (<100,000/mm 3 )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% Mucositis7.4%31% Cardiovascular events8.1%16% Adapted from product inserts of paclitaxel (BMS, n=812) and docetaxel (Aventis, n=2045). *Regardless of premedication.

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 Topical Oral Inhalational IV/IA Protein Insoluble drug Stable nanoparticles ~0.1-0.2 µm, negatively charged Proprietary process Albumin Human albumin Active drug

11 Endothelial cell (EC) Tumor cell EC membrane Caveolae and vesicles Leaky junction Tumor 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

12 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.

13 Phase III Trial of nab Paclitaxel in MBC Gradishar et al. J Clin Oncol. 2005;23:7794-7803. Nab paclitaxel 260 mg/m 2 i.v. over 30 min q 3 wk No standard premedication Cremophor paclitaxel 175 mg/m 2 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

14 Phase III Trial Albumin-Bound Paclitaxel vs. Paclitaxel in MBC Albumin-Bound Paclitaxel N=229 Paclitaxel N=225 P-Value Overall Response Rate33%19%.001 Time to Progression23.0 wk16.9 wk.006 Grade 4 Neutropenia9%22%<.001 Grade 3 Sensory Neuropathy10%*2%<.001 Albumin-bound paclitaxel: 260 mg/m 2 q3w; Paclitaxel:175 mg/m2 q3w * Median time to improvement: 22 days Gradishar et al. JCO 23: 7794; 2005

15 Phase III Every 3w Hematologic Toxicities Hematologic toxicity nab Paclitaxel n=229 Paclitaxel n=225 P-Value* Grade 3Grade 4Grade 3Grade 4 Neutropenia25% 9%31%22%<0.001 Thrombocytopenia<1% 0%<1% 0%0.387 Anemia<1% 0% 0.192 Febrile neutropenia<1% 0%0.491 Septic deaths00-- *Cochran-Mantel-Haenszel test based upon all grades. Gradishar et al. JCO 23: 7794; 2005

16 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 1 Sun Yat Sen University Cancer Centre, Guangdong, China; 2 Cancer Center of CAMS, Beijing, China; 3 Tianjin Tumor Hospital, Tianjin, China; 4 PLA 307 Hospital, Beijing, China; 5 Fudan University Cancer Center, Shanghai, China; 6 Tonghi Hospital, Wuhan, China; 7 Jiansu Tumor Hospital, Jiansu, China, 8 No. 2 Hospital of Medical College, Zhejiang University, Hangzhou, China, 9 Abraxis BioScience, Inc., Los Angeles, CA.

17 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)7.66.20.078** 95% CI6.7 to 8.64.7 to 8.0 Median Progression-free Survival (months)7.66.20.118** 95% CI6.7 to 8.54.7 to 8.0 P-value based on CMH test stratified by study site and line of therapy ** P-value based on log rank test

18 Overall Response Rate By Line of Metastatic Study Drug Therapy and By Prior Anthracycline Therapy P =.132 P =.001 P<.001 Prior Adjuvant or Metastatic Anthracycline Therapy Line of Metastatic Therapy Yes 1 st Line No >1 st 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

19 Comparison of nab Paclitaxel and Docetaxel Arm A: nab paclitaxel 300 mg/m 2 q3w 1 st 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/m 2 weekly 3 out of 4 Arm C: nab paclitaxel 150 mg/m 2 weekly 3 out of 4 Arm D: docetaxel 100 mg/m 2 q3w RANDOMIZERANDOMIZE Gradishar W, et al. ASCO 2007. Abstract 1032.

20 Response Rates for nab Paclitaxel vs. Docetaxel Gradishar W, et al. ASCO 2007. Abstract 1032. Response rate (%) 300 mg/m 2 100 mg/m 2 150 mg/m 2 Docetaxel q3wqw 3/4qw 3/4100 mg/m 2 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%

21 Comparison of Investigator and Independent Radiology Review Response Assessments Response Rate (%) 300 mg/m 2 100 mg/m 2 150 mg/m 2 docetaxel q3wqw 3/4qw 3/4100 mg/m 2 q3w (A: n = 76)(B: n = 76)(C: n = 74)(D: n = 74) nab paclitaxel Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507

22 Neutropenia (Based Upon Central Laboratory Data) Treatment arm Grade (%) Febrile neutropenia (%) P vs docetaxelP vs (B) IIIIIIIV nab paclitaxel 300 mg/m 2 q3w (A) 20293951<0.0010.007 nab paclitaxel 100 mg/m 2 weekly (B) 24322051<0.001 nab paclitaxel 150 mg/m 2 weekly (C) 1534 91<0.0010.004 Docetaxel 100 mg/m 2 q3w (D) 3319757 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 (%) IIIIIIIV P vs docetaxelP vs (B) nab paclitaxel 300 mg/m 2 q3w (A) 3421170.1400.006 nab paclitaxel 100 mg/m 2 weekly (B) 331190.190 nab paclitaxel 150 mg/m 2 weekly (C) 3020160.3450.027 Docetaxel 100 mg/m 2 q3w (D) 321911 Gradishar W, et al. ASCO 2007. Abstract 1032. P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity.

24 Treatment-related Adverse Events Fatigue Treatment Arm Grade (%) IIIIIIIV P vs docetaxelP vs (B) nab paclitaxel 300 mg/m 2 q3w (A) 72440.1310.018 nab paclitaxel 100 mg/m 2 weekly (B) 1813 nab paclitaxel 150 mg/m 2 weekly (C) 201930.1030.015 Docetaxel 100 mg/m 2 q3w (D) 221519 P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity. Gradishar W, et al. ASCO 2007. Abstract 1032.

25 nab Paclitaxel vs Docetaxel in Taxane-naïve MBC Gradishar W, et al. ASCO 2007. Abstract 1032.  Higher overall response rates with weekly nab paclitaxel 100 mg/m 2 and 150 mg/m 2 compared with docetaxel  nab paclitaxel 150 mg/m 2 weekly and 300 mg/m 2 every 3 weeks increased PFS compared to docetaxel with an improved safety profile  nab paclitaxel 100 mg/m 2 weekly was well tolerated and resulted in PFS comparable to docetaxel  nab paclitaxel 150 mg/m 2 weekly produced a longer PFS than nab paclitaxel 100 mg/m 2 weekly

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) Complete3 (9%) Partial15 (44%) Stable disease11 (32%) Disease progression5 (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

27 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 050100150200250300350 Days from first chemo date Survival distribution function

28 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.

29 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.)  Paclitaxel / Bevacizumab  Capecitabine  Paclitaxel / Gemcitabine  nab-Paclitaxel  Doxorubicin Which systemic therapy would you recommend in addition to bisphosphonate (BP) therapy?

31  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.

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 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: 237–41 Sawaki et al, Tumori 2004; 90: 36–9

36 Response Rates: MBC Re-exposure to Single-agent Taxanes 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 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: 237–41 Sawaki et al, Tumori 2004; 90: 36–9

37 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

38 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 Thomas et al, J Clin Oncol 2007; 25: 3399–406 *5/6 responders had not responded to prior taxane therapy

40 Phase II Study of Ixabepilone in Taxane Pre-treated Locally Advanced or MBC Low et al, J Clin Oncol 2005; 23: 2726–34

41 Ixabepilone Efficacy in Heavily Pre-treated MBC Study Design Perez et al, J Clin Oncol 2007; 25: 3407–14

42 Ixabepilone in Heavily Pre-treated MBC Response Perez et al, J Clin Oncol 2007; 25: 3407–14

43 Ixabepilone in Heavily Pre-treated MBC Survival Perez et al, J Clin Oncol 2007; 25: 3407–14

44 Capecitabine ± Ixabepilone in Anthracycline- and Taxane-resistant, Locally Advanced or MBC Response Thomas et al, J Clin Oncol 2007; 25: 5210–7

45 Capecitabine ± Ixabepilone in Anthracycline- and Taxane-resistant, Locally Advanced or MBC Grade 3/4 Adverse Events Thomas et al, J Clin Oncol 2007; 25: 5210–7 *70/79 treated cases resolved after treatment discontinuation, median time to event resolution 6 weeks Most common grade 3/4 events

46 Phase II Study of Ixabepilone in Taxane-naïve, Second-line MBC Denduluri et al, J Clin Oncol 2007; 25: 3421–7

47 Ixabepilone as First-line Therapy in MBC Patients Following Adjuvant Anthracyclines Study Design Roché et al, J Clin Oncol 2007; 25: 3415–20

48 Ixabepilone as First-line Therapy in MBC Patients Following Adjuvant Anthracyclines Efficacy Roché et al, J Clin Oncol 2007; 25: 3415–20

49 Ixabepilone Studies in Taxane-naïve or Pre-treated MBC Response Rate 3 Roché et al, ASCO 2002; Abstract 223 Denduluri et al, J Clin Oncol 2007; 25: 3421–7 4 Roché et al, J Clin Oncol 2007; 25: 3415–20 Moulder et al, SABCS 2007; Abstract 152 1 Thomas 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 2 Thomas et al, J Clin Oncol 2007; 25: 5210–7

50 Ixabepilone Efficacy by Disease Stage and 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

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 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.)

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


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