Presentation on theme: "Clinical Updates Tubulin Inhibition in Breast Cancer: A Therapeutic Target Critical to Improving Outcomes William J. Gradishar, MD Professor of Medicine."— Presentation transcript:
1 Clinical UpdatesTubulin Inhibition in Breast Cancer: A Therapeutic Target Critical to Improving OutcomesWilliam J. Gradishar, MDProfessor of MedicineRobert H. Lurie Comprehensive Cancer CenterNorthwestern University Feinberg School of MedicineChicago, IL
2 Role of Microtubule in Cellular Physiology Microtubules, a key component of cell cytoskeletoncomprise filamentous polymersdynamic structures that depolymerize and rearrange to form mitotic spindle which is essential to cell divisionMicrotubulesthrough mitotic spindle, align and separate chromosomestransport cellular materialengage in intracellular signallingplay integral role in cell growth and mitosisre-organized in cell invasion and migration, processes essential to tumor metastasisBiological function of microtubules regulated by polymerization dynamicsMcIntosh 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 4/6/2017 2:24 PMTaxane-based TherapyActive against a wide spectrum of malignanciesStandard component of breast, ovarian, and NSCLC therapyLimitations with traditional taxanesHydrophobic and require solventsCremophor® with paclitaxelTween 80 with docetaxelvan Zuylen L, et al. Invest New Drugs. 2001;19: ; van Tellingen O, et al. Clin Cancer Res. 1999;5: ; Ellis AG, et al. Cancer Chemother Pharmacol. 1996;38:81-87; LoRusso PM, Pilat MJ. ONS News. 2004;19:75-76.6
11 Mechanisms of Transport of nab Paclitaxel to Tumors 4/6/2017 2:24 PMLeaky junctionTumor interstitiumTumor cell(A) Enhanced permeationand retention (EPR) effectLumen of tumor microvessel(C) Tumor uptakeEndothelial cell (EC)Caveolae and vesiclesTumor cell(B) Receptor mediatedEC membrane11
12 nab Paclitaxel4/6/2017 2:24 PMFirst clinical application of albumin-bound nanoparticle (nab) technology (FDA approved: Jan 2005)Paclitaxel bound to albumin in a nanoparticleIncreases drug selectivity for tumor cells (albumin intake mechanisms)No routine steroid or antihistamine premedication required, no toxic solventsIn a phase III trial, demonstrated superior efficacy vs paclitaxel in MBCRR doubledProlonged TTPImproved grade 4 neutropenia/sensory neuropathyGradishar WJ, et al, J Clin Oncol. 2005;23:12
13 Phase III Trial of nab Paclitaxel in MBC Nab paclitaxel 260 mg/m2i.v. over 30 min q 3 wkNo standard premedicationWomen with measurable stage IV breast cancerNo prior taxane therapyN = 460orCremophor paclitaxel 175 mg/m2 i.v. over 3 hours q 3 wkStandard premedication with dexamethasone and antihistaminesGradishar et al. J Clin Oncol. 2005;23:13
14 Phase III Trial Albumin-Bound Paclitaxel vs. Paclitaxel in MBC Albumin-bound paclitaxel: 260 mg/m2 q3w; Paclitaxel:175 mg/m2 q3wAlbumin-Bound PaclitaxelN=229PaclitaxelN=225P-ValueOverall Response Rate33%19%.001Time to Progression23.0 wk16.9 wk.006Grade 4 Neutropenia9%22%<.001Grade 3 Sensory Neuropathy10%*2%* Median time to improvement: 22 daysGradishar et al. JCO 23: 7794; 200514
15 Phase III Every 3w Hematologic Toxicities Hematologic toxicitynab Paclitaxeln=229Paclitaxeln=225P-Value*Grade 3Grade 4Neutropenia25%9%31%22%<0.001Thrombocytopenia<1%0%0.387Anemia0.192Febrile neutropenia0.491Septic deaths--*Cochran-Mantel-Haenszel test based upon all grades.Gradishar et al. JCO 23: 7794; 200515
16 Randomized Study Comparing nab-Paclitaxel with Solvent-based Paclitaxel in Chinese Patients with Metastatic Breast CancerZhong-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.
17 Response Rate, Time To Progression, Progression-free Survival, and Overall Survival nab-paclitaxel(n =104)SB-paclitaxel(n = 106)P-valueOverall 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 8.0Median Progression-free Survival (months)0.118**6.7 to 8.5For time to progression, 51% of events have occurredFor progression-free survival, 52% of events have occurredP-value based on CMH test stratified by study site and line of therapy** P-value based on log rank test
18 Overall Response RateBy Line of Metastatic Study Drug Therapy and By Prior Anthracycline TherapyP = .132P = .001P< .001Prior Adjuvant or Metastatic Anthracycline TherapyLine of Metastatic TherapyYes1st LineNo>1st LineP = .181P-value based on CMH test stratified by study site and line of therapynab-PaclitaxelSB-paclitaxelN
19 Comparison of nab Paclitaxel and Docetaxel 4/6/2017 2:24 PMComparison of nab Paclitaxel and DocetaxelRANDOMIZE1st line MBC patients(N=300)Comparisonsnab 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 q3wArm B: nab paclitaxel 100 mg/m2 weekly 3 out of 4Arm C: nab paclitaxel 150 mg/m2 weekly 3 out of 4Arm D: docetaxel 100 mg/m2 q3wGradishar W, et al. ASCO Abstract 1032.19
21 Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507 Comparison of Investigator and Independent Radiology Review Response AssessmentsPearson Correlation Coefficient (Investigator vs. IRR) = 0.507Response Rate (%)300 mg/m2 100 mg/m 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 paclitaxel21
22 Neutropenia (Based Upon Central Laboratory Data) 4/6/2017 2:24 PMTreatment armGrade (%)Febrileneutropenia(%)P vs docetaxelP vs (B)IIIIIIIVnab paclitaxel300 mg/m2 q3w (A)20293951<0.0010.007100 mg/m2 weekly (B)2432150 mg/m2 weekly (C)153490.004Docetaxel100 mg/m2 q3w (D)319757P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity.Gradishar W, et al. ASCO Abstract 1032.22
23 Treatment-related Adverse Events Peripheral Neuropathy 4/6/2017 2:24 PMTreatment-related Adverse Events Peripheral NeuropathyTreatment armGrade (%)IIIIIIIVP vs docetaxelP vs (B)nab paclitaxel300 mg/m2 q3w (A)3421170.1400.006100 mg/m2 weekly (B)331190.190150 mg/m2 weekly (C)3020160.3450.027Docetaxel100 mg/m2 q3w (D)3219P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity.Gradishar W, et al. ASCO Abstract 1032.23
24 Treatment-related Adverse Events Fatigue 4/6/2017 2:24 PMTreatment-related Adverse Events FatigueTreatment ArmGrade (%)IIIIIIIVP vs docetaxelP vs (B)nab paclitaxel300 mg/m2 q3w (A)72440.1310.018100 mg/m2 weekly (B)1813150 mg/m2 weekly (C)201930.1030.015Docetaxel100 mg/m2q3w (D)2215P-values by Cochran-Mantel-Haenszel; includes all grades of toxicity.Gradishar W, et al. ASCO Abstract 1032.24
25 nab Paclitaxel vs Docetaxel in Taxane-naïve MBC 4/6/2017 2:24 PMnab Paclitaxel vs Docetaxel in Taxane-naïve MBCHigher overall response rates with weekly nab paclitaxel 100 mg/m2 and 150 mg/m2 compared with docetaxelnab paclitaxel 150 mg/m2 weekly and 300 mg/m2 every 3 weeks increased PFS compared to docetaxel with an improved safety profilenab paclitaxel 100 mg/m2 weekly was well tolerated and resulted in PFS comparable to docetaxelnab paclitaxel 150 mg/m2 weekly produced a longer PFS than nab paclitaxel 100 mg/m2 weeklyGradishar W, et al. ASCO Abstract 1032.25
26 Clinical Response to nab Paclitaxel + Capecitabine 4/6/2017 2:24 PMClinical Response to nab Paclitaxel + CapecitabineMore than 50% of patients achieved at least a partial responsePatient Best ResponseEvaluable Patients(n = 34)Complete3 (9%)Partial15 (44%)Stable disease11 (32%)Disease progression5 (15%)Conclusion: First-line therapy with weekly nanoparticle albumin-bound paclitaxel plus daily capecitabine is active and well toleratedSchwartzberg LS, et al. SABCS Abstract 1096.26
27 nab Paclitaxel + Capecitabine Time to Progression (TTP) 25% Quartile for Time to Progression:133 days Progression-free Survival0.250.50.75150100150200250300350Days from first chemo dateSurvival distribution functionProduct limited estimate curveCensored observationsPreliminary data demonstrates prolonged TTP with this combinationSchwartzberg LS, et al. SABCS Abstract 1096.
28 Case #1A 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 (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.)Which systemic therapy would you recommend in addition to bisphosphonate (BP) therapy?Paclitaxel / BevacizumabCapecitabinePaclitaxel / Gemcitabinenab-PaclitaxelDoxorubicin
31 Case 1 (cont.) Recommended Approach: Which systemic therapy would you recommend in addition to bisphosphonate (BP) therapy?Paclitaxel / BevacizumabCapecitabinePaclitaxel / Gemcitabinenab-PaclitaxelDoxorubicinRecommended Approach:All options are reasonable.
33 New Strategies for Resistant Breast Cancer Taxanes, alone or in combination with anthracyclines, form the mainstay of adjuvant and metastatic breast cancer therapyTaxane pre-treated recurrent breast cancer is an increasingly important clinical issueA 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 actionRandomized 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 %Disease-free interval believed importantIn studies, there is significant variability in DFI criteria and little correlation between interval and observed response rateValero 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: 36–9Nishimura 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
36 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 Yonemori et al, Breast Cancer Res Treat 2005; 89: 237–41Sawaki et al, Tumori 2004; 90: 36–9Nishimura 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
37 Time to Progression: 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: 4216–23Valero 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
38 Epothilones as Anticancer Agents Epothilones are tubulin-binding agentsIxabepilone is currently the only FDA-approved epothilonein combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxaneas monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine
39 Phase II Study of Ixabepilone in Taxane-refractory MBC *5/6 responders had not responded to prior taxane therapyThomas et al, J Clin Oncol 2007; 25: 3399–406
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*70/79 treated cases resolved after treatment discontinuation, median time to event resolution 6 weeksMost common grade 3/4 eventsThomas et al, J Clin Oncol 2007; 25: 5210–7
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 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: 5210–73Roché 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
50 Ixabepilone Efficacy by Disease Stage and Degree of Resistance A/T=anthracycline- / taxane-resistant, Multi=multi-resistant, T=taxane-resistant, T-naïve=taxane-naïveAdapted from, Fumoleau et al, ECCO 2007; Abstract 2119
51 Case #247-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-negativeTreatment 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 bevacizumabCapecitabineCapecitabine and docetaxelGemcitabine and paclitaxelnab-paclitaxel
53 Case #2 (cont.)At this time what systemic treatment would you recommend?Paclitaxel and bevacizumabCapecitabineCapecitabine and docetaxelGemcitabine and paclitaxelnab-paclitaxelRecommended 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 lesionsCapecitabine is continued for 7 months at which time disease progression is documented in the liverPS-1, LFT remain normal
55 Case #2 (cont.) At this time you would recommend: Docetaxel and bevacizumabPaclitaxel and bevacizumabIxabepiloneGemcitabineNavelbine
56 Case #2 (cont.) Recommended Approach: Eliminate Gemcitabine and Navelbine as first choices.Clinical data supports Docetaxel + Bevacizumab, Paclitaxel + Bevacizumab and Ixabepilone
57 ConclusionsThe tolerability profiles of classic solvent-based taxanes are not optimal, warranting the advent of new tubulin inhibitor formulationsnab paclitaxel has demonstrated favorable efficacy versus solvent-based taxanes, while decreasing the severity of neutropenia and shortening the resolution of neuropathyMany 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 challengeIxabepilone represents the first FDA-approved epothilone for treatment of advanced breast cancerIxabepilone has significant antitumor activity in heavily pretreated patients with a manageable toxicity profileOngoing clinical trials will establish the role of ixabepilone in chemo-naïve patients and in combination with biologic agents
59 Clinical UpdatesTubulin Inhibition in Breast Cancer: A Therapeutic Target Critical to Improving Outcomes
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