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Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer. Linda T. Vahdat, MD Medical Director, Breast Cancer Research Program Weill Cornell Medical College New York Presbyterian Hospital New York, NY. Program Goals.
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Integration of Treatment Advances into Clinical Practice:Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Linda T. Vahdat, MD Medical Director, Breast Cancer Research Program Weill Cornell Medical College New York Presbyterian Hospital New York, NY
Program Goals • Review data on new anti-microtubule agents (nab-paclitaxel and ixabepilone) • Background • Mechanism of action • Pharmacology • Pre-clinical data • Clinical data
Why Target Microtubules? • Perform multiple basic cellular functions • Fill the area from nucleus to plasma membrane • At least 3 distinct binding sites for tubulin-targeting drugs • Disruption of microtubule cytoskeleton leads to mitotic arrest and cell death
+ b a – Microtubule Structure and Assembly - Slide courtesy of Dr. Paraskevi (Evi) Giannakakou
Mitosis and Microtubules • Microtubules • Make up the mitotic spindle • Critical to separation of chromosomes in mitosis Slide courtesy of Dr. Paraskevi (Evi) Giannakakou
Microtubule-Stabilizing Agents Derived From Natural Products
Partial Listing of Drugs That Target Microtubules • Vinca alkaloids • Taxanes • Epothilones
nab-paclitaxel • Paclitaxel bound to albumin • Advantages: • No premeds • Cremophor free • Shorter infusion time • Might make use of gp60-albumin mediated receptor transport across endothelial cells
Gp60 Receptor Caveolae SPARC nab-platform Utilizes Endogenous Albumin Pathways of Endothelial Transcytosis (gp60) and Intratumoral Binding of SPARC Albumin-Bound Drug Albumin-Drug Accumulation
A Pharmacokinetic Comparison of nab-paclitaxel and Paclitaxel
PK Comparison-linearityTotal Paclitaxel nab-paclitaxel: 30 min infusion Linear, predictable PK Paclitaxel: 3 hr infusion Non-linear, less-predictable PK
Clinical PK Comparison of Total PaclitaxelStudy C008-0 nab-paclitaxel (dose-adjusted to 175 mg/m2) paclitaxel (175 mg/m2)
nab-paclitaxel Significant differences in Bold; RR= response rate, TTP= time to progression; NR= not reported 1Ibrahim, JCO 2005; 2Mirtschung Breast Ca Res Treat Suppl 2006; 3Gradishar JCO 2005
Phase II Study nab-paclitaxel vs. Docetaxel first-line metastatic breast cancer patients randomized to 4 arms: Comparisons (N=300) 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) R A N D O M I Z E 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 Arms A, C and D administered at the MTD Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.
Phase II Study nab-paclitaxel vs. Docetaxel ABX 300 mg/m2 every 3 wks (N = 76) ABX 100 mg/m2 wkly for 3 of 4 wks (N = 76) MBC and no previous chemotherapy for metastatic disease (N = 300) ABX 150 mg/m2 wkly for 3 of 4 wks (N = 74) Docetaxel 100 mg/m2 every 3 wks (N = 74) Gradishar W, et al. ASCO 2007. Abstract 1032.
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 Comparison of Investigator and Independent Radiology Review Response Assessments Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507 Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.
Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d) ABX 300 mg/m2 q3w ABX 100 mg/m2 qw3/4 ABX 150 mg/m2 qw3/4 Docetaxel 100 mg/m2 q3w P = .002 100 90 P = .007 P = .003 80 P = .016 70 70 62 60 Response Rate (%) 50 43 38 40 30 20 10 n = 76 76 74 74 0 Treatment Gradishar W, et al. ASCO 2007. Abstract 1032.
AB CD Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d) • PFS statistically superior with 150 mg/m2 (P = .002) and 300 mg/m2nab-paclitaxel (P = .046) compared with docetaxel in MBC • PFS statistically superior with 150 mg/m2nab-paclitaxel compared with 100 mg/m2nab-paclitaxel (P = .009) • Lower incidence of neutropenia and fatigue with all schedules of nab-paclitaxel compared with docetaxel • Randomized phase III trial comparing weekly nab-paclitaxel 150 mg/m2 vs. docetaxel 100 mg/m2 in MBC planned Progression-free SurvivalInvestigator Assessments 1.0 0.75 Proportion Not Improved 0.50 0.25 75% of patients off-study 0.0 0 3 6 9 12 15 18 Months Gradishar W, et al. ASCO 2007. Abstract 1032.
nab-paclitaxel: Grade 3/4 Toxicity in MBC Grade 3/4 Neutropenia 19-37%
nab-paclitaxel: Grade 3/4 Toxicity in MBC Febrile Neutropenia 1%
nab-paclitaxel: Grade 3/4 Toxicity in MBC Peripheral neuropathy 7-14 % 100 mg/m² QW least neuropathy compared to two other nab-paclitaxel arms
1.00 nab-paclitaxel 300 mg/m2 q3w (N = 13)nab-paclitaxel 100 mg/m2 weekly (N = 7)nab-paclitaxel 150 mg/m2 weekly (N = 12)Docetaxel 100 mg/m2 ( N = 8) 0.75 Proportion Not Improved A) Median, 16 days, 95% CI, 12 to 24B) Median, 22 days, 95% CI, 14 to 25C) Median, 23 days, 95% CI, 12 to 31D) Median, 41 days, 95% CI, 37 to 44 0.50 0.25 0.00 60 100 40 0 80 20 Days Time to Improvement in Peripheral Neuropathy Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.
nab-paclitaxel: Grade 3/4 Toxicity in MBC Fatigue 0-4 % 100 mg/m2 QW least neuropathy compared to two other nab-paclitaxel arms
Conclusions • The response rates of q3w nab-paclitaxel and docetaxel were comparable • For each regimen of nab-paclitaxel compared to docetaxel • Grade 4 neutropenia, febrile neutropenia and mucositis were less frequent • There were no statistical differences between the rates of peripheral neuropathy
Case: Taxane-naïve First-line Metastatic Breast Cancer • 54 y.o. woman diagnosed with Stage II BC in 1999 (T= 2.5 cm N = 1/15, ER/PR pos. HER2neu = 0) • AC Q3W x 4 followed by Tamoxifen • 2006: increased abdominal fullness • Mild elevation of transaminases EOD: liver metastases • Biopsy: c/w prior BC ER/PR positive and HER2-neu non-amplified by FISH
Case: Taxane-naïve First-line Metastatic Breast Cancer Which treatment option would you recommend? • nab-paclitaxel • Docetaxel • Capecitabine • Vinorelbine
Case: Taxane-naïve First-line Metastatic Breast Cancer Which treatment option would you recommend? • nab-paclitaxel • Docetaxel • Capecitabine • Vinorelbine Recommended Approach: • nab-paclitaxel
Epothilones • Derived from sorangium Cellulosum along the Zambezi River • Myxobacteria • Secondary metabolites (epothilones/fungicides)
Epothilones • Macrolide lactones • Epothilone A, B, E, F (epoxides) • Epothilone C,D (olefins) Goodin et al JCO 2004
Epothilones: Mechanism of Action • Induce microtubule stabilization • Bind to b-tubulin • Compete with same binding site as paclitaxel and neuronal tau protein on b-tubulin • Binding mode different from above • Accumulate in G2/M
Effect of Epothilone B on Tumor Cells Microtubule bundling Control cells displaying normal interphase microtubules . Right: Cells treated with 10 nM epothilone B for 24 h displaying extensive microtubule bundling. Altmann et al Biochim Biophys Acta 2000
Epothilones: Mechanism of Action • Induces conformational changes in Bax (pro-apoptotic protein) • Bcl-2- dependent • Potential for synergism with Bcl-2 inhibitors
Pharmacologic Considerations • Epothilone A and B • High in vitro tumor activity • Modest in vivo activity • Metabolic instability • Unfavorable PK • Narrow therapeutic window • Analogs developed to optimize product
Class-specific Advantages • Low susceptibility to tumor resistance mechanisms • MRP-1 and P-gp efflux pumps • b (III) tubulin overexpression • b-tubulin mutations
Pharmacology ixabepilone
Ixabepilone: Pharmacology • Excreted in the feces (75%) and urine (25%) • Metabolized via P450 (CYP3A4) • Linear (AUC increases with dose) • Linear relationship between microtubule bundle formation in PBMC and plasma concentration • T1/2: 39 hours (range:17-50 hrs) Data: BMS data on file
Ixabepilone: Pharmacology MTD: maximum tolerated dose; DLT: dose-limiting toxicity; Q: every Goodin et al, J Clin Oncol 22:2015, 2004
IC50 of Various Epothilones Against MCF-7 Cell Lines 1 1 1 1 2 1 1 1Watkins EB et al, Current Phamaceutical Design, 2005; 2Hoffman J Breast Cancer Res Treat Abstract 1103, 2006
IC50 Values (nM) for Net Growth Inhibition of Human Carcinoma Cell Lines by Epothilones A and B in Comparison to Paclitaxel Altmann et al Biochim Biophys Acta 2000
Ixabepilone: Phase II Data in Breast Cancer 45 42 30 22 ORR (%) 19 18 pCR 15 12 0 Roché1 After adjuvant anthra Low2 Taxane-pretreated MBC Conte3 Taxane-resistant MBC Thomas4 Multiresistant(anthra / tax / cape) MBC Baselga5 Neoadjuvant T2-4, N0-3, M0 1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol 2005;23:2726–34. 3. Conte P et al. J Clin Oncol 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol 2006;24(18S):abstr 660. 5. Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.
Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 60 BMS 010 40 BMS 081 20 BMS 031 0 Neutropenia Grade 3/4 neutropenia 35 to 58%
Ixabepilone: Grade 3/4 Toxicity in MBC Febrile neutropenia 3-14% with 14 % on NCI0229
Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 60 BMS 010 40 BMS 081 20 BMS 031 0 FN PN Neutropenia Sensory neuropathy ranged from 3-22%
Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 60 BMS 010 40 BMS 081 20 BMS 031 0 FN PN Myalgias Neutropenia Severe myalgias range from 3-26%
100 80 BMS 009 NCI 0229 60 BMS 010 40 BMS 081 20 BMS 031 0 FN PN Fatigue Myalgias Neutropenia Ixabepilone: Grade 3/4 Toxicity in MBC Fatigue variable at 6 to 34%
Ixabepilone: Grade 3/4 Toxicity in MBC Diarrhea at 1 to 11%