Transcript Targeting Microtubules: new drugs in the clinic
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
Microtubule Structure and Assembly
+ b a –
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 Agent Paclitaxel Epothilones Discodermolide Eleutherobin Sarcodictyins Taccalonolide Laulimalide Source Pacific yew Myxobacteria Sponge Corals Corals Plant Sponge Latin Name Taxus brevifolia Sorangium cellulosum Discodermia dissoluta Eleutherobin aurea Sarcodictyon roseum Tacca plantagine/chantrieri Fasciospongia rimosa Cacospongia mycofijiensis
Partial Listing of Drugs That Target Microtubules • Vinca alkaloids • Taxanes • Epothilones
nab
-paclitaxel
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
nab
-platform Utilizes Endogenous Albumin Pathways of Endothelial Transcytosis (gp60) and Intratumoral Binding of SPARC
Albumin-Bound Drug
Tumor endothelial cell
Gp60 Receptor
Albumin-drug complex TUMOR BLOOD VESSEL TUMOR INTERSTITIUM SPARC on Tumor cell surface Alb-drug complex transcytosed by gp60 Internalized SPARC/Alb-drug complex
Caveolae
Surface SPARC bound to Alb-drug complex
SPARC
Tumor cells
Albumin-Drug Accumulation
A Pharmacokinetic Comparison of
nab
-paclitaxel and Paclitaxel
PK Comparison-linearity Total Paclitaxel
nab
-paclitaxel: 30 min infusion Linear, predictable PK
Dose
(mg/m 2 ) % δ
Cmax
(ng/ml) % δ
AUC
(ng*hr/ml) % δ
CL
(L/h/m 2 ) % δ 135 175 ---- 3071 ----
30
5202
70
8604 15048 ----
75
15.9
11.6
----
25
Paclitaxel: 3 hr infusion Non-linear, less-predictable PK
Clinical PK Comparison of Total Paclitaxel Study C008-0 15000 10000
nab-paclitaxel (dose-adjusted to 175 mg/m 2 ) paclitaxel (175 mg/m 2 )
5000 0 0 5 Hours 10
Clinical Studies
nab
-paclitaxel Trial Ibrahim 1 No. pts 63 Setting Schedule No limit 300 mg/m 2 Q3w RR (%) 48 Med TTP (wks) 27 Mirtschung 2 23 Gradishar 3
nab-
paclitaxel vs paclitaxel 460 1st line 125 mg/m 2 QW (3 out of 4 wks) 57 1st line 260 mg/m 2 vs. 175 mg/m 2 Q 3W
33
vs 19 NR
23
vs 17 Significant differences in Bold; RR= response rate, TTP= time to progression; NR= not reported 1 Ibrahim, JCO 2005; 2 Mirtschung Breast Ca Res Treat Suppl 2006; 3 Gradishar 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
R A
( A, B, C vs.
D )
N D
weekly vs. every-3 weeks
nab
-paclitaxel ( B, C vs. A )
O M I
( low vs. high dose weekly
nab
Z
-paclitaxel B vs.
C )
E Arm A
:
nab
-paclitaxel 300 mg/m 2 q3w
Arm B
weekly 3 out of 4 Arm C: nab weekly 3 out of 4
Arm D
:
nab
-paclitaxel 100 mg/m -paclitaxel 150 mg/m : docetaxel 100 mg/m 2 2 2 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 MBC and no previous chemotherapy for metastatic disease (N = 300)
ABX
300 mg/m 2 every 3 wks (N = 76)
ABX
100 mg/m 2 wkly for 3 of 4 wks (N = 76)
ABX
150 mg/m 2 wkly for 3 of 4 wks (N = 74)
Docetaxel
100 mg/m 2 every 3 wks (N = 74) Gradishar W, et al. ASCO 2007. Abstract 1032.
Comparison of Investigator and Independent Radiology Review Response Assessments
80% 70% Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507
70%
Investigator IRR
60% 62% 50% 47% 40% 43% 45% 38% 30% 35% 28% 20% 10% 0%
300 mg/m 2 q3w ( A : N = 76) 100 mg/m 2 qw 3/4 ( B : N = 76) 150 mg/m 2 qw 3/4 ( C : N = 74) docetaxel 100 mg/m 2 q3w ( D : N = 74)
nab-paclitaxel
Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.
Phase II Study Evaluating Various Doses of
nab
paclitaxel vs. Docetaxel (cont’d) 100 90 80 70 60 50 40 30 20 10 0
43
n = 76
P
= .007
P
= .016
62
76
P
= .002
70
P
= .003
Treatment
74
38
74 ABX 300 mg/m 2 q3w ABX 100 mg/m 2 qw3/4 ABX 150 mg/m 2 qw3/4 Docetaxel 100 mg/m 2 q3w Gradishar W, et al. ASCO 2007. Abstract 1032.
Phase II Study Evaluating Various Doses of
nab
paclitaxel vs. Docetaxel (cont’d) • PFS statistically superior with 150 mg/m 2 (
P
= .002) and 300 mg/m 2
nab
paclitaxel (
P
= .046) compared with docetaxel in MBC • PFS statistically superior with 150 mg/m 2
nab
-paclitaxel compared with 100 mg/m 2
nab
-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/m 2 vs. docetaxel 100 mg/m 2 in MBC planned 1.0
0.75
0.50
Progression-free Survival Investigator Assessments
A B C D 0.25
0.0
0 75% of patients off-study 3 6 9
Months
12 15 18 Gradishar W, et al. ASCO 2007. Abstract 1032.
nab
-paclitaxel: Grade 3/4 Toxicity in MBC Grade 3/4 Neutropenia 19-37%
100 80 60 40 20 0 N eu tr op en ia
Docetaxel 100 mg/m 2 q3w 21-74%
300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW
nab
-paclitaxel: Grade 3/4 Toxicity in MBC Febrile Neutropenia 1%
100 80 60 40 20 0 N eu tr op en ia FN
Docetaxel 100 mg/m 2 q3w 7%
300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW
nab
-paclitaxel: Grade 3/4 Toxicity in MBC Peripheral neuropathy 7-14 %
100 80 60 40 20 0 N eu tr op en ia 300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW FN PN
100 mg/m ² QW least neuropathy compared to two other
nab
-paclitaxel arms Docetaxel 100 mg/m 2 q3w 5%
Time to Improvement in Peripheral Neuropathy 1.00
0.75
nab-
paclitaxel 300 mg/m 2 q3w (N = 13)
nab-
paclitaxel 100 mg/m 2 weekly (N = 7)
nab-
paclitaxel 150 mg/m 2 weekly (N = 12) Docetaxel 100 mg/m 2 ( N = 8) 0.50
A) Median, 16 days, 95% CI, 12 to 24 B) Median, 22 days, 95% CI, 14 to 25 C) Median, 23 days, 95% CI, 12 to 31 D) Median, 41 days, 95% CI, 37 to 44 0.25
0.00
0 20 40 Days 60 80 100 Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.
nab
-paclitaxel: Grade 3/4 Toxicity in MBC Fatigue 0-4 %
100 80 60 40 300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW 20 0 N eu tr op en ia FN PN Fa tig ue
100 mg/m 2 QW least neuropathy compared to two other
nab
-paclitaxel arms Docetaxel 100 mg/m 2 q3w 15%
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
Ixabepilone
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 • T 1/2 : 39 hours (range:17-50 hrs) Data: BMS data on file
Ixabepilone: Pharmacology Infusion duration (hr) Dose (mg/m 2 /day) Range MTD DLT Daily x 5Q21d Daily x 3 Q21d Weekly Once Q21 d 1 1 0.5-1 1 1.5 -8 6 8-10 8 1-30 25 Neutropenia, neuropathy 32-65 50 MTD: maximum tolerated dose; DLT: dose-limiting toxicity; Q: every Goodin et al, J Clin Oncol 22:2015, 2004
Pre-clinical Data
IC50 of Various Epothilones Against MCF-7 Cell Lines 7 6 5 4 3.26
3 2 1 0 Paclitaxel 1 2.04
Epo A 1 0.29
Epo B 1 2.31
Epo D 1 6.9
0.7
Epo F 1 1 ZK-EPO 2 1 Watkins EB et al, Current Phamaceutical Design, 2005; 2 Hoffman 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 19 18 pCR 15 12 0 Roch é After adjuvant anthra 1 Low 2 Taxane-pretreated Conte 3 Taxane-resistant MBC MBC Thomas 4 Multiresistant (anthra / tax / cape) MBC Baselga M0 5 Neoadjuvant T2-4, N0-3,
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 60 40 20 0 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 Grade 3/4 neutropenia 35 to 58%
Ixabepilone: Grade 3/4 Toxicity in MBC
100 80 60 40 20 0 N eu tr op en ia FN
Febrile neutropenia 3-14% with 14 % on NCI0229
BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031
Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 60 40 20 0 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 Sensory neuropathy ranged from 3-22%
Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 60 40 20 0 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 Severe myalgias range from 3-26%
Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 60 40 20 0 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 Fatigue variable at 6 to 34%
Ixabepilone: Grade 3/4 Toxicity in MBC
100 80 60 40 20 0
N eu tro pe ni a FN PN Mya lg ia s Fa tig ue D ia rrh ea Diarrhea at 1 to 11%
BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031
Case: Early Relapse After Adjuvant ACT • 53 y.o. woman with a h/o of a stage IIIB breast cancer – Left lumpectomy and AND T= 3.5 cm N= 6/25 ER/PR= pos/neg and HER2-neu negative by FISH – Received AC followed by paclitaxel Q2w – Received chest wall RT followed by anastrozole • Relapse in CW, lungs and liver 8 months after completing adjuvant therapy
Case: Early Relapse After Adjuvant ACT Which treatment option would you recommend?
nab
-paclitaxel Docetaxel Capecitabine Vinorelbine Ixabepilone
Case: Early Relapse After Adjuvant ACT Which treatment option would you recommend?
nab
-paclitaxel Docetaxel Capecitabine Vinorelbine Ixabepilone • Recommended Approach: Ixabepilone
±
capecitabine
Phase III Data
A Multicenter Phase III Clinical Trial Comparing Ixabepilone plus Capecitabine with Capecitabine Alone in Patients with Metastatic Breast Cancer Previously Treated with or Resistant to Anthracycline and Resistant to Taxanes Linda T. Vahdat, MD Weill Cornell Medical College New York, New York On Behalf of the 046 Study Investigators
Study Design: International, Randomized, Open-label, Phase III Trial Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes N = 752 Ixabepilone (40 mg/m 2 IV over 3 hr d1 q3wk) + ( 2000 Capecitabine mg/m 2 /day PO 2 divided doses d1-d14 q3wk) N = 375 ( 2500 Capecitabine mg/m 2 /day PO 2 divided doses d1-d14 q3wk) N = 377
Stratification
•Visceral metastases •Prior chemotherapy for MBC •Anthracycline resistance •Study site
Resistance to Prior Therapy
Strict definition
: patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines and taxanes Setting Metastatic Neo/adjuvant Any Anthracycline ≤3 months of last dose ≤6 months of last dose Minimum cumulative dose Doxorubicin: 240 mg/m 2 Epirubicin: 360 mg/m 2 Taxane ≤4 months of last dose ≤12 months of last dose
Patient Eligibility Criteria
Inclusion Criteria
• Women ≥18 years • Locally advanced or MBC • Anthracycline-resistant or minimum cumulative dose • Taxane-resistant • KPS 70–100 • Life expectancy ≥12 wk
Exclusion Criteria
• >3 prior chemo regimens (adjuvant and metastatic) • ≥G2 motor/sensory neuropathy • Reduced hematologic/ renal function • ≥G2 liver function tests* • CNS metastases *Protocol amendment excluded patients with ≥G2 liver function tests regardless of liver metastases; 377 patients (33 with ≥G2 liver function tests) had been enrolled before amendment
1.0
Progression-free Survival by Independent Radiologic Review
0.8
Ixabepilone + Capecitabine Capecitabine Median 5.8 mo 4.2 mo 95% CI (5.5
–7.0) (3.8
–4.5)
0.6
HR: 0.75 (0.64
–0.88)
P
=0.0003
0.4
0.2
0 0 4 8 12 16 20
Months
24 28 32 36
Response Rate % Response ORR (CR + PR) Stable disease Progressive disease Unable to determine Ixabepilone + Capecitabine N=375 Investigator Capecitabine N=377 Ixabepilone + Capecitabine N=375 IRR Capecitabine N=377 42 23 35 14
P
<0.0001
P
<0.0001
36 38 41 46 14 29 15 27 8 10 9 12
Grade 3/4 Non-hematologic Toxicities
80
Ixabepilone + Capecitabine (N = 369) Capecitabine (N = 368)
60 40 20 23 0 18 17 9 3 8 0.3
6 9 4 2 3 2 3 2 3 0 0
Epothilones in Development • • Patupilone (epothilone B): – – – Phase I trials in breast cancer in combination with other cytotoxics In preliminary efficacy data, toxicity included significant gastrointestinal effects New formulation appears to reduce toxicity • KOS-862 (epothilone D): – – – – Phase II trial in anthracycline- and taxane-pretreated metastatic breast cancer Of the 41 evaluable patients, 5 achieved a PR and 3 had SD Grade 3 neurotoxicity in 43 evaluable patients: neuropathy (12%) and ataxia (9%) Phase I trial combined with trastuzumab: • Unconfirmed response: 3/13 • Grade 3 neurotoxicity: 2/13 ZK-EPO: – – First fully synthetic third-generation epothilone Not recognized by efflux pumps; efficacy in preclinical models in taxane-resistant disease Cortes et al. J Clin Oncol 2006; 24(suppl):86s (abstract 2028).
Buzdar et al. Breast Cancer Res Treat 2005; 94(suppl 1):S69 (abstract 1087).Klar et al. Breast Cancer Res Treat 2005; 94(suppl 1):S64 (abstract 1072).
Case: Refractory Triple Negative Breast Cancer • 46 y.o. woman with a h/o stage I BC (T = 1.8 cm N = 0 ER/PR/HER 2 neu: negative diagnosed in 2000 • RLE and SLNB • AC x 4 Q3w followed by right breast RT • Did well until 2005 when developed soft tissue mass adjacent to sternum – Biopsy c/w recurrent BC ( ER/PR/HER2 neu negative) • Capecitabine: Initial response followed by POD in bone • Docetaxel: Initial response followed by POD in lungs and mediastinal LNs
Case: Refractory Triple Negative Breast Cancer Which treatment option would you recommend?
nab
-paclitaxel Gemcitabine Vinorelbine Ixabepilone
Case: Refractory Triple Negative Breast Cancer Which treatment option would you recommend?
nab
-paclitaxel Gemcitabine Vinorelbine Ixabepilone • Recommended Approach: Ixabepilone
Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Closing Remarks