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Highlights in the Management of Breast Highlights in the Management of Breast CancerCancer
Nanoparticles incapsulated drugs Nanoparticles incapsulated drugs
Alessandra FabiAlessandra Fabi
Medical OncologyMedical Oncology
Rome, 10 May Rome, 10 May 20132013
Mediterranean School of Mediterranean School of OncologyOncology
Trasmission electronic Trasmission electronic Microscopy of nab-Microscopy of nab-
paclitaxel paclitaxel nanoparticlesnanoparticles
Piccart, APJOH 2009 Piccart, APJOH 2009
Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel
Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel
Paclitaxel
Albumin
Mean = 130 nm
cryo-TEM
Concentration dependent dissociation into individual
paclitaxel-bound albumin molecules
Paclitaxel exists in the
albumin particle
in an non-crystalline,
amorphous state
Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24
Athymic mice with human xenografts (n = 10 per group; daily administration for 5 days)Athymic mice with human xenografts (n = 10 per group; daily administration for 5 days)
Breast MX-1 tumor modelBreast MX-1 tumor modelequidose paclitaxel comparisonequidose paclitaxel comparison
0 10 20 30 40 50 60 70 80 90 100 1100
250
500
750
1000
1250
1500
1750
2000 Control
ABI-007 30 mg/kg/dose
Taxol 30 mg/kg/dose
Days postimplant
Tum
or v
olum
e (m
m3 )
0 10 20 30 40 50 60 70 80 90 100 1100
250
500
750
1000
1250
1500
1750
2000 Control
ABI-007 30 mg/kg/dose
Taxol 30 mg/kg/dose
Days postimplant
Tum
or v
olum
e (m
m3 )
Abraxane 30 mg/kg/dose
Taxol 30 mg/kg/dose
0 10 20 30 40 50 60 70 80 90 100 1100
250
500
750
1000
1250
1500
1750
2000 Control
ABI-007 30 mg/kg/dose
Taxol 30 mg/kg/dose
Days postimplant
Tum
or v
olum
e (m
m3 )
0 10 20 30 40 50 60 70 80 90 100 1100
250
500
750
1000
1250
1500
1750
2000 Control
ABI-007 30 mg/kg/dose
Taxol 30 mg/kg/dose
Days postimplant
Tum
or v
olum
e (m
m3 )
0 10 20 30 40 50 60 70 80 90 100 1100
250
500
750
1000
1250
1500
1750
2000 Control
ABI-007 30 mg/kg/dose
Taxol 30 mg/kg/dose
Days postimplant
Tum
or v
olum
e (m
m3 )
0 10 20 30 40 50 60 70 80 90 100 1100
250
500
750
1000
1250
1500
1750
2000 Control
ABI-007 30 mg/kg/dose
Taxol 30 mg/kg/dose
Days postimplant
Tum
or v
olum
e (m
m3 )
Abraxane 30 mg/kg/dose
Taxol 30 mg/kg/dose
Preclinical Finding: Replacing Cremophor with Albumin Enhanced the Efficacy of Paclitaxel in Breast Cancer
Nab-paclitaxel Results in Higher Intra-tumoral Concentration Compared to Taxol
ABI-007 = 1.33 X TaxolABI-007 = 1.33 X Taxol
Desai et al. Clin Can Res, 2006.Desai et al. Clin Can Res, 2006.
Intratumor paclitaxel levels following equal doses ABI-007 and Taxol Intratumor paclitaxel levels following equal doses ABI-007 and Taxol in nude mice bearing MX-1 human breast cancer xenograftsin nude mice bearing MX-1 human breast cancer xenografts
Nab-paclitaxel
✔✔ Clinical dataClinical datamono and combination: efficacy and mono and combination: efficacy and
toxicity in toxicity in breast cancerbreast cancer
Is there the patient Is there the patient who could better benefit??
Future directionsFuture directions
The other clinical fieldsThe other clinical fields
Studies Study Arm Standard Arm End-point
Patients
Gradishar 05
Fase III
NAB-P;260 mg/mq q3W
Paclitaxel175 mg/mq q3w
ORR 1-2+ line;Previous AnthracyclineNo previous taxanes
Gradishar 09
R Fase II
NAB-P300 mg/mq q3w100 mg/mq 3q4w150 mg/mq 3q4w
Docetaxel100mg/mq q3w
ORR 1 line;No previous therapy;Adjuvant 1 year before
clinical data in BC
Nab-paclitaxel as single agent
Phase III Random (1:1)n = 460
nab-paclitaxel 260 mg/m2
Every 3 weeksn = 233
paclitaxel 175 mg/m2 Every 3 weeks
n = 227
Misurable diseaseNo taxanes for metastatic diseaseDFI >1 y from adjuvant taxanes
Gradishar et al. J Clin Oncol 2005; 23:7794-803
Primary end point: ORr, SafetyPrimary end point: ORr, Safety
Secondary end-poit: PFS, OSSecondary end-poit: PFS, OS
Previous Therapies
nab-Paclitaxel
n=229
Paclitaxeln=225
Taxanes Adjuvant or metastatic with taxanes 0% 0%
Adjuvant or metastatic Anthracyclines 77% 78%
Metastatic Anthracycline 50% 58%Previous MBC CT
Nihil1 2 ≥ 3
42%41%10%7%
40%43%16%2%
Gradishar et al. J Clin Oncol 2005; 23:7794-803
Response rateResponse rate
nab-paclitaxel: 229 97 132 176 176paclitaxel: 225 89 136 175 182
ORR, tasso di risposta globale
All patients I line II line anthracyclines visceral disease
P=0,001
0
10
20
30
40
50
60
33,2%
27,0%
42,3%
18,7%
P=0,029
26,5%
13,2%
P=0,006
34,1%
18,3%
33,5%
P=0,002 P=0,002
18,7%
ORR
(± IC
al 9
5%)
Gradishar et al. J Clin Oncol 2005; 23:7794-803
1.00
0.75
0.50
0.25
0.00
Time To disease Progression
Note: P value log-rank test
NAB-P (n = 229)
Solvent-based paclitaxel (n = 224)
Median = 23.0 wks(19.4–26.1)
Mediana = 16.9 wks(15.1–20.9)
P = 0.006HR = 0.75
Pro
po
rtio
n w
tho
ut
pro
gre
ssio
n
weeks
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120
Gradishar et al. J Clin Oncol 2005; 23:7794-803
Overall SurvivalOverall Survival
Gradishar et al. J Clin Oncol. 2005; 23: 7794–7803
Note: P value log-rank test
Median = 65.0 wks(52.1–76.9)
NAB-P (n = 229)
Solvent-based paclitaxel (n = 225)
1.00
0.75
0.50
0.25
0.00
Pro
bab
ilit
y o
f s
urv
iva
l
weeks
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144
Median = 55.7 wks(48.0–66.4)
P = 0.374HR = 0.90
1.00
0.75
0.50
0.25
0.00
weeks
0 8 16 24 32 40 48 56 64 72 80 88 96 104112120128136144
Overall Survival in pts ≥ 2a-line
Note: P value log-rank test
Nab-P (n = 131)
Solvent-based paclitaxel (n = 136)
P = 0.024HR = 0.73
Median = 46.7 wks(39.0–55.3)
Median = 56.4 wks(45.1–76.9)
Gradishar et al. J Clin Oncol. 2005; 23: 7794–7803
Pro
bab
ilit
y o
f s
urv
iva
l
SafetySafetynab-Paclitaxel
n=229Paclitaxel
n=225
AE (%) Grade Grade
3 4 3 4 p
Neutropenia 25 9 32 22 < 0,001
Thrombocytopenia < 1 0 < 1 0 0,290
Anemia < 1 < 1 0 < 1 0,279
Febbrile Neutropenia < 1 < 1 < 1 0 0,491
Death for sepsis 0 0 –
Gradishar et al. J Clin Oncol 2005; 23:7794-803
nab-Paclitaxel
n=229
Paclitaxel n=225
AE (%) Grade Grade p
2 3 4 2 3 4
Ipersensibility† < 1 0 0 0 1 0 0,150
Hot flash < 1 0 0 5 0 0 < 0,001
Sensorial Neuropaty 20 10 0 10 2 0 < 0,001
Fatigue 13 8 < 1 16 3 < 1 0,062
Mialgie 12 7 0 15 2 0 0,567
Emesis 4 3 < 1 4 1 0 0,022
Aedema 2 0 0 < 1 < 1 0 0,851
Neuropaty and nab-paclitaxel : time of Neuropaty and nab-paclitaxel : time of durationduration
1,00
0,75
0,50
0,25
0,00Days from grade 3 to 1
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140
% o
f u
nre
so
lve
d c
as
es
nab-Paclitaxel (n=24)
++
++
++++
● improvement: medain 22 days (95%CI 17-22) vs 79 days of paclitaxel
● 3% of pts (6/233) discontinued therapy with nab-paclitaxel due to sensorial neuropaty. No case of motor neuropaty
Gradishar et al. J Clin Oncol 2005; 23:7794-803
Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for MBC
302 MBC pts in I line therapy
Braccio A (n = 76): nab-paclitaxel 300 mg/m2 ogni 3 settimane
Braccio B (n = 76): nab-paclitaxel 100 mg/m2 alla settimana
x 3/ogni 4 settimane
Braccio C (n = 74): nab-paclitaxel 150 mg/m2 alla settimana x 3/ogni 4 settimane
Braccio D (n = 74): docetaxel 100 mg/m2 ogni 3 settimane
R
A
N
D
O
M
I
Z
E
nab-paclitaxel versus docetaxel(A,B,C vs D)
nab-paclitaxelqw versus q3w(B,C vs A)nab-paclitaxel bassa vs alta dose qw(B vs C)
Comparing
Endpoint primario: ORR
Arms A, C e D somministrati alla MTD3q4w, ripetuta wkly per 3 wks / 4 Gradishar et al. J Clin Oncol 2009;27:3611–3619
Response RateResponse Rate
Gradishar et al. J Clin Oncol 2009;27:3611–3619
37
4549
35
46
63
74
39
0
10
20
30
40
50
60
70
80
300 mg/m2 q3w 100 mg/m2 qw 150 mg/m2 qw 100 mg/m2 q3w
Independent
Investigator
P=0.024
P<0.001P=0.002
% o
f p
atie
nts
nab-Paclitaxel Docetaxel
n=302
*
° nab-paclitaxel 150 mg/m2 versus docetaxel P = 0,001* nab-paclitaxel 100 mg/m2
versus docetaxel P = 0,002
Progression Free Survival
Gradishar et al. J Clin Oncol 2009;27:3611–3619
Overall Survival
1.00
0.75
0.50
0.25
010 20 30 40 50
Months
0
HR = 0.688
1. Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].2. Gradishar et al. J Clin Oncol. 2009;27(22):3611-3619.
• The 150 mg/m2 qw NAB-paclitaxel arm demonstrated a numerically longer OS versus docetaxel (not statistically significant)
NAB-paclitaxel 300 mg/m2 q3w and 100 mg/m2 qw arms not shownOS calculated when 58% of patients had died.HR, hazard ratio; OS, overall survival; qw 3/4, first 3 of 4 weeks; q3w, every 3 weeks.
NAB-paclitaxel 150 mg/m2 qw 3/4 (n = 74)
Docetaxel 100 mg/m2 q3w (n = 74)
26.6 33.8
For the purpose of clarity, only these 2 (out of 4) patient groups were
included here.
+7.2+7.2
qw or q3w ABRAXANE® vs q3w docetaxel: toxicity†
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
ABRAXANE® Docetaxel
300 mg/m2 q3w (n = 76)
100 mg/m2 qw (n = 76)
150 mg/m2 qw (n = 74)
100 mg/m2 q3w (n = 74)
Neuropatia, n (%)
grade 2 17 (22) 11 (14) 19 (26) 14 (19)
grade 3 13 (17) 6 (8) 10 (14) 9 (12)
grade 4 0 (0) 0 (0) 0 (0) 0 (0)
Fatigue, n (%)
grade 2 17 (22) 5 (7) 15 (20) 12 (16)
grade 3 4 (5) 0 (0) 2 (3) 14 (19)
grade 4 0 (0) 0 (0) 0 (0) 0 (0)
† reported in ≥ 25% of patients
ASCO Breast Symposium, Abstract # 275
nab-paclitaxel 150 mg/m2 qw ¾ demonstreted the best as I line MBC
Final Overall Survival Analysis of a Randomized Phase 2 Trial
O’Shaughnessy et al, Poster P1-12-07, San Antonio 2012
Who patients could better benefit
Visceral metastasesVisceral metastasesShort DFIShort DFI
Weekly nab-paclitaxel is safe and effective in 65 years old patientswith metastatic breast cancer:
A post-hoc analysis
Matti Aapro, Sergei Tjulandin, Paul Bhar, William Gradishar
ORr - DCR
In the phase 2 study
ORR nab-paclitaxel 22% 300 mg/m2 q3w
64% 100 mg/m2 weekly
60% 150 mg/m2 weekly
docetaxel 32% 100 mg/m2 q3w
In the phase 3 study
ORR nab-paclitaxel 27% 260 mg/m2 q3w
paclitaxel 19% 175 mg/m2 q3w
Aapro M et al, The Breast 2011
In the phase 2 study
DCR nab-paclitaxel 56% 300 mg/m2 q3w
86% 100 mg/m2 weekly
90% 150 mg/m2 weekly
docetaxel 79% 100 mg/m2 q3w
In the phase 3 study
DCR nab-paclitaxel 53 % 260 mg/m2 q3w
paclitaxel 41% 175 mg/m2 q3w
PFS
In the phase 3 study
PFS median nab-paclitaxel 5.6 260 mg/m2 q3w
paclitaxel 3.5 175 mg/m2 q3w
Aapro M et al, The Breast 2011
In the phase 2 studyPFS median nab-paclitaxel 13.8 300 mg/m2 q3w
9.2 100 mg/m2 weekly 18.9 150 mg/m2 weekly
docetaxel 8.5 100 mg/m2 q3w
Combination therapy
Phase II combinationsPhase II combinationsNab-P + gemcitabine
I line ORr 50%PFS 7.9 mos
Roy et al. Ann Oncol 2009;20:449–453
Nab-P + capecitabine
I line ORr 61%PFS 8.2 mos
Somer et al. Presented at ASCO Meeting 2007; Abstract 1053
Nab-P + trastuzumab + carboplatin
I lineHER2+
ORr 63%PFS 16.6 mos
Conlin et al. Clin Breast Cancer 2010; 281-7
Nab-P + lapatinib II lineHER2+
ORr 54%PFS 9.3. mos
Yardley et al. SABCS 2011
Nab-P + Bevacizumab
I line ORr 75.9%PFS 10.7 mos
Lobo et al. Breast Cancer Res Treat 2010
Considerations
• The actual indication of NAB-paclitaxel is at three-weekly
schedule (260 mg/m2), but the evidences justify the weekly
administration (150, 125, 100 mg/m2 )
• Clinical data support the use of NAB-paclitaxel in MBC from the
1- line, also for pts pretreated with taxanes in adjuvant
setting, relapsed or refractory
• The sensorial neuropaty usual occur late in course of
treatment, and it can be manage with dose reduction, short drug
interruption and rapidly improve
• Future marker will be evaluated, such as caveolin and SPARC
Future DirectionsFuture Directions
Targeted therapyTargeted therapy
Piccart, APJOH 2009 Piccart, APJOH 2009
Phase III in first - line Phase III in first - line NSCLC: NSCLC: nabnab-Paclitaxel + -Paclitaxel + carboplatin demonstrated carboplatin demonstrated improved activity vs improved activity vs conventional paclitaxel + conventional paclitaxel + carboplatincarboplatin
ORr: 41% vs 24% (p=.005)ORr: 41% vs 24% (p=.005)
higher in squamous higher in squamous subtypesubtype
Lung Lung Cancer Cancer
Phase III in first-line metastatic Phase III in first-line metastatic melanoma:melanoma:nab-paclitaxel vs dacarbazinenab-paclitaxel vs dacarbazine
PFS: 4.8 vs 2.5 mos (p=.04)PFS: 4.8 vs 2.5 mos (p=.04)
MelanomaMelanomaBreast Breast CancerCancer
First approved in the US in First approved in the US in 2005 and in the EU in 2008 for 2005 and in the EU in 2008 for the treatment of MBC.the treatment of MBC.
nab®-Paclitaxel Improves Clinical Outcomes Across Multiple Tumor Types, Including Historically Non-Taxane Sensitive Tumors1-9
Pancreatic Pancreatic CancerCancer
Phase III trial IMPACT: Phase III trial IMPACT: nabnab--paclitaxel + gemcitabine vs paclitaxel + gemcitabine vs gemcitabine alone. gemcitabine alone.
OS: 14.8 vs 11.5 mosOS: 14.8 vs 11.5 mos
(p=.0000015)(p=.0000015)
nabnab®® is a registered trademark of Celgene Corporation.is a registered trademark of Celgene Corporation.
1.1. Gradishar et al. Gradishar et al. J Clin OncolJ Clin Oncol. 2009;27(22):3611-3618.. 2009;27(22):3611-3618.2.2. Gradishar et al. Gradishar et al. J Clin OncolJ Clin Oncol. 2005;23(31):7794-7803.. 2005;23(31):7794-7803.
3.3. Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].4.4. Von Hoff et al. Published online ahead of print October 3, 2011. Von Hoff et al. Published online ahead of print October 3, 2011.
J Clin OncolJ Clin Oncol. doi: 10.1200/JCO.2011.36.5742.. doi: 10.1200/JCO.2011.36.5742.5.5. Burris et al. Burris et al. J Clin OncolJ Clin Oncol. 1997;15(6):2403-2413.. 1997;15(6):2403-2413.
6.6. Hersh et al. Hersh et al. CancerCancer. 2010;116(1):155-163.. 2010;116(1):155-163.7.7. Boasberg et al. ASCO. 2011 [Abstract 8543].Boasberg et al. ASCO. 2011 [Abstract 8543].
8.8. Kottschade et al. ASCO. 2011 [Abstract 8532].Kottschade et al. ASCO. 2011 [Abstract 8532].9.9. Socinski et al. ASCO. 2010 [Abstract LBA7511].Socinski et al. ASCO. 2010 [Abstract LBA7511].
Comparing views of patients with those of doctors, nurses and general public
Slevin ML, Br Med J 300:1458, 1990
Respondents accepting intensive treatments Respondents accepting intensive treatments with a supposed minimum chance of effectivenesswith a supposed minimum chance of effectiveness
Thanks for attentionThanks for attention