Overview of Nanoparticle Albumin Bound (nabTM)-Paclitaxel

1
Highlights in the Management of Breast
Cancer Nanoparticles incapsulated drugs
Alessandra Fabi Medical Oncology
Mediterranean School of Oncology
Rome, 10 May 2013
2
Trasmission electronic Microscopy of
nab-paclitaxel nanoparticles
Piccart, APJOH 2009
3
Nab-paclitaxel is Albumin-bound Cremophor-free
Paclitaxel
Albumin
cryo-TEM
Paclitaxel exists in the albumin particle in an
non-crystalline, amorphous state
Mean 130 nm
Concentration dependent dissociation into
individual paclitaxel-bound albumin molecules
Paclitaxel
4
Preclinical Finding Replacing Cremophor with
Albumin Enhanced the Efficacy of Paclitaxel in
Breast Cancer
Breast MX-1 tumor model equidose paclitaxel
comparison
Athymic mice with human xenografts (n 10 per
group daily administration for 5 days)
Desai N, et al. Clin Cancer Res 200612(4),
1317-24
5
Nab-paclitaxel Results in Higher Intra-tumoral
Concentration Compared to Taxol
Intratumor paclitaxel levels following equal
doses ABI-007 and Taxol in nude mice bearing MX-1
human breast cancer xenografts
ABI-007 1.33 X Taxol
Desai et al. Clin Can Res, 2006.
6
Nab-paclitaxel

• ? Clinical data
• mono and combination efficacy and toxicity in
  breast cancer
• Is there the patient who could better benefit?
• Future directions
• The other clinical fields

7
clinical data in BC Nab-paclitaxel as single
agent
Studies Study Arm Standard Arm End-point Patients
Gradishar 05 Fase III NAB-P 260 mg/mq q3W Paclitaxel 175 mg/mq q3w ORR 1-2 line Previous Anthracycline No previous taxanes
Gradishar 09 R Fase II NAB-P 300 mg/mq q3w 100 mg/mq 3q4w 150 mg/mq 3q4w Docetaxel 100mg/mq q3w ORR 1 line No previous therapy Adjuvant 1 year before
8
nab-paclitaxel 260 mg/m2 Every 3 weeks n 233
Phase III Random (11)n 460
paclitaxel 175 mg/m2 Every 3 weeks n 227
Primary end point ORr, Safety Secondary
end-poit PFS, OS
Misurable disease No taxanes for metastatic
disease DFI gt1 y from adjuvant taxanes
Gradishar et al. J Clin Oncol 2005 237794-803
9
Previous Therapies
nab-Paclitaxel n229 Paclitaxel n225
Taxanes Adjuvant or metastatic with taxanes 0 0
Adjuvant or metastatic Anthracyclines 77 78
Metastatic Anthracycline 50 58
Previous MBC CT Nihil 1 2 3 42 41 10 7 40 43 16 2
Gradishar et al. J Clin Oncol 2005 237794-803
10
Response rate
60
P0,001
P0,029
P0,006
P0,002
P0,002
50
42,3
40
34,1
33,2
33,5
ORR ( IC al 95)
30
27,0
26,5
18,7
18,7
18,3
20
13,2
10
0
All patients I line II line anthracyclines viscera
l disease
nab-paclitaxel 229 97 132 176 176paclitaxel 225
89 136 175 182
ORR, tasso di risposta globale
Gradishar et al. J Clin Oncol 2005 237794-803
11
Time To disease Progression
NAB-P (n 229)
Solvent-based paclitaxel (n 224)
P 0.006 HR 0.75
Median 23.0 wks (19.426.1)
Proportion wthout progression
Mediana 16.9 wks (15.120.9)
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120

weeks
Note P value log-rank test
Gradishar et al. J Clin Oncol 2005 237794-803
12
Overall Survival
NAB-P (n 229)
Solvent-based paclitaxel (n 225)
P 0.374 HR 0.90
Median 65.0 wks (52.176.9)
Probability of survival
Median 55.7 wks (48.066.4)
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 1
28 136 144
weeks
Note P value log-rank test
Gradishar et al. J Clin Oncol. 2005 23
77947803
13
Overall Survival in pts 2a-line
Nab-P (n 131)
Solvent-based paclitaxel (n 136)
P 0.024 HR 0.73
Median 56.4 wks (45.176.9)
Probability of survival
Median 46.7 wks (39.055.3)
Note P value log-rank test
Gradishar et al. J Clin Oncol. 2005 23
77947803
14
Safety
nab-Paclitaxel n229 nab-Paclitaxel n229 Paclitaxel n225 Paclitaxel n225
AE () Grade Grade Grade Grade
3 4 3 4 p
Neutropenia 25 9 32 22 lt 0,001
Thrombocytopenia lt 1 0 lt 1 0 0,290
Anemia lt 1 lt 1 0 lt 1 0,279
Febbrile Neutropenia lt 1 lt 1 lt 1 0 0,491
Death for sepsis 0 0
nab-Paclitaxel n229 nab-Paclitaxel n229 nab-Paclitaxel n229 Paclitaxel n225 Paclitaxel n225 Paclitaxel n225
AE () Grade Grade Grade Grade Grade Grade p
2 3 4 2 3 4
Ipersensibility lt 1 0 0 0 1 0 0,150
Hot flash lt 1 0 0 5 0 0 lt 0,001
Sensorial Neuropaty 20 10 0 10 2 0 lt 0,001
Fatigue 13 8 lt 1 16 3 lt 1 0,062
Mialgie 12 7 0 15 2 0 0,567
Emesis 4 3 lt 1 4 1 0 0,022
Aedema 2 0 0 lt 1 lt 1 0 0,851
Gradishar et al. J Clin Oncol 2005 237794-803
15
Neuropaty and nab-paclitaxel time of duration

• improvement medain 22 days (95CI 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

nab-Paclitaxel (n24)

1,00 0,75 0,50 0,25 0,00



of unresolved cases
0 10 20 30 40 50 60 70
80 90 100 110 120 130 140
Days from grade 3 to 1

Gradishar et al. J Clin Oncol 2005 237794-803
16
Significantly longer progression-free survival
with nab-paclitaxel compared with docetaxel as
first-line therapy for MBC
302 MBC pts in I line therapy
R A N D OMI ZE
Braccio A (n 76) nab-paclitaxel 300 mg/m2
ogni 3 settimane
Comparing
nab-paclitaxel versus docetaxel (A,B,C vs D)
Braccio B (n 76) nab-paclitaxel 100 mg/m2
alla settimana x 3/ogni 4 settimane
nab-paclitaxel qw versus q3w (B,C vs A)
Braccio C (n 74) nab-paclitaxel 150
mg/m2 alla settimana x 3/ogni 4 settimane
nab-paclitaxel bassa vs alta dose qw (B vs C)
Braccio D (n 74) docetaxel 100 mg/m2 ogni 3
settimane
Endpoint primario ORR
Arms A, C e D somministrati alla MTD3q4w,
ripetuta wkly per 3 wks / 4
Gradishar et al. J Clin Oncol 20092736113619
17
Response Rate
P0.002
Plt0.001
P0.024
n302

of patients
nab-Paclitaxel
Docetaxel
nab-paclitaxel 150 mg/m2 versus docetaxel P
0,001 nab-paclitaxel 100 mg/m2 versus docetaxel
P 0,002
Gradishar et al. J Clin Oncol 20092736113619
18
Progression Free Survival
Gradishar et al. J Clin Oncol 20092736113619
19
Overall Survival
NAB-paclitaxel 150 mg/m2 qw 3/4 (n 74)
Docetaxel 100 mg/m2 q3w (n 74)
7.2
26.6
33.8
HR 0.688
For the purpose of clarity, only these 2 (out of
4) patient groups were included here.

• 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 shown OS 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.
1. Gradishar et al. ASCO Breast Cancer Symposium.
2011 Abstract 275. 2. Gradishar et al. J Clin
Oncol. 200927(22)3611-3619.
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qw or q3w ABRAXANE vs q3w docetaxel toxicity
ABRAXANE ABRAXANE 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
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
21
Final Overall Survival Analysis of a Randomized
Phase 2 Trial
nab-paclitaxel 150 mg/m2 qw ¾ demonstreted the
best as I line MBC
ASCO Breast Symposium, Abstract 275
22
Who patients could better benefit
Visceral metastases
Short DFI
OShaughnessy et al, Poster P1-12-07, San Antonio
2012
23
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

24
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

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
Aapro M et al, The Breast 2011
25
PFS
In the phase 2 study PFS 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

• 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
26
Combination therapy
27
Phase II combinations Phase II combinations Phase II combinations Phase II combinations
Nab-P gemcitabine I line ORr 50 PFS 7.9 mos Roy et al. Ann Oncol 200920449453
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 line HER2 ORr 63 PFS 16.6 mos Conlin et al. Clin Breast Cancer 2010 281-7
Nab-P lapatinib II line HER2 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
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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

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Future Directions Targeted therapy
Piccart, APJOH 2009
30
nab-Paclitaxel Improves Clinical Outcomes Across
Multiple Tumor Types, Including Historically
Non-Taxane Sensitive Tumors1-9

1. Gradishar et al. J Clin Oncol. 200927(22)3611-36
   18.
2. Gradishar et al. J Clin Oncol. 200523(31)7794-78
   03.
3. Gradishar et al. ASCO Breast Cancer Symposium.
   2011 Abstract 275.
4. Von Hoff et al. Published online ahead of print
   October 3, 2011. J Clin Oncol. doi
   10.1200/JCO.2011.36.5742.
5. Burris et al. J Clin Oncol. 199715(6)2403-2413.
6. Hersh et al. Cancer. 2010116(1)155-163.
7. Boasberg et al. ASCO. 2011 Abstract 8543.
8. Kottschade et al. ASCO. 2011 Abstract 8532.
9. Socinski et al. ASCO. 2010 Abstract LBA7511.

nab is a registered trademark of Celgene
Corporation.
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Comparing views of patients with those of
doctors, nurses and general public
Respondents accepting intensive treatments with
a supposed minimum chance of effectiveness
Slevin ML, Br Med J 3001458, 1990
32
Thanks for attention