Abraxane (paclitaxel albumin)

1
nab-paclitaxel in monoterapia
Dati clinici e safety
2
nab-paclitaxel in monoterapia
Studi clinici che hanno portato allindicazione
3
Gli studi pre-registrativi nell MBC
1. Ibrahim et al. Clin Cancer Res.
2002810381044 2. American BioScience, Inc.
Data on File3.Ibrahim et al. J Clin Oncol.
200523601960264. Gradishar et al. J Clin
Oncol. 20052377947803
4
Studi di Fase 1

• Phase I
• MTD, PK, etc.
• Phase II
• Phase III
• Registration RCT
• Other

5
Studio fase I DOSE FINDING

• No premedicazione steroidea
• No reazioni acute di ipersensibilità
• Tossicità Dose-limitanti da taxano a 375
  mg/m2 (neuropatia, cheratite, stomatite)
• Dose Massima Tollerata 300 mg/m2
• Durata infusione tollerabile 30 minuti
• AUCs lineari nel range di dose clinicamente
  rilevante

6
A new paradigm in cancer therapy the nabTM
platform
Phase I and Pharmacokinetic Study of ABI-007, a
cremophore-free, protein-stabilized, nanoparticle
formulation of paclitaxel

• Receptor-mediated transport (via gp60) and
  specific protein (SPARC) binding in tumour with
  the goal of improving efficacy and the
  therapeutic index
• Phase I studies were conducted to determine the
  safety, MTD and PK profile of this novel
  formulation

100 80 60 40 20 0
140 120 100 80 60 40
Paclitaxel
Mortality ()
Paclitaxel (nCi/g)
0 20 40 60 80 100
0.01 0.1 1 10 100
Dose (mg/kg)
Hrs
50 higher paclitaxel dose
33 higher intra-tumour paclitaxel
Ibrahim et al. Clin Cancer Res. 2002810381044
7
NAB-P was administered safely over 30 minu with
no HSR

• 19 patients treated
• No HSRs observed during the infusion period
• Haematological toxicity (characterised by ANC and
  PLT nadirs) mild and dose-dependent
• DLTs (in three of six patients treated at dose
  level 3) sensory neuropathy (n 3), stomatitis
  (n 2) and superficial keratopathy (n 2)
• MTD defined as 300 mg/m2

Dose level ANC nadir x 103/mm3 (range) PLT nadir x 103/mm3 (range)
0 2.229 (1.8505.040) 204 (174292)
1 1.845 (0.5863.729) 197 (118270)
2 0.960 (0.2643.680) 200 (105609)
3 0.966 (0.0181.804) 173 (25251)
ANC, absolute neutrophil count DLT,
dose-limiting toxicity HSR, hypersensitivity
reaction PLT, platelet
Ibrahim et al. Clin Cancer Res. 2002810381044
8
Paclitaxel PK for nab-Paclitaxel are Linear
Paclitaxel
nab-Paclitaxel
Paclitaxel AUC 3 hr1 Paclitaxel AUC 3
hr2 Paclitaxel AUC 1 hr3
nab-Paclitaxel4
50 000 45 000 40 000 35 000 30 000 25 000 20
000 15 000 10 000 5000 0
35 000 30 000 25 000 20 000 15 000 10 000 5000 0
y 3213e0.0095x R2 0.9328
y 3023.2e0.0089x R2 0.9683
AUCinf (ng hr/mL)
Mean AUCinf (ng hr/ml)
N 3 6 5 1 3 3 12 5 4
100 150 200 250 300
75 100 125 150 175 200 225 250 275 300 325 350 37
5
Dose (mg/m2)
nab-Paclitaxel dose (mg/m2)
1Kearns. Pharmacotherapy. 199717105S109S2Taxol
package insert3Ross et al. Cancer Chemother
Pharm. 20004nab-paclitaxel NDA
9
Studi di fase II

• Phase I
• MTD, PK, etc.
• Phase II
• Phase III
• Registration RCT
• Other

10

• nab-paclitaxel 300mg/m2 q 3w
• MBC w measurable disease
• No taxanes within past 6 months

11
nab-Paclitaxel Phase II Trial Purpose

• To evaluate the safety and antitumor activity of
  nab-Paclitaxel in MBC patients
• Treatment Regimen
• nab-paclitaxel 300 mg/m2 q3w, no standard
  pre-medication
• Primary endpoint
• tumor response rate (CR or PR)
• Secondary endpoints
• TTP
• OS
• Antitumor activity in anthracycline-naïve vs.
  anthracycline-exposed patients
• Changes in quality of life from baseline

Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
12

• Metodi Statistici
• Endpoint primario di efficacia basato su
  popolazione ITT
• Criteri Successo / Fallimento
• 30 tasso di risposta (ORR) per nab-paclitaxel in
  pazienti pre-trattati con anthracycline
• Tutti i pazienti che ricevevano una dose erano
  inclusi in analisi di risposta e tossicità

13
nab-paclitaxel Trial Fase II

• Pazienti
• N 63 pazienti con malattia misurabile CMM
• Precedente Taxano gt 6 mesi
• Caratteristiche
• Lesioni Metastatiche gt 3 41
• Polmone / Fegato 57
• 1a Linea di Terapia per CMM 62
• Naïve Chemoterapia 24
• Precedente Anthraciclina 59
• Precedente Taxano 17

Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
14
nab-paclitaxel Trial Fase II

• Risultati primari
• ORR 48
• WHO criteri RECIST
• 1a Linea 64
• Pretrattate con antracicline 41
• 3a Linea 22
• Risultati secondari
• TTP 26.6 settimane
• Responders 48.1 settimane
• OS 63.6 settimane

Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
15
Treatment-related toxicities
Treatment-related grade 3 and 4 toxicities/AEs (N 63) Treatment-related grade 3 and 4 toxicities/AEs (N 63) Treatment-related grade 3 and 4 toxicities/AEs (N 63)
Grade 3 Grade 4
Haematological toxicities No. () No. ()
Neutropaenia 17 (27) 15 (24)
Leucopoenia 12 (19) 3 (5)
Infection with unknown absolute neutrophil count 4 (6) 0 (0)
Febrile neutropaenia 0 (0) 3 (5)
Anaemia 3 (5) 1 (2)
Thrombocytopenia 3 (5) 0 (0)
N 62
Note if a patient reported the same toxicity
more than once, that patient was only counted
once for the summary of that toxicity, using the
most severe intensity. Haematological toxicities
were based on laboratory values others were
based on AE reports from the clinical
investigators
Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
16
Treatment-related toxicities (cont.)
Treatment-related grade 3 and 4 toxicities/AEs (N 63) Treatment-related grade 3 and 4 toxicities/AEs (N 63) Treatment-related grade 3 and 4 toxicities/AEs (N 63)
Grade 3 Grade 4
Non-haematological toxicities No. () No. ()
Fatigue 8 (13) 0 (0)
Sensory neuropathy 7 (11) 0 (0)
Myalgia 5 (8) 0 (0)
Diarrhoea 3 (5) 0 (0)
Cardiac - ischaemia/infarction 0 (0) 1 (2)
Jaundice 0 (0) 1 (2)
Vomiting 1 (2) 0 (0)
Nausea 1 (2) 0 (0)
Headache 1 (2) 0 (0)
Mucositis 1 (2) 0 (0)
Rash/desquamation 1 (2) 0 (0)
Stomatitis/pharyngitis 1 (2) 0 (0)
Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
17
Treatment-related toxicities
100 90 80 70 60 50 40 30 20 10 0
Grade 1 Grade 2 Grade 3 Grade 4
Percentage of patients
Nausea
Myalgia
Vomiting
Alopecia
Anaemia
Leukopenia
Neutropenia
Sensory neuropathy
Stomatitis/pharyngitis
Fatigue
Infection with unknown ANC
Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
18
Treatment-Related Toxicities

• Grade 4 neutropeenia
• Primarily during the first treatment cycle and
  managed with dose reductions
• Grade 3 neuropathy
• All occurrences were sensory neuropathy
• Five patients discontinued due to neuropathy (8)
  
• Myalgia
• Episodes were worse immediately after dosing and
  resolved by next dose (no discontinuation)
• Ocular/visual
• Mostly dry eye and blurred vision (no G3)

Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
19
Conclusioni

• NAB-P demonstrated significant antitumour
  activity and a favourable safety profile in
  patients with MBC
• No premedication, prolonged infusions or special
  IV infusion sets are required with NAB-P
• The significant antitumour activity and
  favourable safety profile of NAB-P may be related
  to both
• exploitation of albumin to obtain high
  intratumoral concentration via gp60 and SPARC
• the absence of polyethylated castor oil
• The low incidence of neutropaenia makes NAB-P a
  good candidate for combination treatment regimens

Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
20

• Conclusioni Review Punti principali

• Popolazione Eterogenea 63 pazienti con CMM (1a -
  3a Linea), (Precedentemente trattati con/senza
  Anthracicline)
• ORR 48 (1a Linea 64), (Antrac. 41)
• Effetti collaterali (Grado 4 Neutropenia 24),
  (NF 5), (Grado 3 Neuropatia 11)

Ibrahim NK et al. J Clin Oncol. 2005 23
6019-6026
21
Studi di Fase III

• Phase I
• MTD, PK, etc.
• Phase II
• Phase III
• Registration RCT
• Other

22
Phase III Trial of Nanoparticle Albumin-bound
Paclitaxel Compared with Polyethylated Castor
Oil- based Paclitaxel in Women with Breast Cancer
CA-O12 nab-paclitaxel Trial Pivotal Fase III
William J. Gradishar, Sergei Tjulandin, Neville
Davidson, Heather Shaw, Neil Desai, Paul Bhar,
Michael Hawkins, and Joyce OShaughnessy
Gradishar et al. J Clin Oncol 23 7794-7803. Nov
2005.
23
Phase III Trial of nab-Paclitaxel Compared with
Polyethylated Castor Oil-Based Paclitaxel in
Women with Breast Cancer
Gradishar et al. J Clin Oncol. 20052377947803
24
Fase III obiettivi

• Goals
• Confrontare lattività anti-tumorale di
  nab-paclitaxel e paclitaxel convenzionale in
  pazienti con carcinoma mammario metastatico.
• Valutare la safety e tollerabilità di
  nab-paclitaxel confrontata al paclitaxel
  convenzionale.

Endpoints Primari
Objective response rates (ORR) Tutti I pazienti trattati 1 linea (analisi pianificata) RECIST criteria Safety e tollerabilità
Endpoints Secondari
Time to tumour progression (TTP) Overall survival (OS)
Gradishar et al. J Clin Oncol. 20052377947803
25
Phase III inclusion criteria

• Females 18 yrs of age
• Measurable MBC
• ECOG PS 1 or 2
• Patients stratified for prior anthracycline
  exposure
• No prior taxane for metastatic disease
• No limit on number of prior therapies in the
  metastatic setting

Gradishar et al. J Clin Oncol. 20052377947803
26
Select Baseline Characteristics
Primary Site of Measurable Disease
nab-Paclitaxel n229 Paclitaxel n225
Mean Age (yr) 53 53
Liver 40 43
Lung 32 35
LN, soft tissue only 16 13
Abdominal 4 3
Bone involvement 6 6
Unknown 1 0
Gradishar et al. J Clin Oncol 23 7794-7803. Nov
2005.
27
DemographicsTerapie precedenti
nab-Paclitaxel n229 Paclitaxel n225
Anthracycline-adiuvante e/o metastatico 77 78
Anthracycline per malattia metastatica 50 58
Precedente CT per malattia metastatica Nessuna 1 regime 2 regimi gt2 regimi 42 41 10 7 40 43 16 2
Gradishar et al. J Clin Oncol 23 7794-7803. Nov
2005.
28
Overall Response Rate (RECIST)
Tutti i pazienti Tutti i pazienti Pazienti 1a linea Pazienti 1a linea
nab-paclitaxel (N 229) Standard paclitaxel (N 225) nab-paclitaxel (N 97) Standard paclitaxel (N 89)
CRPR 33 19 42 27
95 CI 27-39 14-24 32-52 18-36
P-value P 0.001 P 0.001 P 0.029 P 0.029
Cochran-Mantel-Haenszel testCR, complete
responsePR, partial response
Gradishar WJ et al. J Clin Oncol 200523
7794-7803
29
Phase III NAB-P improved ORR independent of line
of therapy and across various subgroups
60
P 0.001
P 0.029
P 0.006
P 0.002
P 0.002
50
42.3
40
34.1
33.2
33.5
ORR ( 95 CI)
30
27.0
26.5
18.7
18.3
18.7
20
13.2
10
0
All First-line gt First-line Anthracycline Viscera
l patients therapy therapy exposed
disease
NAB-P 229 97 132 176 176Paclitaxel 225 89 136 175
182
Greater ORR was confirmed by an independent
review committee
Gradishar et al. J Clin Oncol. 20052377947803
30
Phase III NAB-P was associated with increased
paclitaxel intensity and improved outcome

• Cross trial comparison (consistent with phase III
  data)

CALGB 93421 (n 474) CALGB 93421 (n 474) CALGB 93421 (n 474) Pivotal phase III trial2 (n 454) Pivotal phase III trial2 (n 454) Pivotal phase III trial2 (n 454)
q3w regimen (mg/m2) Paclitaxel175 Paclitaxel 210 Paclitaxel 250 NAB-P260 Paclitaxel 175
ORR () 23 26 21 33 19 P 0.001
TTP 3.9 mo(16.8 wks) 4.1 mo(17.6 wks) 4.9 mo (21.1 wks) P 0.045 23.0 wks 16.9 wks P 0.006
Neutropaenia grade 4 () 34 44 53 9 22 P 0.001
Neuropathy grade 3 () 7 19 32 10 2 P 0.001
Wks mo x 4.3
Cancer and leukaemia group B 9342 data with
paclitaxel may not reflect on the active
ingredient per se, but rather on the increased
concentrations of Cremophor EL implicated in
drug entrapment in micelles and added toxicities
1. Winer et al. J Clin Oncol. 200422206120682.
Gradishar et al. J Clin Oncol. 20052377947803
31
Fase III nab-paclitaxel prolungato time to
disease progression in tutti i pazienti

• Median TTP was significantly longer with NAB-P
  vs. solvent-based paclitaxel for all patients
  (23.0 vs. 16.6 weeks HR 0.726 P 0.002)

P 0.006 HR 0.75
NAB-P (n 229)
Paclitaxel (n 224)
Median 23.0 wks (19.426.1)
Proportion not progressed
Median 16.9 wks (15.120.9)
120
0 8 16 24 32 40 48 56 64 72 80 88 96
104
112
Wk
Note P value from log-rank test
Gradishar et al. J Clin Oncol. 20052377947803
32
Phase III OS in tutti i pazienti

• All patients treated with NAB-P showed a trend
  for greater median OS vs. solvent-based
  paclitaxel (65 vs. 55.7 weeks P0.374)

NAB-P (n 229)
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
128
136
144
Wk
Gradishar et al. J Clin Oncol. 20052377947803
Note P value from log-rank test
33
Phase III NAB-P significantly prolonged OS in gt
first-line patients

• NAB-P significantly prolonged median OS in
  patients receiving gt first-line therapy vs.
  solvent-based paclitaxel (56.4 vs 46.7 weeks
  HR0.73 P0.024)

Gradishar et al. J Clin Oncol. 20052377947803
Note P value from log-rank test
34
Phase III tossicità ematologiche nab-paclitaxel
ben tollerato
NAB-Pn 229 NAB-Pn 229 Paclitaxeln 225 Paclitaxeln 225
AE () Grade Grade Grade Grade
3 4 3 4 P value
Neutropaenia 25 9 32 22 lt 0.001
Thrombocytopaenia lt 1 0 lt 1 0 0.290
Anaemia lt 1 lt 1 0 lt 1 0.279
Febrile neutropaenia lt 1 lt 1 lt 1 0 0.491
Septic deaths 0 0
Gradishar et al. J Clin Oncol. 20052377947803
Cochran-Mantel-Haenszel test based upon all
grades
35
Phase III NAB-P was associated with increased
sensory neuropathy
NAB-Pn 229 NAB-Pn 229 NAB-Pn 229 Paclitaxel n 225 Paclitaxel n 225 Paclitaxel n 225
AE () Grade Grade Grade Grade Grade Grade
2 3 4 2 3 4 P value
Hypersensitivity lt 1 0 0 0 1 0 0.150
Flushing lt 1 0 0 5 0 0 lt 0.001
Sensory neuropathy 20 10 0 10 2 0 lt 0.001
Fatigue 13 8 lt 1 16 3 lt 1 0.062
Myalgias 12 7 0 15 2 0 0.567
Vomiting 4 3 lt 1 4 1 0 0.022
Oedema 2 0 0 lt 1 lt 1 0 0.851
Gradishar et al. J Clin Oncol. 20052377947803
Cochran-Mantel-Haenszel test based upon all
grades
36
Phase III sensory neuropathy following NAB-P
260 mg/m2 q3w improved rapidly

1.00 0.75 0.50 0.25 0.00

NAB-P (n 24)


Proportion not resolved
NAB-P median time to resolution to a lesser
grade 22 days (95 CI 1722 days) vs. 79 days
with solvent-based paclitaxel
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Days since grade 3 to lower grade
Gradishar et al. J Clin Oncol. 20052377947803
Censored
37
Fase III neuropatia migliorata rapidamente nella
maggior parte dei pazienti
24 pazienti (10) con nab-paclitaxel hanno
sviluppato grado 3 neuropatia

• 14 / 24 rapido miglioramento con una mediana di
  22 giorni
• 71 (10/14) con miglioramento hanno ripreso
  nab-paclitaxel ad una dose ridotta
• solo 3 (6/233) interrotto nab-paclitaxel a
  causa della neuropatia sensoriale
• no neuropatia motoria in entrambi I bracci di
  trattamento

Gradishar et al. J Clin Oncol. 20052377947803
38
Phase III nab-paclitaxel ben tollerato in
pazienti 65 aa

• AEs erano simili in pazienti lt 65 e 65 aa in
  entrambi I gruppi

AE () NAB-Pn 229 Paclitaxeln 225
Neutropenia 23 59
Leucopenia 10 31
Nausea 20 38
Iperglicemia 0 19
Flushing 0 16
NO effetti collaterali addizionali per
nab-paclitaxel in pazienti 65 aa rispetto a
pazienti più giovani
Gradishar et al. J Clin Oncol. 20052377947803
39
Conclusioni

• Confronto con solvent-based paclitaxel
• nab-paclitaxel ha dimostrato un
  significativamente maggiore tasso di risposta e
  prolungato TTP
• nab-paclitaxel ha prolungato sopravvivenza in
  pazienti con CMM trattati come seconda linea
• Lincidenza di grade 4 neutropenia è stata
  significativamente più bassa per nab-paclitaxel
• Maggiore tasso di neuropatia sensoriale grade 3
  con nab-paclitaxel ma risolta rapidamente con
  una mediana di 22 giorni verso 79 giorni per
  solvent-based taxano
• no Severe HSRs con nab-paclitaxel con assenza
  di premedicazione e più breve tempo di infusione

HSR, hypersensitivity reaction
Gradishar et al. J Clin Oncol. 2005 23
77947803
40
Phase III Subgroup Analysis Comparing
nab-paclitaxel with Paclitaxel in Patients with
MBC Previously Treated with Anthracycline
Davidson et al.EBCC. 2008. Poster 569
41
Phase III prior anthracycline patient
demographics
Metastatic anthracycline(n 245) Metastatic anthracycline(n 245) Metastatic or adjuvant anthracycline(n 351) Metastatic or adjuvant anthracycline(n 351)
nab-paclitaxel(n 115) Paclitaxel(n 130) nab-paclitaxel(n 176) Paclitaxel(n 175)
Age (yrs)
mean 53.3 53.8 52.6 52.8
range 2779 3483 2779 3083
Race, n ()
white 111 (97) 128 (98) 169 (96) 169 (97)
other 4 (3) 2 (2) 7 (4) 6 (3)
ECOG PS, n ()
1 109 (95) 127 (98) 165 (94) 172 (98)
2 6 (5) 3 (2) 10 (6) 3 (2)
3 0 (0) 0 (0) 1 (lt 1) 0 (0)
Davidson et al. EBCC. 2008. Poster 569
42
Phase III CA012 nab-paclitaxel significantly
improved ORR by 16 over paclitaxel
Sub-analysis of anthracycline pretreated patients
nab-paclitaxel
P 0.002
Paclitaxel
P 0.01
ORR ()
Davidson et al. EBCC. 2008. Poster 569
43
Phase III CA012 nab-paclitaxel had a
significantly longer TTP compared with
paclitaxel
Prior anthracycline in metastaticsetting only
Prior anthracycline (adjuvant or metastatic
setting)
1.00
1.00
P 0.004
P 0.011
0.75
0.75
nab-paclitaxel Paclitaxel
Proportion not progressed
0.50
0.50
Proportion not progressed
0.25
0.25
0.00
0.00
0 16 32 48 64 80 96 120
0 16 32 48 64 80 96 120
Wks
Wks
Davidson et al. EBCC 2008. Poster 569
44
Phase III CA012 nab-paclitaxel significantly
prolonged OS compared with paclitaxel
Prior anthracycline in metastaticsetting onlyB
Prior anthracycline (adjuvant or metastatic
setting)A
1.00
1.00
P 0.049
P 0.049
0.75
0.75
nab-paclitaxel Paclitaxel
0.50
Probability of survival
0.50
Probability of survival
0.25
0.25
0.00
0.00
0 16 32 48 64 80 96 112 128 152
0 16 32 48 64 80 96 112 128 152
Wks
Wks
Davidson et al. EBCC 2008. Poster 569
45
CA012 conclusions from subgroup analysis

• This subset analysis evaluating patients
  previously treated with anthracycline shows that,
  compared with paclitaxel, treatment with
  nab-paclitaxel
• significantly improved clinical outcomes in
  patients with MBC
• nab-paclitaxel achieved significantly higher
  ORRs
• nab-paclitaxel had a significantly longer TTP
• nab-paclitaxel significantly prolonged survival
  benefit
• is effective for the treatment of patients with
  MBC

46
nab-paclitaxel in monoterapia
Altri dati/studi pazienti pesantemente trattate
con taxani
47
November 2007

• nab-paclitaxel 100 or 125mg/m2 qw
• MBC w measurable disease
• PD on taxanes or relapse within 12 months from
  adjuvant taxanes

48
nab-Paclitaxel QW Regimen Phase II Trial in
Taxane-Refractory MBC Purpose

• To explore whether nab-paclitaxel has antitumor
  activity in patients with MBC that had progressed
  on conventional taxane therapy
• Primary Endpoint
• Percentage of patients who achieved a confirmed
  objective, complete, or partial response
• Secondary Endpoints
• SD after gt 16 weeks
• PFS
• OS
• Safety

Blum et al. Clin Breast Cancer. 20077850856
49
nab-Paclitaxel QW Regimen Phase II Trial in
Taxane-Refractory MBC Trial Design

• Heavily pre-treated, taxane-refractory patients

PATIENT COHORTS
nab-Paclitaxel 100 mg/m2 qw 3/4 n 106
nab-Paclitaxel 125 mg/m2 qw 3/4 n 75
Study initiated at 100 mg/m2 qw 3 of 4 wks.
Because minimal toxicities were observed at this
dose and schedule, protocol was amended to
include additional cohort of patients to receive
125 mg/m2 qw 3 of 4 wks. Each cohort was analyzed
separately.
Blum et al. Clin Breast Cancer. 20077850856
50
nab-Paclitaxel QW Regimen Phase II Trial in
Taxane-Refractory MBC Select Demographics and
Baseline Characteristics
100 mg/m2(n106) 125 mg/m2(n75)
Median (range) age, yrs 53 (3476) 53 (3374)
Visceral disease () 94 89
gt 3 metastatic sites () 65 69
Tumour progression while on taxane therapy for metastatic disease () 88 89
Previous taxane therapy on a qw schedule for metastatic disease (no. of pts) 58 41
paclitaxel () 40 44
docetaxel () 34 37
paclitaxel/docetaxel (sequential) () 26 20
Median (range) no. of previous chemotherapy regimens for metastatic disease 3 (07) 3 (114)
Previous adjuvant chemotherapy (no. of pts) 85 79
anthracycline-containing () 75 56
taxane-containing () 29 27
Blum et al. Clin Breast Cancer. 20077850856
51
nab-Paclitaxel QW Regimen Responses in
Taxane-Refractory MBC
100 mg/m2 100 mg/m2 100 mg/m2 125 mg/m2 125 mg/m2 125 mg/m2
n ORR () DiseaseControl () n ORR () DiseaseControl ()
Antitumour activity all patients 106 14 26 75 16 37
Prior taxane therapy for metastatic disease Docetaxel Paclitaxel Docetaxel and Paclitaxel 34 30 29 21 13 7 32 30 21 28 20 19 21 20 0 46 45 21
Cochran-Mantel-Haenszel test based upon all
grades
Blum et al. Clin Breast Cancer. 20077850856
52
nab-Paclitaxel QW Regimen Similar Survival
Between Patients Who Achieved SD 16 wks and
Those With a Confirmed Response
100
Survival curves for the 100 and 125 mg/m2 cohorts
combined (n 181)
Confirmed responders
75
SD 16 wks
Non-responders
50
Probability of survival ()
25
P 0.7106
0
0 3 6 9 12 15 18 21 24 27 30
Mo
Blum et al. Clin Breast Cancer. 20077850856
53
NAB-P qw regimen safety
100 mg/m2 100 mg/m2 125 mg/m2 125 mg/m2
NCI CTC toxicity/AE Grade 3 Grade 4 Grade 3 Grade 4
Haematological toxicities ()
leucopaenia 19 lt 1 33 3
neutropaenia (without G-CSF) 14 4 31 3
Non-haematological toxicities ()
fatigue 5 0 12 0
sensory neuropathy 8 0 19 0
nausea 4 0 3 0
diarrhoea 1 0 5 0
vomiting 3 0 1 0
alopaecia 0 0 0 0
41 of patients treated with NAB-P 100 mg/m2
and 35 of those treated with 125 mg/m2 had
pre-existing grade 1 peripheral
neuropathyG-CSF, granulocyte-colony stimulating
factor NCI CTC, National Cancer Institute common
toxicity criteria
Blum et al. Clin Breast Cancer. 2007 7 850856
54
NAB-P qw regimen peripheral neuropathy improved
rapidly

• Grade 3 neuropathy
• 100 mg/m2 cohort, nine patients (8)
• 125 mg/m2 cohort, 14 patients (19)
• grade 1 pre-existing neuropathy
• three patients in 100 mg/m2 and three patients in
  125 mg/m2
• Of the 23 patients with grade 3 PN, 15 (65)
  restarted NAB-P at a lower dose
• patients who continued treatment were able to
  resume dosing, typically in 12 wks

PN, peripheral neuropathy
Blum et al. Clin Breast Cancer. 2007 7 850856
55
Conclusions

• QW nab-paclitaxel at 100 mg/m2 and 125 mg/m2
  achieved
• Disease control in 26 and 36 of pts,
  respectively
• PFS of 3.0 mo and 3.5 mo
• OS of 9.2 mo and 9.1 mo
• There was no significant difference in OS between
  patients who achieved an objective response and
  non-responders who had SD 16 wks
• nab-Paclitaxel 100 mg/m2 was well tolerated with
  no HSR and a low rate of treatment cessation for
  peripheral neuropathy
• Minimal myelosuppression grade 4 neutropenia and
  leukopaenia occurred in lt 5 of patients in both
  cohorts

Blum et al. Clin Breast Cancer. 20077850856
56
nab-paclitaxel in monoterapia
Altri dati/studi confronto verso docetaxel
57
nab-paclitaxel JCO Editorial
58
nab-paclitaxel JCO Editoriale
CA-012 nab-paclitaxel vs Taxol
TAX 311 Taxotere vs Taxol
nab-paclitaxel 260mg/m2 (30min) q 3 wk No
premedicazione No special tubing
DOCETAXEL 100mg/m2 (1h) q 3 wk Dexametasone 8mg
po bid x 5 d Dal giorno precedente all infusione
R
R
PACLITAXEL 175mg/m2 (3h) q 3 wk Dexametasone
20mg po 12 6 h Difenidramine 50mg IV
Cimetidine 300mg or Ranitidine 50mg IV 30-60
min prima dell infusione
PACLITAXEL 175mg/m2 (3h) q 3 wk Dexametasone
20mg po 12 6 h Difenidramine 50mg IV
Cimetidine 300mg or Ranitidine 50mg IV 30-60
min prima dell infusione
59
JCO Editorial CA-012 vs. TAX 311

• Entrambi i trials mostrano avere simili
  caratteristiche di pazienti e malattia
• Simile numero di pazienti in ogni trial
• Mix di pazienti trattati e non trattati per CMM
• Precedente trattamento con antracicline
• Simili Fattori Prognostici
• Sia nab-paclitaxel che Taxotere confrontati con
  Taxol alla dose di 175mg/m2 ogni 3 settimane

60
nab-paclitaxel JCO Editoriale
61
Significantly Longer Progression-Free Survival
with nab-Paclitaxel Compared with Docetaxel as
First-Line Therapy for Metastatic Breast Cancer

• W.J. Gradishar, D. Krasnojon, S. Cheporov, A.N.
  Makhson, G.M. Manikhas, A. Clawson, P. Bhar

Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
62
Study Objectives

• To obtain comparative safety and preliminary
  antitumor response data for
• nab-paclitaxel vs docetaxel
• weekly (QW) vs every-3-week (Q3W)
  nab-paclitaxel
• lower vs higher dose QW nab-paclitaxel
• Design open-label, randomized, phase II,
  multi-center study

Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
63
qw or q3w NAB-P vs q3w docetaxel study design

• 302 first-line MBC patients randomised to four
  arms (300 pts received study drug and were
  evaluable)

R A N D OMI S E
Arm A NAB-P 300 mg/m2 q3w
Comparisons
NAB-P vs docetaxel(A, B, C vs D)
Arm B NAB-P 100 mg/m2 3q4w
qw vs q3w NAB-P (B, C vs A)
Arm C NAB-P 150 mg/m2 3q4w
low- vs high-dose qw NAB-P (B vs C)
Arm D docetaxel 100 mg/m2 q3w
Arms A, C and D administered at the MTD3q4w,
repeated wkly for 3 wks out of 4
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
64
qw or q3w nab-paclitaxel vs q3w docetaxel
obiettivi dello studio

• Ottenere confronto tossicità e dati preliminari
  di risposta antitumorale per
• nab-paclitaxel vs docetaxel
• qw vs q3w nab-paclitaxel
• lower- vs higher-dose qw nab-paclitaxel
• Utilizzare dati di questo trial per disegnare
  futuri trials con nab-paclitaxel

Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
65
qw or q3w nab-paclitaxel vs q3w docetaxel
analisi finale - status dello studio
nab-paclitaxel nab-paclitaxel nab-paclitaxel Docetaxel
300 mg/m2 q3w (n 76) 100 mg/m2 3q4w(n 76) 150 mg/m2 3q4w(n 74) 100 mg/m2q3w (n 76)
Terapia in corso () 4 (5) 6 (8) 14 (19) 3 (4)
Interrotta () 72 (95) 70 (92) 60 (81) 71 (96)
Motivi per interruzione ()
PD 37 (51) 48 (69) 33 (55) 27 (38)
tossicità inaccettabile 10 (14) 5 (7) 10 (17) 15 (21)
AEs 0 1 (1) 2 (3) 2 (3)
decisione investigatore 7 (10) 5 (7) 6 (10) 14 (20)
decisione paziente 18 (25) 11 (16) 8 (13) 13 (18)
PD, progressive disease
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
66
qw or q3w nab-paclitaxel vs q3w docetaxel
(RECIST) sperimentatore-ORR
C vs D P lt 0.001
B vs D P 0.002
A vs D NS
ORR
300 mg/m2q3w(A n 76)
100 mg/m23q4w(B n 76)
150 mg/m23q4w(C n 74)
Docetaxel100 mg/m2q3w(D n 74)
nab-paclitaxel
A vs B P 0.024A vs C P 0.002B vs C
NSNS, not significant
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
67
qw or q3w nab-paclitaxel vs q3w docetaxel
controllo della malattia (ORR SD gt 16 wks)
P 0.009
Disease Control Rate stable disease for 16 weeks
or confirmed overall PR or CR
P 0.017

of Patients
100 mg/m2 q3w
300 mg/m2 q3w
100 mg/m2 qw 3/4
150 mg/m2 qw 3/4
Docetaxel
nab-Paclitaxel
P-Values for Investigator-assessed DCR are not
shown
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619
68
qw or q3w nab-paclitaxel vs q3w docetaxel PFS
(Investigator Review)
1.00
Regimen Median PFS (mo) P value vs docetaxel
nab-paclitaxel (A) 300 mg/m2 q3w 10.9 NS
nab-paclitaxel (B) 100 mg/m2 3q4w 7.5 NS
nab-paclitaxel (C) 150 mg/m2 3q4w(n 74) 14.6 P 0.012 HR 0.568
Docetaxel (D) 100 mg/m2 q3w 7.8 NA
0.75
Proportion not progressed
0.50
0.25
0.00
0 3 6 9 12 15 18 21 24
Mo
A vs B P 0.076, HR 0.702 B vs C P 0.001
HR 1.972
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
69
qw or q3w nab-paclitaxel vs q3w docetaxel
tossicità
nab-paclitaxel nab-paclitaxel nab-paclitaxel 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)
Tossicità legate al trattamento riportate in
25 dei pazienti
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
70
qw or q3w nab-paclitaxel vs q3w docetaxel
tossicità
nab-paclitaxel nab-paclitaxel nab-paclitaxel 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)
Artralgia
grade 2 20 (26) 5 (7) 14 (19) 10 (14)
grade 3 1 (1) 0 (0) 0 (0) 0 (0)
grade 4 0 (0) 0 (0) 0 (0) 0 (0)
Neutropenia
grade 2 22 (29) 25 (33) 24 (32) 2 (3)
grade 3 29 (39) 15 (20) 26 (35) 14 (19)
grade 4 4 (5) 4 (5) 7 (9) 54 (75)
Medio nadir SD, x 109/l 1.21 1.00 1.51 0.96 1.11 0.63 0.38 0.34
Tossicità legate al trattamento riportate in
25 dei pazienti
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
71
qw or q3w nab-paclitaxel vs q3w docetaxel grade
3 neuropatia migliorata più rapidamente con
nab-paclitaxel
Proportion not improved

• Neuropatia con simile frequenza in tutti i
  bracci di trattamento
• Tempo mediano al miglioramento
• per nab-paclitaxel 300 mg/m2, 100 mg/m2, 150
  mg/m2 22, 22, 19 giorni
• vs docetaxel 37 giorni

1.00
nab-paclitaxel 300 mg/m2 q3w (A) nab-paclitaxel
100 mg/m2 qw (B) nab-paclitaxel 150 mg/m2 qw
(C) Docetaxel 100 mg/m2 q3w (D)
0.75
0.50
0.25
0.00
0 10 20 30 40 50 60
70 80 90 100
Giorni
Gradishar W, et al. J Clin Oncol, 2009 27(22)
3611-3619.
72
Conclusioni

• nab-paclitaxel ha dimostrato migliore
  tollerabilità ed efficacia rispetto a docetaxel
  
• Tutti e tre i bracci di nab-paclitaxel con più
  bassi tassi di neutropenia, neutropenia febbrile
  e fatigue
• Il braccio più efficace di nab-paclitaxel
  basato su PFS e ORR è risultato 150 mg/m2 qw
• nab-paclitaxel 150 mg/m2 qw è risultato
  superiore in maniera statisticamente
  significativa in termini di ORR e PFS rispetto a
  docetaxel
• nab-paclitaxel 100 mg/m2 qw è risultato
  associato con la minore tossicità
• Gradishar W, et al. J Clin Oncol, 2009
  27(22) 3611-3619.

73
Ultimi Aggiornamenti- Dati di Overall Survival
- Older patients with MBC
74
Nab- Paclitaxel Versus Docetaxel for the
First-line Treatment of Metastatic Breast Cancer
(MBC) Final Overall Survival (OS) Analysis of a
Randomized Phase 2 Trial
ASCO Breast Symposium, September 8-10 , 2011,
California Abstract 275
75
Overall Survival
Median OS (mo) P HR
AB-Pac 150mg/m2 qw (C) 33.8 Overall 0.047 C vs B 0.008 C vs D - - 0.575 0.688
AB-Pac 300mg/m2 q3w (A) 27.7 Overall 0.047 C vs B 0.008 C vs D - - 0.575 0.688
Taxotere 100mg/m2 q3w (D) 26.6 Overall 0.047 C vs B 0.008 C vs D - - 0.575 0.688
AB-Pac 100mg/m2 qw (B) 22.2 Overall 0.047 C vs B 0.008 C vs D - - 0.575 0.688

• The 150 mg/m2 qw albumin-bound paclitaxel arm
  demonstrated
• A significantly longer median OS versus the 100
  mg/m2 arm
• A longer OS versus docetaxel, although this
  difference was not statistically significant
• The OS benefit of the 150 mg/m2 arm was
  consistent among patient subgroups
• Age lt65 vs 65 years
• Visceral vs non-visceral disease
• No. of visceral lesion sites lt5 vs 5
• Pre-menopausal vs post-menopausal

ASCO Breast Symposium, Abstract 275
76
Overall Efficacy Analyses

• A significant (P .047) treatment effect on OS
  was observed among the 4 tratment arms
• The OS benefit of 150 mg/mq qw nab-paclitaxel arm
  was consistent with results observed in
  investigator-assessed ORR and PFS

ASCO Breast Symposium, Abstract 275
77
Conclusion

• Based on event-driven analysis of final OS, the
  nab-paclitaxel 150 mg/m2 qw 3/4 regimen provided
  the best clinical benefit for the forst-line
  treatment of patients with MBC
• The median OS of 33.8 months compares favorably
  with historical values for taxane monotherapy for
  MBC
• The OS benefit of the 150 mg/mq qw regimen in
  consistent with trends seen in investigator-assess
  ed ORR and PFS
• nab.-paclitaxel was generally well tolerated, and
  the safety profile is consistent with previous
  reports
• These results support further eveluation of the
  150 mg/mq qw dosing schedule of nab-paclitaxel in
  a randomized, phase 3 trial for the first-line
  treatment on MBC

ASCO Breast Symposium, Abstract 275
78
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

79
Purpose

• This post-hoc analysis of 2 studies (Gradishar
  W. 2005 and Gradishar W. 2009) investigated the
  safety and efficacy of weekly and every-3-week
  (q3w) nanoparticle albumin-bound paclitaxel
  (nab-paclitaxel) in older patients with
  metastatic breast cancer (MBC) compared with q3w
  solvent-based paclitaxel and docetaxel.

Aapro M et al, The Breast 2011
80
Patient Population
Among the total treatment population in the 2
studies 114 (15) were 65 years old (phase 2, n
52 phase 3, n 62)

• In the phase 2 study
• 33 pt randomized to nab-paclitaxel n 9 300
  mg/m2 q3w
• n 14 100 mg/m2 weekly
• n 10 150 mg/m2 weekly
• 19 pt randomized to docetaxel

In the phase 3 study 30 pt randomized to
nab-paclitaxel 32 pt randomized to paclitaxel
Aapro M et al, The Breast 2011
81
Demographics/Baseline Characteristics
Aapro M et al, The Breast 2011
82
Efficacy (1)

• 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
83
Efficacy (2)
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
84
Response and Survival
Aapro M et al, The Breast 2011
85
Safety and Tolerability
In general, treatment related grade 3 and 4 AEs
were similar for the elderly patients compared
with results from all patients in the 2 studies.
Aapro M et al, The Breast 2011
86
Conclusion
Weekly nab-paclitaxel was safe and more
efficacious compared with the q3w schedule and
with solvent-based taxanes in older patients with
MBC.

• In particular, the 150 mg/m2 weekly for 3 weeks
  followed by 1 week of rest nab-paclitaxel
  resulted in 60 ORR and 21 months of median OS
  along with no SAEs and no deaths thus, it may be
  the optimal dose of nab-paclitaxel therapy in
  patients 65 years old. These findings warrant
  further examination of weekly nab-paclitaxel in
  older patients with MBC.

Aapro M et al, The Breast 2011
87
nab-PaclitaxelOngoing Study in MBC
88
Cooperative Group Trial with Biomarker Analysis
Tumor biopsy on accessible tissue
RANDOMI ZE
Paclitaxel 90 mg/m2 qw 3/4
Bevacizumab 10 mg/kg q2w
nab-Paclitaxel 150 mg/m2 qw 3/4
Ixabepilone 16 mg/m2 qw 3/4
Serum for Caveolin-1 Tumor block for SPARC,
tubulin mutations, Circulating Tumor Cells (CTC)
and Circulating Endothelial Cells (CEC)
Serial serum measurement of caveolin-1 Serial
measurement of CTC and CEC
CALGB and NCCTG, PI Hope Rugo, Alvino Moreno
N900