Download nab

nab-paclitaxel in combinazione
Dati clinici e safety
nab-paclitaxel IN BREAST CANCER
Essential Concepts
• Better efficacy and safety than TAX in MBC:
– In Q3W schedule –Ph III trial (CA012)
• Better efficacy and safety than Q3W TXT in MBC:
– In Q1W schedule –Ph II randomized trial (CA024)
• Combinable with large number of drug partners without compromise in
efficacy or safety – several studies
• Promising activity when combined with GEM + BEV in Q2W schedule (Lobo)
• Not feasible and probably unnecessary to run Ph III for registration vs. Q3W
TXT
• Not feasible to run a Ph III adjuvant study in unselected pt populations
• No more neoadjuvant studies to be done in unselected patient populations
• Mammaprint study may open door for early breast cancer positioning
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
nab-Paclitaxel - studi di
combinazione
Dual
Phase II
open-label
n=50
first-line
+ gemcitabine
Roy et al. Ann Oncol 2009;20:449–
453
Phase II
n=50
first-line
+ capecitabine
Somer et al. Presented at ASCO
Meeting 2007; Abstract 1053
Phase II
Dose comparison
Target n=225
first-line
+ bevacizumab
Conlin et al. Presented at ASCO
2009; Abstract 1006
Phase II
n=50
first-line
+ bevacizumab
Danso et al. Presented at ASCO
Meeting 2008; Abstract 1075
Retrospective
subgroup analysis
n=40
heavily pretreated
+ bevacizumab
Link et al. Clin Breast Cancer
2007;7: 779–783
Phase II
n. 72
first line
+ trastuzumab
Mirtsching et al. Clin Breast Cancer
2011; 1-8
Phase II
n=25
first-line
+ gemcitabine + bevacizumab
Lobo, Gluck et al. Breast Cancer
Res 2010; 123: 427-435
Phase II
Target n=50
HER2+ve
+ carboplatin + trastuzumab
Conlin et al. Clin Breast Cancer
2010; 281-7
Triple
*nab-paclitaxel monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for
metastatic disease and for whom standard, anthracycline containing therapy is not indicated. The recommended dose of nab-paclitaxel is 260
mg/m2 administered intravenously over 30 minutes every nab-paclitaxel is not approved for use in combination chemotherapy
nab-paclitaxel in MBC –
Synoptic Table
Conlin
N
Conlin
Lobo
Roy
Somer
50
73
78
29
50
50
100 q1w
260 q3w
130 q1w
150 q2w
125 q1w
125 q1w
Carbo Her
Bev
Bev
Gem Bev
Gem
Xel
Age
52.0
< 65
< 65
54.0
56.0
59.0
ORR
63%
44%
46%
75.9%
50%
60.9%
CR
9%
1%
1%
27.6%
8%
4.3%
PR
54%
43%
45%
48.3%
42%
56.5%
PFS
16.6 mo
NR
NR
10.4 mo
7.9 mo
270 days
TTP
NR
7.7 mo
9.0 mo
NR
NR
NR
OS
NR
NR
NR
Not reached
Not reached
Not reached
mg/m2
Partner Drug
Toxicities (Grade 3 + 4 only)
ANC
50%
2% FN
0% FN
1%
55%
10%
PLT
3%
NR
NR
1%
12%
NR
PN
3%
30%
39%
1%
6%
NR
Fatigue
16%
16%
17%
0%
29%
9%
*nab-paclitaxel monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for
metastatic disease and for whom standard, anthracycline containing therapy is not indicated. The recommended dose of nab-paclitaxel is 260
mg/m2 administered intravenously over 30 minutes every 3 weeks. nab-paclitaxel is not approved for use in first-line chemotherapy, weekly
regimen or combination chemotherapy
nab-paclitaxel in combinazione con:
Gemcitabine
Capecitabine
Trastuzumab
Bevacizumab
NCCTG Phase II Trial N0531 of Weekly nabPaclitaxel in Combination with Gemcitabine in
Patients with Metastatic Breast Cancer
V. Roy, B. R. LaPlant, G. G. Gross,
C. L. Bane, F. M. Palmieri, E. A. Perez,
on behalf of the North Central Cancer
Treatment Group
Roy V, et al. Ann Oncol 2009; 20(3):449-453
Study Rationale
• nab-paclitaxel significantly reduced acute toxicity and
showed superior efficacy to solvent-based paclitaxel¹
• A phase III study of GEM + TAX demonstrated superior
antitumor activity in anthracycline-pretreated patients
with MBC with 41% vs. 26% ORR for (doublet vs. TAX
alone)²
• This study was to evaluate the combination of nabpaclitaxel and gemcitabine for MBC
1) Gradishar et al, J Clin Oncol 2005 2) Albain et al, J Clin Oncol 2008
2) Roy V, et al. Ann Oncol 2009; 20(3):449-453
Patient Eligibility
• Key Inclusion Criteria
– Age ≥18 years of age
– Confirmed histological and cytological invasive breast cancer with clinical
evidence of metastatic disease
– ECOG PS 0-1
– No previous chemotherapy for MBC
– Previous taxanes allowed if completed >6 mo before
• Key Exclusion Criteria
– No active CNS metastasis
– No >grade 1 peripheral neuropathy
Roy V, et al. Ann Oncol 2009; 20(3):449-453
Study Design & Treatment
• Open-label, multicenter phase II study conducted
through the North Central Cancer Treatment Group
(NCCTG)
nab-paclitaxel 125 mg/m2
IV over 30 min
Days 1 and 8 every 21 days
Gemcitabine 1000 mg/m2
IV over 30 min
Days 1 and 8 every 21 days
• Primary Endpoint:
– Response rate (RR)
• Secondary Endpoints:
– Overall survival (OS)
– Progression-free survival (PFS)
– Duration of Response
Roy V, et al. Ann Oncol 2009; 20(3):449-453
Efficacy Results (N = 50)
Median # of Cycles Administered (range)
7 (1 – 17)
CR, n (%)
4 (8)
PR, n (%)
20 (42)
Overall Confirmed Response (CR + PR), n (%)
(95% CI)
25 (50)
(36 - 64)
Median Duration of Response, months
(95% CI)
6.9
(5.7, not reached)
Median PFS months (95% CI)
7.9 (5.4 – 10)
Median OS months (95% CI)
not reached
Rate of PFS at 6 months, % (95% CI)
60 (48 - 76)
Rate of OS at 6 months, % (95% CI)
92 (85 - 100)
Roy V, et al. Ann Oncol 2009; 20(3):449-453
Adverse Events (AEs) occurring in
>5% of patients
N = 50
Grade 3 (%)
Grade 4 (%)
Neutropenia
21 (43)
6 (12)
Fatigue
14 (29)
0 (0)
Anemia
7 (14)
0 (0)
Dyspnea
7 (14)
0 (0)
Thrombocytopenia
5 (10)
1 (2)
Arthralgia
4 (8)
0 (0)
Vomiting
4 (8)
0 (0)
Neuropathy
3 (6)
0 (0)
Myalgia
3 (6)
0(0)
Nausea
3 (6)
0 (0)
Pain - Abdominal
3 (6)
0 (0)
AST
3 (6)
0 (0)
AST, aspartate aminotransferase
Roy V, et al. Ann Oncol 2009; 20(3):449-453
Conclusions
• Weekly nab-paclitaxel in combination with
gemcitabine demonstrated significant activity as firstline therapy in patients with MBC
• Toxicities were manageable; neutropenia was the
most common AE
• No significant nonhematologic toxicities were
encountered
• Grade 3 neuropathy occurred in 3 (6%) patients
Roy V, et al. Ann Oncol 2009; 20(3):449-453
Phase II Trial of nab-Paclitaxel +
Capecitabine in First-line Treatment of
Metastatic Breast Cancer
B. G. Somer, L.S. Schwartzberg,
F. Arena, D. Mintzer, A. Epperson,
D. Fu, B.V. Fortner
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Study Rationale
• nab-Paclitaxel and capecitabine have substantial single
agent activity in MB1-4
• Taxane and anti-metabolite doublets improve RR and
TTP compared with single agent therapy5
• Weekly nab-paclitaxel has an excellent safety and
efficacy profile with maintenance of dose intensity6
• This study was designed to evaluate the safety and
efficacy of nab-paclitaxel and capecitabine given in a
novel combination schedule
1) Gradishar et al, J Clin Oncol 2005 2) Talbot et al, Br J Cancer 2002 3) O’Shaughnessy et al, Ann Oncol 2001
4) Bajetta et al, J Clin Oncol 2005 5) Miles et al, Clin Breast Cancer 2004 6) Blum et al, Proc ASCO 2003
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Study Design & Treatment
• This was a phase II, multicenter, open-label study
• Treatment
– nab-Paclitaxel 125 mg/m2 IV on days 1 and 8 q3w without
premedication
– capecitabine 825 mg/m2 orally bid on days 1-14 q3w
• Primary endpoint:
– RR
• Secondary endpoints:
– PFS
– OS
– Safety
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Select Patient Characteristics
Patients Enrolled (N = 50)
Median Age, years (range)
59.0 (23.7-83.8)
Prior Treatment, n (%)
Chemotherapy
Anthracycline
Taxane
Radiotherapy
25 (50)
20 (40)
17 (34)
17 (34)
Number of Metastatic Sites, n (%)
1
2
3
>3
13 (26)
19 (38)
14 (28)
4 (8)
Most Common Metastatic Sites, n (%)
Bone
Liver
Other Lymph Node
Pulmonary
27 (54)
24 (48)
19 (38)
17 (34)
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Tumor Response
• 4 out of 50 patients were not evaluable for response
• ORR: 28 (60.9%) patients
• CR: 2 (4.3%) patients
• PR: 26 (56.5%) patients
• SD: 10 (21.5%) patients
• PD: 8 (17.4%) patients
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Progression-free Survival
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Overall Survival
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
GRADE 3/4 Adverse Events
N (patients)
Grade 3
Neutropenia
Sensory Neuropathy
Mucositis
Hand Foot Syndrome
Fatigue
Nausea/Vomiting
Anorexia
Grade 4
Febrile Neutropenia
Neutropenia
Fatigue
4
1
4
3
3
1
2
1
1
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Dose Modifications
Reduction
Held
Delayed
Drug
Total Patients, n
nab-Paclitaxel
Capecitabine
5
8
11
5
3
--
Total Cycles, n (%)
nab-Paclitaxel
Capecitabine
5 (1.7)
8 (2.8)
13 (4.4)
6 (2.1)
4 (1.4)
--
Most Frequent Grade 3/4 AEs
Fatigue, n
nab-Paclitaxel
Capecitabine
1
2
-1
---
Hand Foot Syndrome,
n
nab-Paclitaxel
Capecitabine
1
1
1
2
---
Neutropenia, n
nab-Paclitaxel
Capecitabine
1
--
4
1
1
--
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
Conclusion
• nab-Paclitaxel and capecitabine is a highly active
combination regimen in first-line MBC with an ORR of
61%
• Days 1 and 8 nab-paclitaxel at 125 mg/m2 plus
capecitabine 825 mg/m2 bid days 1-14 q3w is well
tolerated
• A favorable PFS with a median of 270 days was
observed with this combination regimen
Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053
nab-paclitaxel + Trastuzumab
nab-paclitaxel qw + trastuzumab
have shown first-line efficacy in MBC
• Include details from 2 phase II studies in first line
MBC:
• Conlin 2010 (nab-paclitaxel + carboplatin +
trastuzumab)
– ORR: 62.5%
– ORR + SD>16 weeks: 81%
• Mirtsching 2011 (nab-paclitaxel ± trastuzumab)
– ORR 42.2% (52% in HER2+)
– Overall benefit (ORR +SD): 68.8%
Conlin et al. Clin Breast Cancer 2010;10:281-287; Mirtsching et al. Clin Breast Cancer 2011; Jan 11:1-8 (Epub)
Phase II Trial of Weekly Nanoparticle
Albumin-Bound Paclitaxel With Carboplatin and
Trastuzumab as First-line Therapy
for Women With HER2-Overexpressing Metastatic
Breast Cancer
AK. Conlin, AD. Seidman, A. Bach, D. Lake,
M. Dickler, G. D’Andrea, T. Traina, M. Danso,
AM. Brufsky, M. Saleh, A. Clawson, CA. Hudis
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Study Rationale
• Carbo improves ORR and TTP when added to q3w TAX+
HER as first-line therapy for HER2+ MBC¹
• Qw TAX + HER is highly active and safe as first-line
treatment of HER2+ MBC²
• Qw TAX + carbo + HER is highly active and is better
tolerated than q3w TAX³
• Weekly nab-paclitaxel is more active than q3w in firstline MBC patients4
1) Robert et al, J Clin Oncol 2006
2) Seidman et al, J Clin Oncol 2001, Seidman et al, J Clin Oncol, 2008
3) Perez et al, Clin Breast Cancer, 2005
4) Gradishar et al, CJ Clin Oncol, ASCO 2009
Patient Eligibility
• Key Inclusion Criteria
– Females >18 years of age
– Stage IV adenocarcinoma
– Measurable disease (≥1 lesion with diameter ≥2 cm by
conventional techniques or ≥1 cm by spiral CT)
– HER2 overexpressing (IHC 3+) or amplified (FISH+) disease
– ≥4 weeks since radiotherapy or major surgery
– Adequate hepatic/renal function
– Normal LVEF
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Patient Eligibility
• Key Exclusion Criteria
– Prior chemotherapy for MBC
– < 9 months since prior taxanes
– Concurrent immunotherapy or hormone therapy
– Parenchymal brain metastases (unless stable for at least 6 mo)
– Pregnant or breast feeding
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Study Design & Treatment
• Phase II, open-label, multi-centre
• Planned N = 50
• Primary Endpoints:
– ORR (CR + PR)
– Safety/Tolerability
• Secondary Endpoints:
–
–
–
–
SD >16 weeks + CR or PR
TTP and PFS
Response duration
OS
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Original Phase II Schema
Admin: HER  ABX  Carbo
nab-Paclitaxel
100 mg/m2
Carboplatin
AUC = 2
Trastuzumab
2 mg/kg after loading dose of 4 mg/kg
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Revised Phase II Schema
(due to hypersensitivity to Qw carbo)
Admin: HER  ABX  Carbo
nab-Paclitaxel
100 mg/m2
Carboplatin
AUC = 6
Trastuzumab
2 mg/kg after loading dose of 4 mg/kg
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Results: Patient Treatment
• 32 patients treated
– 17 treated solely on original regimen
– 3 switched from original to revised regimen
– 12 treated only on revised regimen
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Select Patient Demographics
• Median age: 52.0 yrs (range 29-76)
• 78% postmenopausal
• ECOG PS: 0: 59%, 1: 38%, 2: 3%
• Sites of metastases:
– Lymph node:75%
– Soft tissue/breast:
66%
– Liver:
47%
– Lung:
59%
– Bone:
69%
• Prior adjuvant or neoadjuvant chemotherapy:
– Prior anthracycline:
44%
– Prior taxane:
34%
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Results
Confirmed Response
ORR
N (%)
20 (63)
CR
3 (9)
PR
17 (53)
SD ≥ 16 wk
6 (19)
Clinical Benefit*
26 (81)
95% CI: 45.7-79.33
* CR + PR +SD ≥ 16 wk
• Median PFS: 16.6 months (95% CI, 7.5-26.5 months)
• OS (monitored q3mo for 2 yr): 10 pts (31%) had died at time of
reporting
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Results – PFS in Treated Population
• Median PFS: 16.6 months (95% CI, 7.5-26.5 months)
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Results: Response by regimen
• Original regimen only (n = 17)
– 11/17 (65%) had confirmed responses
• Revised regimen only (n = 12)
– 8/12 (67%) had confirmed responses
• Original + revised (n = 3)
– 1/3 (33%) responded after switching
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Safety (pooled)
Incidence (%) of Therapy-Related Adverse Events
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Neutropenia
13
34
41
9
Leukopenia
22
28
44
3
Anemia
25
63
3
3
Thrombocytopenia
38
34
3
0
Sensory Neuropathy
47
13
3
0
Nausea
56
16
0
0
Diarrhea
19
25
0
0
Rash/Desquamation
22
9
0
0
Arthralgia
16
3
0
0
Fatigue
38
31
16
0
Stomatitis
28
13
0
0
Elevated ALT
9
6
3
0
Elevated AST
9
0
0
0
Hematologic a,b
Non-Hematologic
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase
A Based on laboratory data graded by National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
B 1 episode of febrile neutropenia was observed
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Hypersensitivity Reactions
• Total of 9 hypersensitivity reactions
– Carboplatin:
5 patients (none during monthly regimen)
– Trastuzumab:
4 patients
– nab-paclitaxel: none
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Safety: Dose Reductions
• At least 1 dose reduction
– nab-Paclitaxel: 22 (69%)
– Carboplatin: 19 (59%): 2 due to hypersensitivity reactions
– 95% for hematologic toxicity (each drug)
• At least 1 dose delay
– 69% pts
– 82% were for hematologic toxicities
– None for peripheral neuropathy
• Dose interruption
– nab-paclitaxel: 2 pts
– Trastuzumab: 6 pts had at least 1 missed dose
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Drug Exposure
• The median dose intensity:
– nab-paclitaxel:
76% of the planned dose
– Carboplatin:
62% of the planned dose
• Median number of cycles: 8 (range, 2-39 cycles)
• 8 patients who responded and had at least 6 cycles of
nab-paclitaxel and carboplatin were continued on
trastuzumab alone until progression of disease.
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
Conclusion
• Weekly ABX+ HER+ Carbo (weekly or monthly) is
active as first-line therapy for HER2+ MBC
• HS reactions to weekly Carbo (generally on infusion
#6-8) make monthly dosing preferable
• Regimen (perhaps in a lower dose to avoid
hematologic toxicities), may be preferred for patients
with HER2+ MBC who need or want to avoid
premedication
Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.
nab-paclitaxel + Bevacizumab
nab-Paclitaxel Phase II Trials in Combination with
Bevacizumab
• 3 different dosing schedules of nab-paclitaxel +
bevacizumab as first line treatment in MBC
(Conlin/Seidman)
• Retrospective Analysis: nab-paclitaxel + bevacizumab
in heavily pretreated MBC (Link)
• nab-Paclitaxel + gemcitabine + bevacizumab as firstline treatment in MBC (Lobo/Gluck)
Final Results of a Phase 2 Study
of nab-Paclitaxel, Bevacizumab,
and Gemcitabine as First-line Therapy for
Patients with HER2-Negative Metastatic
Breast Cancer
C. Lobo, G. Lopes, O. Baez, A. Castrellon,
Ferrell, C. Higgins, E. Hurley, J. Hurley, I. Reis,
S. Richman, P. Seo, O. Silva, J. Slingerland,
K. Tukia, C. Welsh, S. Gluck
Breast Cancer Res Treat (2010) 123:427–435
Study Features
• Objective: efficacy of combination therapy with nab-paclitaxel,
BEV + GEM as 1st line treatment for MBC patients
• Design: Multi-centre, open label Phase II study
• Patients: untreated HER2-negative MBC or metastases diagnosed
≥ 6 months after adjuvant or neo-adjuvant systemic treatment
• Primary endpoint:
– Progression-free survival (PFS)
• Secondary endpoints
–
–
–
–
Overall Survival (OS)
Response rate (CR or PR)
Safety
Toxicity
Breast Cancer Res Treat (2010) 123:427–435
Study Design
Gemcitabine 1500 mg/m2
nab-paclitaxel 150 mg/m2
Bevacizumab 10 mg/kg
Evaluate response
After 2 cycles
Day
1
15
Treatment continued until
• Disease progression
• Unacceptable toxicity
• Patient withdrawal
28
CT scans every
2 cycles
Cycle 1
Additional cycles
Breast Cancer Res Treat (2010) 123:427–435
Patient Characteristics
and Demographics
Patients, no. (%)
(N = 29)
Median age, years (range)
54 (34 – 69)
Sex
Female
Male
ER status
ER+/ERPR status
PR+/ PR-/ unknown
Triple Negative
Location of metastases
Liver
Bone
Lung
Lymph nodes
Chest wall
Brain
Gastrohepatic Ligament
28 (96.6)
1 (3.4)
16 (55.2) / 13 (44.8)
7 (24.1) / 19 (65.5) / 3 (10.3)
13 (44.8)
10 (34.5)
10 (34.5)
10 (34.5)
5 (17.2)
2 (6.9)
1 (3.4)
1 (3.4)
Breast Cancer Res Treat (2010) 123:427–435
Chemotherapy Delivery
TREATMENT CYCLES
1.5
2-5
n (%)
1 (3.4)
8 (27.6)
> 5 to 10
> 10
15 (51.7)
5 (17.2)
Breast Cancer Res Treat (2010) 123:427–435
Best Response to Treatment
Complete response (CR)
Partial response (PR)
Overall Response (OR)
Stable disease for > 6 months (SD)
Progressive disease (PD)
Clinical Benefit Rate (CR + PR + SD)
Patients, no. (%)
(N = 29)
8 (27.6)
14 (48.3)
22 (75.9)
5 (17.2)
2 (6.9)
27 (93.1)
Breast Cancer Res Treat (2010) 123:427–435
Progression-Free Survival
Breast Cancer Res Treat (2010) 123:427–435
Progression-Free Survival
TN vs. non-TN patients
Breast Cancer Res Treat (2010) 123:427–435
Overall Survival
Breast Cancer Res Treat (2010) 123:427–435
Safety Results
• The most commonly reported grade ≤ 2 side effects
were:
– alopecia (in 65.5% of patients),
– fatigue (37.9%),
– bone pain (31%),
– nausea (31%), and
– skin rash/lesion (27.6%)
Breast Cancer Res Treat (2010) 123:427–435
Safety Results
Adverse Events
Patients, n (%) (N = 29)
Overall
Grade 2
Grade 3
Alopecia
19 (65.5)
16 (55.2)
-
Nausea/loss of appetite
9 (31.0)
8 (27.6)
0 (0)
Fatigue
11 (37.9)
5 (17.2)
0 (0)
Bone Pain
9 (31.0)
7 (24.1)
0 (0)
Headache
7 (24.1)
5 (17.2)
0 (0)
Rash
8 (27.6)
6 (20.7)
0 (0)
Epistaxis
6 (20.7)
2 (6.9)
0 (0)
Insomnia
4 (13.8)
4 (13.8)
0 (0)
Neutropenia
3 (10.3)
3 (10.3)
0 (0)
Febrile Neutropenia
1 (3.4)
0 (0)
1 (3.4) (Gr 4)
Hand-foot syndrome
7 (24.1)
7 (24.1)
0 (0)
3 (12)
1 (3.4)
2 (6.9)
Peripheral neuropathy
6 (20.7)
5 (17.2)
1 (3.4)
Anxiety
3 (10.3)
3 (10.3)
0 (0)
Diarrhea
4 (13.8)
4 (13.8)
0 (0)
Hypertension
3 (10.3)
3 (10.3)
0 (0)
Oral infection
2 (6.9)
2 (6.9)
0 (0)
Port infection
Breast Cancer Res Treat (2010) 123:427–435
Conclusions
• Combination of nab-paclitaxel + Avastin + GEM appears to be
very well tolerated in patients with MBC
• First-line therapy with this combination showed: 75.9% ORR
and 10.4 mo PFS – Median OS at 2 years not reached
• Although these data should be interpreted with caution, this
combination had a high response rate compared with previous
studies of GEM + TAX (41%) or BEV + TAX (37%)
• This triplet regimen may represent an important new first-line
treatment option for patients with MBC
• A large, randomized trial is being planned
Breast Cancer Res Treat (2010) 123:427–435
Ribbon-1 and Ribbon-2
summary
Study
Treatment
Outcomes
Conclusion
Ribbon-1:
randomised
Phase III
combining
bevacizumab
(BV) with firstline chemo for
MBC
• Capecitabine 1000 mg/m2 BID
x14d
• Taxane (paclitaxel weekly,
docetaxel every 3 weeks or
protein-bound paclitaxel every
3 weeks)
• Anthracycline-based chemo
(AC, EC, FAC, FEC)
• Placebo or BV 15 mg/kg every 3
weeks
ORR: capecitabine
+ BV: 35.4% vs
23.6% (chemo + PL)
(P=0.0097)
T/Anthr + BV: 51.3
vs 37.9 (P=0.0054)
• Establishes the efficacy of
combining BV with taxane
chemotherapies used for
first-line treatment of MBC
• Safety profile of BV in
combination with these
chemotherapies was
consistent with that
reported from previous
Phase III trials
Ribbon-2:
Phase III trial
of second-line
BV +
chemotherapy
in MBC
• Chemotherapy regimens:
Taxane (paclitaxel weekly,
docetaxel every 3 weeks or
protein-bound paclitaxel every 3
weeks) or gemcitabine or
capecitabine or vinorelbine
• Bevacizumab 15 mg/kg every
3 weeks or 10 mg/kg every 2
weeks + chemotherapy (n=459)
• Placebo + chemotherapy (n=225)
Median PFS: 7.2 vs.
5.1 months; HR:
0.78 (P=0.0072) for
chemo/BV vs
chemo/PL;
ORR: 39.5% vs
29.6%, P=0.0193 for
chemo/BV vs
chemo/PL
• Improved PFS with
combination BV + standard
chemotherapy vs
chemotherapy alone for
second-line treatment of
HER2– MBC
• BV-combination
chemotherapy regimens
well tolerated with no
unexpected AEs
*nab-paclitaxel monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment
for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. The recommended dose of nab-paclitaxel
is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. nab-paclitaxel is not approved for use in combination
chemotherapy
Chemotherapy + bevacizumab:
RIBBON-2
Median PFS (months)
Group
Chemo + PL Chemo + BV
HR (95% CI)
All patients (n=684)
5.1
7.2
0.78 (0.64-0.93)
Triple negative patients (n=159)
2.7
6.0
0.49 (0.33-0.74)
5.8
8.0
0.64 (0.49-0.84)
nab-Paclitaxel* (n=56)
4.8
7.2
0.55 (0.31-0.99)
Docetaxel (n=88)
4.3
7.6
0.76 (0.43-1.32)
Paclitaxel (n=157)
8.1
9.1
0.59 (0.39-0.90)
Gemcitabine (n=160)
5.5
6.0
0.90 (0.61-1.32)
Capecitabine (144)
4.1
6.9
0.73 (0.49-1.08)
Vinorelbine (n=76)
7.0
5.7
1.42 (0.78-2.59)
Chemotherapy
Taxanes (n=304)
*nab-Paclitaxel given 260 mg/m2 q3w
*nab-paclitaxel monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line
treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. The recommended dose of
nab-paclitaxel is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. nab-paclitaxel is not approved for use in
combination chemotherapy
Brufsky A, et al. Cancer Res. 2009;69(Suppl): Abstract 42.
An ongoing Phase III study is
investigating qw nab-paclitaxel* for first-line treatment of
MBC
•
CALGB 40502: A randomized Phase III trial of weekly paclitaxel compared with
Weekly nab-paclitaxel or Ixabepilone** combined with bevacizumab as first-line
therapy for locally recurrent or metastatic breast cancer
*nab-paclitaxel monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line
treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. The recommended dose of
nab-paclitaxel is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. nab-paclitaxel is not approved for use as firstline chemotherapy or on a weekly schedule.
**Ixempra (ixabepilone) is not approved in Europe, it has received marketing authorization from the Swissmedic for Switzerland only.
nab-paclitaxel impiegato nel trattamento del
carcinoma mammario metastatico
• nab-paclitaxel è un taxano efficace che ha dimostrato di produrre esiti
clinici favorevoli nel trattamento di prima e seconda linea del carcinoma
mammario metastatico
• È stato dimostrato un controllo migliore della malattia in associazione
all’impiego di nab-paclitaxel, in confronto a paclitaxel o docetaxel
• Sono stati osservati un tasso inferiore di neutropenia, rispetto ad altri
taxani e, soprattutto, di neuropatie sensoriali che si sono risolte
solitamente in modo rapido
• Sono stati riportati risultati promettenti ottenuti con nab-paclitaxel in
pazienti affette da mBC e pesantemente pretrattate con taxani
• L’impiego di nab-paclitaxel in associazione con altri agenti antitumorali
contribuirà ad ampliare il ventaglio delle opzioni terapeutiche efficaci
“nab-paclitaxel non è semplicemente
un altro taxano: è una chemioterapia target che
rappresenta un passo avanti nel trattamento delle
pazienti affette da MBC” 1
....e inoltre si sta studiando nab-paclitaxel
per altri tipi di tumori!!!!
1. Piccart M. nab™-Paclitaxel: A Targeted Chemotherapy to Improve Outcomes in Metastatic Breast Cancer, APJOH 2009