Transcript Slide 1

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NAB-Paclitaxel
in Metastatic Breast Cancer
Combination Studies
2
Phase II Multicenter Trial of Nab–Paclitaxel
and Capecitabine in First-Line Treatment of
Patients with with Metastatic Breast Cancer
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Background
• Cremophor® ELa paclitaxel1 and capecitabine1-3 have single
agent activity in metastatic breast cancer
• Taxane and antimetabolite doublets may improve response
rate and time to progression compared with single agent
therapy4
• Weekly NAB- paclitaxel has demonstrated safety and efficacy
for the first-line treatment of MBC5
aCremophor
is a registered trademark of BASF.
1. Talbot DC, et al. Br J Cancer. 2002;86:13671372.
2. O’Shaughnessy, et al. Ann Oncol. 2001.
3. Bajetta, et al. J Clin Oncol. 2005.
4. Miles, et al. Clin Breast Cancer. 2004.
5. Gradishar et al J Clin Onc. 2009;27:361-36919.
MBC, metastatic breast cancer.
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Objectives
• To evaluate the safety and efficacy of NAB- paclitaxel and
capecitabine in a novel combination schedule in previously
untreated MBC
• Endpoints
– Primary:
• Response rate (ORR)
– Secondary:
• Progression-free survival (PFS)
• Overall survival (OS)
• Safety
MBC, metastatic breast cancer.
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Key Eligibility Criteria
• Inclusion criteria
–
–
–
–
Measurable MBC by RECIST criteria
Age > 18
ECOG PS ≤ 2
At least 6 months since adjuvant fluoropyrimidine or Cremophor®
EL paclitaxel
– Adequate bone marrow, kidney, and liver function
• Exclusion criteria
– Prior chemotherapy for metastatic disease
– Prior capecitabine therapy
ECOG PS, Eastern Cooperative Oncology Group
performance status; MBC, metastatic breast
cancer; RECIST, response evaluation criteria in
solid tumors.
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Study Design and Treatment
Purpose: A single arm, multi-center phase II trial to determine efficacy of
NAB-paclitaxel + capecitabine as first line treatment of MBC patients
(HER2-)
– N = 50
– Patients with ECOG PS 0-2, HER2-, adequate organ function
– Cycles of 21 days until disease progression or dose-limiting toxicity
NAB- paclitaxel
125 mg/m2
IV over 30 min
Days 1 and 8 q3w without
premedication
Capecitabine 825 mg/m2
Orally bid
Days 1-14 q3w
Endpoints
• Primary: ORR
• Secondary: PFS, OS, safety
bid, twice daily; IV, intravenous; MBC,
metastatic breast cancer; q3w, every 3
weeks.
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Patient Characteristics
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Select Patient Characteristics
Baseline characteristic (N = 50)
Age in years, median (range)
MBC, metastatic breast cancer.
Value
59.0 (23.7-83.8)
Prior chemotherapy, n (%)
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 site, n (%)
Bone
Liver
Other lymph node
Pulmonary
27 (54)
24 (48)
19 (38)
17 (34)
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Results: Tumor Response
Outcome (N = 46)
n (%)
ORR
CR
PR
28 (61)
2 (4)
26 (57)
SD
10 (22)
PD
8 (17)
Note: 4 of the 50 patients not evaluable for response.
CR, complete response; MBC, metastatic breast
cancer; ORR, overall response rate; PD,
progressive disease; PR, partial response; SD,
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
stable disease.
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Results: Progression Free Survival
The red line indicates product limit estimate of survival curve and circles indicate a censored observation
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Results: Overall Survival
The red line indicates product limit estimate of survival curve and circles indicate a censored observation
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Results: Change in target lesions
Change in Target Lesions from Baseline to Best Response. The x-axis represents individual patients
who remained on study through the first scheduled restaging (n 45). The y-axis represents the
percentage change in tumor size from baseline.
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Results: Dose Modifications
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Treatment related adverse events
Frequency for all events 12 or any event grade 3. Patients may have had more than 1
adverse event.
Abbreviations: ALP alkaline phosphatase; AST aspartate aminotransferase.
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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First-Line NAB-Paclitaxel and Capecitabine in MBC
Conclusions
• NAB- paclitaxel plus capecitabine is a highly active combination
regimen in first-line MBC with an ORR of 61%
• This combination therapy led to a favorable median PFS of 10.6
months
• This regimen is well tolerated and the schedule has a favorable
safety profile with efficacy similar to known combinations
• This regimen could be considered for addition of biological therapy
and/or in a phase III trial compared with other standard strategies for
first-line treatment of MBC
Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication
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Phase II Trial of Weekly NAB- Paclitaxel
in Combination With Gemcitabine in
Patients With Metastatic Breast Cancer
V. Roy, B. R. LaPlant, G. G. Gross,
C. L. Bane, F. M. Palmieri,
on behalf of the North Central Cancer
Treatment Group
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Background
• A randomized phase III trial showed superior efficacy of NABpaclitaxel to Cremophor® EL paclitaxel¹
• In a phase III study, the addition of gemcitabine to Cremophor
EL paclitaxel therapy increased tumor response in MBC
patients previously treated with anthracyclines2
– Overall response rate of 41% vs. 26% for Cremophor EL
paclitaxel alone
MBC, metastatic breast cancer.
Roy V et al. Ann Oncol. 2009;20(3):449-453.
1. Gradishar WJ, et al, J Clin Oncol.
2005;23(31):7794-7803.
2. Albain KS, et al. J Clin Oncol. 2008;26(24):39503957.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Objectives
• To evaluate the combination of NAB- paclitaxel and
gemcitabine for the treatment of MBC
• Endpoints
– Primary:
• Confirmed response rate per RECIST criteria on 2 consecutive
evaluations ≥ 6 weeks apart
MBC, metastatic breast cancer; RECIST,
Response Evaluation Criteria in Solid Tumors.
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Key Eligibility Criteria
• Inclusion criteria
– Age ≥ 18 years
– Histologically and cytologically confirmed invasive breast cancer
with clinical evidence of metastatic disease
– Eastern Cooperative Oncology Group performance status of 0 - 1
– Patients may have received prior hormonal therapy for MBC
– Taxane therapy allowed as adjuvant or neoadjuvant treatment if
completed ≥ 6 months before study entry
• Exclusion criteria
– Active central nervous system metastasis
– Higher than grade 1 peripheral neuropathy
– Previous chemotherapy for metastatic disease
MBC, metastatic breast cancer.
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Study Design and Treatment
• This was an open-label, multicenter phase II study conducted
through the North Central Cancer Treatment Group
NAB- paclitaxel
125 mg/m2
Days 1 and 8 every 21 days
IV, intravenous; MBC, metastatic breast cancer.
Gemcitabine
1000 mg/m2
Days 1 and 8 every 21 days
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Baseline Patient Characteristics
Baseline characteristic (N = 50)
Age in years, median (range)
Value
56 (29 - 86)
ECOG PS, n (%)
0
1
23 (46)
27 (54)
Prior chemotherapy, n (%)a
Anthracycline
Taxane
25(50)
24 (48)
15 (30)
Number of metastatic sites, n (%)
1
2
3+
5 (10)
15 (30)
30 (60)
a Patients
may have had more than one type of prior therapy.
ECOG PS, Eastern Cooperative Oncology Group
performance status;
MBC, metastatic breast cancer.
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Results: Efficacy
Outcome (N = 50)
Value
Number of administered cycles, median (range)
ORRa (≥ PR), n (%; 95% CI)
7 (1-17)
25 (50; 36-64)
CR, n (%)
4 (8)
PR, n (%)
20 (42)
Duration of response in months, median (95% CI)
6.9 (5.7, NR)
PFS in months, median (95% CI)
7.9 (5.4-10)
OS in months, median (95% CI)
NR
6-month PFS, % (95% CI)
60 (48-76)
6-month OS, % (95% CI)
92 (85-100)
a
Overall confirmed response.
CI, confidence interval; CR, complete response;
MBC, metastatic breast cancer; NR, not reached;
ORR, overall response rate; OS, overall survival;
PFS, progression-free survival; PR, partial
response.
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Safety: Grade 3/4 Adverse Events Occurring in > 5% of
Patients
Adverse event, N = 50
Grade 3, n (%)
Grade 4, n (%)
Neutropenia
21 (42)
6 (12)
Fatigue
14 (28)
0
Anemia
7 (14)
0
Dyspnea
7 (14)
0
Thrombocytopenia
5 (10)
1 (2)
Arthralgia
4 (8)
0
Vomiting
4 (8)
0
Neuropathy
4 (8)
0
Myalgia
3 (6)
0
Nausea
3 (6)
0
Pain, abdominal
3 (6)
0
AST elevation
3 (6)
0
• Neutropenia and thrombocytopenia were the only grade 4 AEs reported
• Fatigue was the most commonly reported nonhematologic grade 3/4 AE
AE, adverse event; AST, aspartate
aminotransferase; MBC, metastatic breast cancer.
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB- Paclitaxel Plus Gemcitabine in MBC
Conclusions
• Weekly NAB- paclitaxel in combination with gemcitabine
demonstrated significant activity as first-line 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 4 (8%) patients
AE, adverse event; MBC, metastatic
breast cancer.
Roy V et al. Ann Oncol. 2009;20(3):449-453.
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NAB-Paclitaxel and Bevacizumab Treatment
in Metastatic Breast Cancer
J. S. Link, J. R. Waisman, B. Nguyen,
C. I. Jacobs
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
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NAB- Paclitaxel and Bevacizumab in MBC
Background
• It has been demonstrated that the combination of bevacizumab
and Cremophor® EL paclitaxel has significant activity in MBC1
• Compared to Cremophor EL paclitaxel, NAB- paclitaxel has
been shown to:
– Have increased paclitaxel delivery to tumor2
– Produce a higher response for MBC compared with Cremophor
EL paclitaxel3
MBC, metastatic breast cancer.
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
1. Miller K, et al. N Engl J Med.
2007;357:2666-2676.
2. Desai N, et al. Clin Cancer Res.
2006:12(4):1317-1324.
3. Gradishar WJ, et al. J Clin Oncol.
2005;23(31):7794-7803.
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NAB- Paclitaxel and Bevacizumab in MBC
Objectives
• To investigate the safety and efficacy of NAB- paclitaxel with
bevacizumab in heavily pretreated women with MBC
• This retrospective chart analysis examined patients treated
consecutively with NAB- paclitaxel and bevacizumab in the
second-line setting
– Outcomes examined include:
• ORR
– CR
– PR
• SD
• TTP
• Safety: adverse events
CR, complete response; MBC, metastatic
breast cancer; ORR, overall response rate;
PFS, progression-free survival; PR, partial
response; SD, stable disease; TTP, time to
tumor progression..
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
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NAB- Paclitaxel and Bevacizumab in MBC
Study Design
• Retrospective chart review to identify all patients treated
consecutively with a combination of NAB- paclitaxel and
bevacizumab
NAB- paclitaxel
Dose 1: 80-125 mg/m2
qw 3/4
OR
Dose 2: 170-200 mg/m2
q2w on 28-day cycle
MBC, metastatic breast cancer; q2w,
every 2 weeks; qw 3/4, first 3 of 4 weeks.
Bevacizumab 10 mg/kg q2w
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
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NAB- Paclitaxel and Bevacizumab in MBC
Baseline Patient Characteristics
• Forty women with heavily pretreated MBC received
treatment
– Thirty-four patients (85%) received a minimum of 3 prior
chemotherapy regimens for adjuvant or metastatic disease
– Prior taxanes: n = 35 (87%)
– Prior anthracyclines: n = 34 (85%)
MBC, metastatic breast cancer.
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
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NAB- Paclitaxel and Bevacizumab in MBC
Results: Tumor Response
Responses (n = 33)a
n (%)
ORR (≥ PR)
CR
PR
16 (49)
3 (9)
13 (39)
SD
5 (15)
CR + PR + SD
21 (64)
PD
12 (36)
a
Evaluable patients.
• Median TTP among responding patients:
– q2w group (n = 14): 103 days
– Weekly group (n = 19): 148 days
CR, complete response; MBC, metastatic breast
cancer; ORR, overall response rate; PR, partial
response; PD, progressive disease; q2w, every 2
weeks; SD, stable disease; TTP, time to tumor
progression.
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
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NAB- Paclitaxel and Bevacizumab in MBC
Results: Most Common Adverse Events
Grade 2
n (%)
Grade 3
n (%)
Fatigue
9 (23)
0
Pain (including bone pain)
5 (13)
3 (8)
Neuropathy
4 (10)
1 (3)
Hypertension
3 (8)
0
Anemia
2 (5)
2 (5)
Adverse Events (N = 40)
• No grade 4 adverse events were observed during this analysis
MBC, metastatic breast cancer.
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
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NAB- Paclitaxel and Bevacizumab in MBC
Conclusions
• NAB- paclitaxel + bevacizumab is a relatively effective and
safe treatment option for heavily pretreated MBC patients
• The safety profile of these patients was considered to be
acceptable
• Additional studies may be warranted with this regimen
AE, adverse event; MBC, metastatic
breast cancer.
Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.
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Phase II Trial of Weekly
NAB-Paclitaxel in Combination With
Bevacizumab as
First-line Treatment in Metastatic
Breast Cancer
M. Danso, J. Blum, N. Robert,
L. Krekow, R. Rotche, D. Smith,
P. Richards, T. Anderson, D. Richards,
J. O’Shaughnessy
Danso M et al. ASCO. 2008 [Abstract 1075].
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First-Line NAB- Paclitaxel and Bevacizumab for MBC
Background
• A clinical trial of Cremophor® EL paclitaxel ± bevacizumab in
patients with locally recurrent MBC1
– N = 722
– Cremophor EL paclitaxel 90 mg/m² was administered weekly for
3 weeks followed by a week of rest
• With or without bevacizumab 10 mg/kg every 2 weeks
– Results
• The combination had a longer median progression-free
survival (11.8 vs. 5.9 months; P < 0.001) and overall
response rate (36.9% vs. 21.2%; P < 0.001)
MBC, metastatic breast cancer.
Danso M et al. ASCO. 2008 [Abstract 1075].
1. Miller K et al. N Engl J Med.2007;357:2666-2676.
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First-Line NAB- Paclitaxel and Bevacizumab for MBC
Objectives
• To evaluate safety, tolerability and efficacy of NAB- paclitaxel
in combination with bevacizumab in MBC
• Endpoints
– Primary:
• Incidence of treatment-emergent AEs, serious AEs
• Median PFS
– Secondary:
• ORR: CR + PR determined according to RECIST guidelines
• Total Response: CR + PR + SD ≥ 16 weeks
• Duration of Response
• Overall survival
AE, adverse event; CR, complete response;
MBC, metastatic breast cancer; ORR, overall
response rate; PFS, progression-free survival;
PR, partial response; RECIST, Response
Evaluation Criteria In Solid Tumors.
SD, stable disease.
Danso M et al. ASCO. 2008 [Abstract 1075].
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First-Line NAB- Paclitaxel and Bevacizumab for MBC
Study Design and Treatment
• This was a multicenter, open-label, phase II study
• Therapy with one or both study drugs could continue in the
absence of disease progression or unacceptable toxicity
NAB- paclitaxel
125 mg/m2
IV over 30 min q3w
28-day cycle
IV, intravenous; MBC, metastatic breast cancer;
q2w, every 2 weeks; q3w, every 3 weeks.
Bevacizumab 10 mg/kg q2w
Danso M et al. ASCO. 2008 [Abstract 1075].
28-day cycle
37
First-Line NAB- Paclitaxel and Bevacizumab for MBC
Baseline Patient Characteristics
Baseline characteristic (N = 50)
Age in years, median (range)
Value
58 (35 - 88)
ECOG PS, n (%)
0
1
2
24 (49)
23 (47)
2 (4)
Prior adjuvant therapiesa, n (%)
Chemotherapy
Docetaxel
Cremophor® EL paclitaxel
Doxorubicin
24 (48)
7 (14)
7 (14)
2 (4)
a Patients
may have had more than one type of prior therapy.
ECOG PS, Eastern Cooperative Oncology Group
performance status; MBC, metastatic breast
cancer.
Danso M et al. ASCO. 2008 [Abstract 1075].
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First-Line NAB- Paclitaxel and Bevacizumab for MBC
Results: Efficacy
Response (N = 45)a
Value
ORR, n (%)
CR
PR
15 (33)
1 (2)
14 (31)
SD of any duration, n (%)
10 (22)
PFS in months, median (95% CI)
A 45
7.4 (5.4-9.2)
of 50 patients were evaluable for response.
CI, confidence interval; CR, complete response;
MBC, metastatic breast cancer; ORR, overall
response rate; PFS, progression-free survival;
PR, partial response; SD, stable disease.
Danso M et al. ASCO. 2008 [Abstract 1075].
39
First-Line NAB- Paclitaxel and Bevacizumab for MBC
Safety: Grade 3/4 Hematologic AEs in ≥ 5% of Patients
Grade 3,
n (%)
Grade 4,
n (%)
Mean nadir ± SD
(× 109/L)
Neutropenia
15 (34)
7 (16)
1.35 ± 1.19
Leukopenia
12 (27)
3 (7)
2.73 ± 1.45
3 (7)
2 (5)
105.0 ± 16.33
Adverse Event (N = 50)
Anemia
AE, adverse event; MBC, metastatic breast
cancer; SD, standard deviation.
Danso M et al. ASCO. 2008 [Abstract 1075].
40
First-Line NAB- Paclitaxel and Bevacizumab for MBC
Safety: Nonhematologic AEs in ≥ 10% of patients
• Sensory neuropathy and dehydration were the only grade 4 nonhematologic
AEs reported in this study
AE, adverse event; MBC, metastatic
breast cancer.
Danso M et al. ASCO. 2008 [Abstract 1075].
41
First-Line NAB- Paclitaxel and Bevacizumab for MBC
Conclusions
• In patients with MBC, weekly NAB- paclitaxel + bevacizumab
demonstrated a 33% ORR and a median PFS of 7.4 months
• Overall, NAB- paclitaxel + bevacizumab as first-line therapy
had manageable AEs
– < 50% of patients experienced grade 3/4 hematologic AEs
– Only 1 patient experienced grade 4 nonhematologic AEs
(sensory neuropathy and dehydration)
AE, adverse event; MBC, metastatic breast
cancer; ORR, overall response rate; PFS,
progression-free survival.
Danso M et al. ASCO. 2008 [Abstract 1075].
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Randomized Phase II Trial of NAB- Paclitaxel
in 3 Dosing Schedules With Bevacizumab as
First-line Therapy for
HER2- Metastatic Breast Cancer
A.K. Conlin, C.A. Hudis, A. Bach,
M.E. Moynahan, D. Lake, A. Forero-Torres,
G. Wright, M.H. Hackney, A. Clawson,
A.D. Seidman
Conlin AK et al. ASCO. 2009 [Abstract 1006].
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First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Background
• Q3w 260 mg/m2 NAB- paclitaxel demonstrates higher
response rates and time to tumor progression compared with
q3w 175 mg/m2 Cremophor® EL paclitaxel1
• Weekly uninterrupted Cremophor EL paclitaxel is more
effective than q3w Cremophor EL paclitaxel in MBC2
• Dose-dense every-2-week Cremophor EL paclitaxel confers a
survival advantage over q3w as a component of adjuvant
therapy3
• The addition of bevacizumab to weekly Cremophor EL
paclitaxel for first-line therapy of MBC increases response rate
(RR) and prolonged progression-free survival (PFS)4
• The combination of NAB- paclitaxel with bevacizumab has
shown significant synergy in animal models5
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; q3w, every 3
weeks.
1. Gradishar WJ, et al. J Clin Oncol. 2005;23(31):7794-7803.
2. Seidman AD, et al. J Clin Oncol. 2008;26(10):1642-1649.
3. Citron ML, et al. J Clin Oncol. 2003;21(8):1431-1439.
4. Miller K, et al. N Eng J Med. 2007;357:2666-2676.
5. Volk LD, et al. Neoplasia.
2008;10(6):613-623.
Conlin AK, et al. ASCO. 2009 [Abstract 1006].
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First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Objectives
• Endpoints
– Primary
• Safety and tolerability
• ORR
– Secondary
• TTP
• OS
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; ORR, overall
response rate; OS, overall survival; TTP, time to
tumor progression.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
45
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Key Eligibility Criteria
• Inclusion
–
–
–
–
Stage IV adenocarcinoma of the breast
Not a candidate for trastuzumab
Measurable disease by RECIST criteria
Adequate renal, hepatic, and bone marrow function
• Exclusion
– Adjuvant taxane < 12 months or any chemotherapy < 6 months
prior to study enrollment
– Peripheral neuropathy > grade 1 at baseline
– Central nervous system metastases
– Uncontrolled hypertension, proteinuria, vascular disease or
coagulopathy
– Prior chemotherapy in the metastatic setting
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; RECIST,
Response Evaluation Criteria in Solid Tumors.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
46
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Study Design
Target N = 225
Arm A: NAB- paclitaxel
260 mg/m2 q3w, bevacizumab 15 mg/kg q3w
Cycle: 1 infusion q3w
Arm B: NAB- paclitaxel
260 mg/m2 q2w + G-CSF support,
bevacizumab 10 mg/kg q2w
Cycle: 1 infusion q2w
Randomization
Stratification:
Adjuvant Therapy
ECOG PS
ECOG PS, Eastern Cooperative Oncology
Group performance status; G-CSF, granulocyte
colony-stimulating factor; HER2, human
epidermal growth factor receptor 2; MBC,
metastatic breast cancer; qw, weekly; q2w,
every 2 weeks; q3w, every 3 weeks.
130
Arm C: NAB- paclitaxel
qw, bevacizumab 10 mg/kg q2w
Cycle: weekly infusions
mg/m2
Conlin AK, et al. ASCO. 2009 [Abstract 1006].
47
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Baseline Patient Characteristics
AB-paclitaxel Dose
Baseline characteristic (N = 205)
260 mg/m2 q3w
(n = 73)
260 mg/m2 q2w
(n = 54)
130 mg/m2 qw
(n = 78)
59 (29-80)
52 (71)
21 (29)
56 (36-79)
41 (76)
13 (24)
56 (32-85)
62 (79)
16 (21)
ECOG performance status, n (%)
0
1
43 (59)
27 (37)
33 (61)
17 (31)
47 (60)
27 (35)
Visceral dominant disease, n (%)
Yes
No
Unknown
64 (88)
8 (11)
1 (1)
49 (92)
3 (6)
1 (2)
68 (87)
10 (13)
0
Premenopausal patients, n (%)
11 (15)
11 (20)
15 (19)
Prior chemotherapy, n (%)a
Cremophor® EL paclitaxel
Docetaxel
Doxorubicin
Epirubicin
46 (63)
18 (25)
9 (12)
35 (48)
2 (3)
33 (61)
14 (26)
7 (13)
23 (43)
4 (7)
47 (60)
18 (23)
13 (17)
37 (47)
3 (4)
Median age, years (range)
< 65 years, n (%)
≥ 65 years, n (%)
aPrior
neoadjuvant or adjuvant treatment.
AB, NAB-; ECOG; Eastern Cooperative
Oncology Group; 2; HER2, human epidermal
growth factor receptor ; MBC, metastatic
breast cancer; qw, weekly; q2w, every 2
weeks; q3w, every 3 weeks.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
48
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Preplanned Dose Reductions
AB-paclitaxel Dose
Dose level
260 mg/m2 q3w
260 mg/m2 q2w
130 mg/m2 qw
0
260
260
130
-1
220
220
110
-2
180
180
90
• Doses were modified as shown if patients experienced excessive
toxicities
AB, NAB-; HER2, human epidermal growth factor
receptor 2; MBC, metastatic breast cancer; qw,
weekly; q2w, every 2 weeks; q3w, every 3
weeks.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
49
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Results: Dose Parameters
Dose Parameter
AB-P
260 mg/m2
q3w
(n = 73)
AB-P
260 mg/m2
q2w
(n = 54)
AB-P
130 mg/m2
qw
(n = 78)
Patients with ≥ 1 dose reduction, n (%)
Due to grade 3/4 neurotoxicity, n/N (%)
30 (41)
11/30 (37)
26 (48)
15/26 (58)
50 (64)
23/50 (46)
Patients with ≥ 1 dose delay, n (%)
Due to neurotoxicity, n/N, (%)
Due to other reasons, n/N (%)
36 (49)
19/36 (53)
20/36 (56)
22 (41)
11/22 (50)
17/22 (77)
67 (86)
38/67 (57)
49/67 (73)
20
13
22
79 (45.7-88.8)
114 (68.6134.8)
97 (61.7-130)
91 (79/86)
88 (114/130)
75 (97/130)
Weeks of therapy, median
Dose intensity in mg/m2/week, mean
(range)
Relative dose intensity, %
(Delivered/planned)
AB-P, NAB- paclitaxel; MBC, metastatic breast
cancer; qw, weekly; q2w, every 2 weeks; q3w,
every 3 weeks; HER2, human epidermal growth
factor receptor 2.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
50
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Results: Adverse Events
AB-P
260 mg/m2
q3w
(n = 73)
AB-P
260 mg/m2
q2w
(n = 54)
AB-P
130 mg/m2
qw
(n = 78)
≥ 1 AE reported
Grade 3
Grade 4
Grade 5
42 (58)
9 (12)
1 (1)a
39 (72)
5 (9)
1 (2)a
52 (67)
11 (14)
0
Sensory neuropathy
Grade 2
Grade 3
Grade 4
20 (27)
22 (30)
0
8 (15)
25 (46)
1 (2)
18 (23)
30 (38)
1 (1)
2 (2)
1 (2)
0
Adverse Event, n (%)
Febrile neutropenia
Grade 3/4b
a
Not treatment related.
Only AEs of grade 3/4 reported. AEs based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0.
Note: none of these overall comparisons were statistically significant.
b
AB-P, NAB- paclitaxel; AE, adverse event;
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; qw, weekly;
q2w, every 2 weeks; q3w, every 3 weeks.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
51
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Results: Adverse Events (cont.)
AB-P
260 mg/m2 q3w
(n = 73)
AB-P
260 mg/m2 q2w
(n = 54)
AB-P
130 mg/m2
qw (n = 78)
P value
Fatigue, Grade 3/4
12 (16)
18 (33)
13 (17)
Overall: .015
Nausea, Grade 3/4
3 (4)
4 (7)
1 (1)
Overall: .111
Arthralgia
Grade 2
Grade 3
9 (12)
4 (5)
9 (17)
1 (2)
1 (1)
0
Overall: < .001
Myalgia
Grade 2
Grade 3
6 (8)
0
2 (4)
3 (6)
0
0
Bone pain
Grade 2
Grade 3
6 (8)
2 (3)
8 (15)
3 (6)
2 (3)
1 (1)
Overall: .002
13 (18)
5 (9)
8 (10)
Overall: NS
0
3 (6)
5 (6)
Overall: .048
A vs. C: .014
2 (3)
0
2 (4)
3 (6)
10 (13)
7 (9)
Adverse event, n (%)
Hypertension, Grade 2/3
Diarrhea, Grade 3/4
Nail changes
Grade 2
Grade 3
Overall: NS
B vs. C: .021
Overall: .001
A vs. C: < .001
Note: Adverse events graded on National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. P-values based on Cochran-Mantel-Haenszel test.
AB-P, NAB- paclitaxel; HER2, human epidermal
growth factor receptor 2; MBC, metastatic breast
cancer; qw, weekly: q2w, every 2 weeks; q3w,
every 3 weeks.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
52
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Results: Sensory Neuropathy
• AE sensory neuropathy grade profiles were similar among the 3 groups
(comparison P values not significant)
AB-P, NAB- paclitaxel; AE, adverse event;
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; qw, weekly;
q2w, every 2 weeks; q3w, every 3 weeks.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
53
First-Line NAB- Paclitaxel and Bevacizumab in HER2Metastatic Breast Cancer
Results: Improvement in Sensory Neuropathy
AB-P
260 mg/m2 q3w
(n = 73)
AB-P
260 mg/m2 q2w
(n = 54)
AB-P
130 mg/m2 qw
(n = 78)
Baseline grade 3/4 sensory
neuropathy, n (%)
22 (30)
26 (48)
31 (40)
Improvement (≤ grade 2), n (%)
16 (73)
20 (77)
29 (94)
37 (22-43)
22 (15-45)
15 (8-28)
Parameter
Time to improvement in days,
median (95% CI)
AB-Pac, NAB- paclitaxel; CI, confidence interval;
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; qw, weekly;
q2w, every 2 weeks; q3w, every 3 weeks.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
54
First-Line NAB- Paclitaxel and Bevacizumab in HER2Metastatic Breast Cancer
Results: Confirmed Overall Response Rate
AB-P
260 mg/m2 q3w
(n = 73)
AB-P
260 mg/m2 q2w
(n = 54)
AB-P
130 mg/m2
qw (n = 78)
32 (44)
32.5-55.2
21 (39)
25.9-51.9
36 (46)
35.1-57.2
Confirmed CR, n (%)
1 (1)
1 (2)
1 (1)
Confirmed PR, n (%)
31 (42)
20 (37)
35 (45)
Patients with progressive disease, n (%)
38 (52)
28 (52)
32 (41)
7.7 (7.0-10.3)
6.3 (5.4-7.9)
9.0 (7.3-14.2)
Response
ORRa (≥ confirmed PR), n (%)
95% CI
TTP in months, median (95% CI)
a Overall
ORR P value = 0.575.
• Data are immature; only 40% of patients have progressed
• All analyses were performed on the treated population of patients
AB-P, NAB- paclitaxel; CI, confidence interval;
CR, complete response; HER2, human
epidermal growth factor receptor 2; MBC,
metastatic breast cancer; ORR, overall response
rate; PR, partial response; qw, weekly; q2w,
every 2 weeks; q3w, every 3 weeks; TTP, time to
tumor progression.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
55
First-Line NAB- Paclitaxel and Bevacizumab in HER2Metastatic Breast Cancer
Results: Time to Tumor Progression
• The median TTPs by investigator assessment for the q3w, q2w, and qw arms
were 7.7, 6.3, and 9.0 months, respectively
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; qw, weekly;
q2w, every 2 weeks; q3w, every 3 weeks; TTP,
time to tumor progression.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
56
First-Line NAB- Paclitaxel and Bevacizumab in HER2MBC
Conclusions
• Sustained q2w NAB- paclitaxel at 260 mg/m2 with filgrastim for
more than 4 cycles is not feasible in this population due to
nonhematologic toxicity
• Neurotoxicity limited treatment in all 3 arms
• All 3 arms demonstrated similar efficacy
• Dose delay and reduction with weekly (uninterrupted) NABpaclitaxel were common
• NAB- paclitaxel for the first 3 weeks of a 4-week schedule,
adopted by prospective studies like CALGB 40502, might be
preferable
CALGB, Cancer and Leukemia Group B; HER2,
human epidermal growth actor receptor 2; MBC,
metastatic breast cancer; q2w, every 2 weeks.
Conlin AK et al. ASCO. 2009 [Abstract 1006].
57
Final Results of a Phase II Study of
NAB- Paclitaxel, Bevacizumab, and
Gemcitabine as First-Line Therapy for
Patients With HER2- Metastatic Breast
Cancer
C. Lobo, G. Lopes, O. Baez, A. Castrellon,
A. Ferrell, C. Higgins, E. Hurley, J. Hurley,
I. Reis, S. Richman, P. Seo, O. Silva,
J. Slingerland, K. Tukia, C. Welsh, S. Gluck
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
58
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Background
• NAB- paclitaxel was found to be more efficacious than
Cremophor® EL paclitaxel in a phase III study of patients with
MBC1
– Higher overall response rate (33% vs. 19%, P = .001)
– Significantly longer time to tumor progression (P = .006)
• The addition of gemcitabine² or bevacizumab³ to Cremophor
EL paclitaxel has been shown to improve TTP and response
rates
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; TTP, time to
tumor progression.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
1. Gradishar WJ et al, J Clin Oncol
2005;23(31):7794-7803.
2. Albain KS et al. J Clin Oncol. 26(24):39503957.
3. Miller K et al. N Engl J Med.
2007;357:2666-2676.
59
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Objective
• Objective: to examine the efficacy and safety of NABpaclitaxel plus bevacizumab plus gemcitabine as first-line
treatment for patients with MBC
• Primary endpoint: progression-free survival
• Secondary endpoints
– Overall survival
– Overall response rate (ORR)
• Complete and partial response rates
– Clinical benefit (ORR + stable disease rate)
– Safety/Tolerability
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
60
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Key Eligibility Criteria
• HER2-, MBC treatment-naïve, or metastasis diagnosed ≥ 6
months after completion of primary or adjuvant systemic
treatment
• No previous chemotherapy within 1 month of enrollment
• Measurable disease as defined by Response Evaluation
Criteria in Solid Tumors (RECIST)
• Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1
• Life expectancy > 3 months
• Adequate laboratory values
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
61
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Study Design and Treatment
• This was a phase II open-label single-center study
Gemcitabine 1500 mg/m2
NAB- paclitaxel
150 mg/m2
Bevacizumab 10 mg/kg
Day
1
15
Evaluate response
after 2 cycles
Treatment continued until:
Disease progression
Unacceptable toxicity
Patient withdrawal
28
CT scans every
2 cycles
Cycle 1
Additional Cycles
• All drugs were administered by IV infusion over 30 minutes on Days 1
and 15 of a 28-day cycle
• All dose reductions followed the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) (version 3.0)
for hematologic and nonhematologic toxicity
HER2; human epidermal growth factor receptor
2; IV, intravenous.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
62
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Baseline Patient Characteristics
Baseline characteristics ( N = 29)
Age in years, median (range)
Female sex, n (%)
Race, n (%)
White
Black
Asian
Site of metastasis, n (%)
Bone
Liver
Lung
Lymph nodes
Chest wall
Brain
Gastrohepatic ligament
HER2, human epidermal growth factor
receptor 2.
Value
54 (34-69)
28 (96.6)
20 (69)
8 (27.6)
1 (3.4)
10 (34.5)
10 (34.5)
10 (34.5)
5 (17.2)
2 (6.9)
1 (3.4)
1 (3.4)
Baseline characteristics (N = 29)
n (%)
Positive estrogen receptor status
16 (55.2)
Progesterone receptor status
Negative
Positive
Unknown
19 (65.5)
7 (24.1)
3 (10.3)
Number of treatment cycles
1.5
2-5
6-10
> 10
Median (range)
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
1 (3.4)
8 (27.6)
15 (51.7)
5 (17.2)
6.5 (1.5-23)
63
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Results: Efficacy
All evaluable
patients (N = 29)
n (%, 95% CI)
TNBC patientsa
(n = 13)
n (%)
CR
8 (27.6, 13-47)
5 (38)
PR
14 (48.3, 29-68)
4 (31)
SD
5 (17.2, 6-36)
2 (15)
PD
2 (6.9, 0.8-23)
2 (15)
27 (93.1, 77-99)
11 (85)
Best patient response
Clinical benefit (CR + PR + SD)
aNegative
for the expression of estrogen receptor, progesterone receptor, and HER2.
• Twenty-two of 29 patients (76%) exhibited a confirmed response, including 8
complete responses
CI, confidence interval; CR, complete response;
HER2, human epidermal growth factor receptor
2; PD, progressive disease; PR, partial response;
SD, stable disease; TNBC, triple-negative breast
cancer.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
64
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2 Metastatic Breast Cancer
Results: Progression-Free Survival
CI, confidence interval; HER2, human epidermal
growth factor receptor 2.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
65
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Results: Overall Survival
• Overall survival at 24 months was 61.7% (95% CI: 25.4 - 84.4)
CI, confidence interval; HER2, human epidermal
growth factor receptor 2.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
66
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Results: Progression-Free Survival in Select Subgroups
• The 18 month TNBC PFS was 10.6% (95% CI: 0.6 - 36.8)
• The 18 month ER+ PFS was 25.0% (95% CI: 7.8 - 47.2)
CI, confidence interval; ER, estrogen receptor;
HER2, human epidermal growth factor receptor
2; PFS, progression-free survival; TNBC, triplenegative breast cancer.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
67
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Select Safety Results: Grade 2 AEs Reported in > 2 Patients
Grade 2 adverse event (N = 29)
n (%)
Alopecia
16 (55)
Nausea
8 (28)
Bone pain
7 (24)
Hand-foot syndrome
7 (24)
Skin rash/lesion
6 (21)
Fatigue
5 (17)
Headache
5 (17)
Peripheral neuropathya
5 (17)
Insomnia
4 (14)
Diarrhea
4 (14)
Neutropenia
3 (10)
Anxiety
3 (10)
Hypertension
3 (10)
aGrade
3 event reported in 1 patient (3.4%).
AE, adverse event; HER2, human epidermal
growth factor receptor 2.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
68
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Conclusions
• This novel combination demonstrated high efficacy
– Median PFS = 10.4 months (95% CI: 5.6-15.2)
– The ORR was 75.9%
• In the challenging-to-treat subgroup of patients with triple
negative disease, the ORR was 69% and the clinical benefit
rate (ORR+ SD) was 85%
• Treatment was well tolerated; there was a very low incidence
of severe adverse events
• This novel combination of cytotoxic and biologic agents may
represent an important new treatment option for the first-line
treatment of patients with MBC
CI, confidence interval; HER2, human epidermal
growth factor receptor 2; MBC, metastatic breast
cancer; ORR, overall response rate; SD, stable
disease; PFS, progression-free survival.
Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.
69
SPARC, EGFR, and VEGFR Expression
May Predict Response to NAB- Paclitaxel
/ Carboplatin / Bevacizumab
Chemotherapy in Triple Negative
Metastatic Breast Cancer
E. Hamilton, G. Kimmick, N. Desai,
B. Peterson, S. Singh, J. Hopkins,
P. Marcom, V. Chadaram, R. Welch, V. Trieu,
K. Blackwell
Hamilton E et al. ASCO. 2010 [Abstract 1109].
70
SPARC in NAB- Paclitaxel- / Carboplatin- /
Bevacizumab-Treated TNMBC Patients
Background
• Triple-negative breast cancer (TNBC)
-
Negative for expression of ER, PR, and HER2
-
TNBC is associated with aggressive histology, early recurrences
and shorter post-recurrence survival1-3
-
Chemotherapy may represent the most effective treatment for
these cancers because they offer no opportunity for targeted
therapies against hormone receptors or HER2
-
Instances of metastatic TNBC are referred to as triple-negative
metastatic breast cancer
ER, estrogen receptor; HER2, human epidermal
growth factor 2; PR, progesterone receptor;
TNBC, triple-negative breast cancer; TNMBC,
triple-negative metastatic breast cancer.
1. Liedtke C et al. J Clin Oncol. 2008;28(8):1275-1281.
2. Bauer KR et al. Cancer. 2007;109(9):1721-1728.
3. Anders C and Carey LA. Oncology (Williston Park).
Hamilton E et al. ASCO. 2010 [Abstract 1109].
2008;22(11):1233-1243.
71
SPARC in NAB- Paclitaxel- / Carboplatin- /
Bevacizumab-Treated TNMBC Patients
Background (cont.)
• SPARC (secreted protein acidic and rich in cysteine) plays a
role in extracellular matrix remodeling and invasion, which are
elements of epithelial-mesenchymal transition1
• Albumin uptake is selectively enhanced in SPARC-expressing
tumor cells2
– Albumin binds the gp60 receptor on the endothelial cell
membrane
– This binding activates caveolin-1 to initiate an opening in the
endothelial cell membrane, allowing entry of NAB- paclitaxel into
tumor cells
TNMBC, triple-negative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
1. Sarrio D et al. Cancer Res. 2008;68:989-997.
2. Hawkins MJ et al. Adv Drug Deliv Rev.
2008;60:876-885.
72
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Background (cont.)
• Multiplexed Collaborative Proximity ImmunoAssay (COPIA:
Prometheus) platform used to determine expression/activation
of the following pathways:
– EGFR (human epidermal growth factor receptor 1)
– HER2 (human epidermal growth factor receptor 2)
– HER3 (human epidermal growth factor receptor 3)
– IGF1-R (insulin-like growth factor 1 receptor)
– c-KIT (stem cell growth factor)
– PI3K (phosphoinositide-3 kinase)
– MAPK (mitogen-activated protein kinase)
– VEGFR (vascular endothelial growth factor receptor)
– AKT (protein kinase B)
TNMBC, triple-negative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
73
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Objectives
• Expression profiles of TNMBC biopsies were measured to:
– Determine intratumoral SPARC expression
– Describe expression/activation of signaling pathways (EGFR,
VEGFR, others) in TNMBC
– Correlate expression patterns with response (ORR, PFS)
• Endpoints
– Primary
• Safety and tolerability
– Secondary
• PFS, ORR, CBR
EGFR, epithelial growth factor receptor; ORR,
overall response rate; PFS, progression-free
survival; SPARC, secreted protein acidic and rich
in cysteine; TNBC, triple-negative breast cancer;
TNMBC, triple-negative metastatic breast cancer;
VEGFR, vascular endothelial growth factor
receptor.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
74
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Key Eligibility Criteria
• Measurable disease according to RECIST criteria
• Triple-negative (ER-, PR-, HER2-)
• ECOG performance status 0 or 1
• ≤ 1 prior chemotherapy regimen (excluding taxanes) in the
metastatic setting
ECOG, Easter Cooperative Oncology Group; ER,
estrogen receptor; HER2, human epidermal
growth factor receptor 2; PR, progesterone
receptor; RECIST, Response Evaluation Criteria
in Solid Tumors; TNMBC, triple-negative
metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
75
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Study Design
• Open-label, phase II study
• Target enrollment: 35 first-line and 35 second-line TNMBC patients
(for this analysis, 29 subjects with 18 biopsies)
• Primary and metastatic biopsies
– First-line subjects only
NAB- paclitaxel
100 mg/m2 IV
qw 3/4 (28-day cycle)
Bevacizumab
10 mg/kg IV
q2w (28-day cycle)
Carboplatin
AUC = 2 IV
qw 3/4 (28-day cycle)
AUC, area under the curve; IV, intravenous; q2w,
every 2 weeks; qw 3/4, first 3 of 4 weeks;
TNMBC, triple-negative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
76
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Baseline Patient Characteristics
Baseline characteristics (N = 29)
Age in years, median (range)
Value
51.4 (29.9 – 75.7)
Race, n (%)
White
Black
Asian
Unknown
17 (58.6)
10 (35.6)
1 (3.4)
1 (3.4)
Number of metastatic sites, n (%)
1
2
≥3
12 (41.4)
9 (31.0)
8 (27.6)
Line of therapy, n (%)
First
Second
25 (86)
4 (14)
• Nineteen patients (65.5%) had visceral metastases
TNMBC, triple-negative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
77
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Results: Preliminary Response and Survival
Outcome (N = 27)a
n (%)
ORR
CR
PR
24 (89)
4 (14)
20 (69)
SD
2 (7)
PD
1
a2
of 29 patients were not evaluable.
• Median PFS: 160 days (= 23 weeks; 95% CI: 131233 days)
CI, confidence interval; CR, complete response;
ORR, overall response rate; PD, progressive
disease; PFS, progression-free survival; PR,
partial response; SD, stable disease; TNMBC,
triple-negative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
78
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Results: Metastatic Biopsies
• Metastatic biopsies available for 18 subjects
• Total EGFR
– Expressed in 11/18 (61%) biopsies
– Activated in 3/18 (17%) biopsies
• PI3K and AKT
– Overexpressed in 11/18 (61%) and 8/18 (44%) biopsies,
respectively
– Co-expressed in 6/18 (33%) biopsies
AKT, protein kinase B; EGFR, epidermal growth
factor receptor; PI3K, phospho-inositol 3 kinase;
TNMBC, triple-negative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
79
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Safety: Most Common Adverse Events
Adverse events (N = 29), n (%)
Grade 2
Grade 3
Grade 4
Fatigue
11 (38)
0
0
Alopecia
7 (24)
0
0
Gastrointestinal disturbancesa
5 (17)
0
0
Neutropenia
5 (17)
10 (34)
0
Anemia
5 (17)
2 (7)
0
Neuropathy
4 (14)
2 (7)
0
Rash
4 (14)
0
0
Epistaxis
0
0
0
Thrombocytopenia
0
4 (14)
1 (3)
a Nausea,
TNMBC, triple-negative breast cancer.
vomiting, mucositis, diarrhea, constipation.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
80
Marker Prediction of TNMBC Patient Response to NABPaclitaxel/Carboplatin/Bevacizumab
Conclusions
• NAB- paclitaxel/carboplatin/bevacizumab offers a
well-tolerated therapy with a high ORR in patients with TNMBC
• Overexpression of SPARC, specifically percent of tumor
SPARC stain, appears to be predictive of response
ORR, overall response rate; SPARC, secreted
protein acidic and rich in cysteine; TNMBC, triplenegative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 [Abstract 1109].
81
NAB-Paclitaxel
in Metastatic Breast Cancer
Combination Studies
HER2+ patients
82
NAB- Paclitaxel Combination Studies in MBC
Trial Description
Phase
HER2+ Patients
NAB- paclitaxel + carboplatin + trastuzumab in HER2+ MBC1
II
NAB- paclitaxel + lapatinib as first- or second-line treatment for HER2+ MBC2
II
HER2, human epidermal growth factor receptor 2;
MBC, metastatic breast cancer.
1. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
2. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
83
NAB- Paclitaxel Combination Studies in MBC
Trial Description
Phase
Main Idea
HER2+ Patients
NAB- paclitaxel + carboplatin +
trastuzumab in HER2+ MBC1
II
This therapy is active as first-line therapy
for HER2+ MBC
NAB- paclitaxel + lapatinib as first- or
second-line treatment for HER2+ MBC2
II
Accrual to this trial is ongoing, with
complete safety and efficacy data to be
reported in the future
HER2, human epidermal growth factor receptor 2;
MBC, metastatic breast cancer.
1. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
2. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
84
Phase II Trial of Weekly NAB- Paclitaxel With
Carboplatin and Trastuzumab as First-Line
Therapy for Women
With HER2-Overexpressing
Metastatic Breast Cancer
A. K. Conlin, A. D. Seidman, A. Bach, D. Lake,
B. M. Dickler, G. D’Andrea, T. Traina, M. Danso,
A. M. Brufsky, M. Saleh, A. Clawson, C. A. Hudis
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
85
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Background
• Weekly Cremophor® EL paclitaxel + trastuzumab is active and
tolerable as first-line treatment of HER2+ MBC1
• On a q3w schedule, adding carboplatin to Cremophor EL
paclitaxel + trastuzumab improves response rate and
progression-free survival as first-line therapy for HER2+ MBC2
• Weekly Cremophor EL paclitaxel + carboplatin + trastuzumab
is also active and appears to be better tolerated than q3w
administration3
• NAB- paclitaxel appears to be more active in first-line MBC
patients when administered weekly vs. q3w4
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; q3w, every 3
weeks.
1. Seidman AD et al. J Clin Oncol.
2008;26(10):1642-1649.
2. Robert N et al. J Clin Oncol. 2006;24(18):27862792.
3. Perez EA et al. Clin Breast Cancer.
2005;6(5):425-432.
4. Gradishar WJ et al. J Clin Oncol.
2009;25(22):3611-3619.
Conlin AK, et al. Clin Breast Cancer. 2010;10(4):281-287.
86
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Objectives
• Objective: to examine the safety and efficacy of weekly
administration of NAB- paclitaxel, trastuzumab, and carboplatin
in patients with previously untreated HER2+ MBC
• Primary endpoints:
– Confirmed CR or PR based on RECIST
– Safety/tolerability: toxicity, myelosuppression, dosing
modifications
• Secondary endpoints:
– PFS
– DoR
– Overall survival
CR, complete response; DoR, duration of
response; HER2, human epidermal growth
factor receptor 2; MBC, metastatic breast
cancer; OS, overall survival; PFS, progressionfree survival; PR, partial response; RECIST,
Response Evaluation Criteria in Solid Tumors.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
87
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Key Eligibility Criteria
• Key inclusion criteria
– Measurable, pathologically confirmed adenocarcinoma of the
breast (stage IV at enrollment)
– HER2-overexpressing
• Confirmed by either IHC (protein level) or FISH (genetic level)
– ≥ 4 weeks since radiotherapy or major surgery
– Adequate hematologic, hepatic, and renal function
– Normal LVEF
FISH, fluorescence in situ hybridization;
HER2, human epidermal growth factor
receptor 2; IHC, immunohistochemistry;
LVEF, left ventricular ejection fraction; MBC,
metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
88
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Key Eligibility Criteria (cont.)
• Key exclusion criteria
– Prior chemotherapy for MBC
– < 9 months since taxane-based adjuvant chemotherapy
– Concurrent immunotherapy or hormone therapy
– Parenchymal brain metastases not documented to be clinically
and radiographically stable for ≥ 6 months
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
89
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Original Phase II Schema
AUC, area under the curve; HER2, human
epidermal growth factor receptor 2; MBC,
metastatic breast cancer; wk, week.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
90
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Revised Phase II Schema
AUC, area under the curve; HER2, human
epidermal growth factor receptor2; MBC,
metastatic breast cancer; wk, week.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
91
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Baseline Patient Characteristics
Baseline characteristic ( N = 32)
Age in years, median (range)
Value
52 (29 – 76)
ECOG PS, n (%)
0
1
2
19 (59)
12 (38)
1 (3)
Site of metastatic disease, n (%)
Lymph node
Skin/soft tissue/breast
Liver
Lung
Bone
24 (75)
21 (66)
15 (47)
19 (59)
22 (69)
Prior adjuvant or neoadjuvant chemotherapy, n (%)
Anthracycline
Taxane
14 (44)
11 (34)
ECOG PS, Eastern Cooperative Oncology Group
performance status; HER2, human epidermal
growth factor receptor 2; MBC, metastatic breast
cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
92
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Results
Confirmed responses (N = 32)
Value
ORR (CR + PR), n (%; 95% CI)
20 (63; 45.7-79.3)
CR, n (%)
3 (9)
PR, n (%)
17 (53)
SD ≥ 16 weeks, n (%)
6 (19)
Clinical benefit (CR + PR + SD ≥ 16 weeks), n (%)
26 (81)
• Median response duration: 17.8 months (95% CI, 15.9-37.0)
• Median PFS: 16.6 months (95% CI, 7.5-26.5)
• Thirty-two patients treated
– Seventeen treated solely on original regimen
– Three switched from original to revised regimen
– Twelve treated only on revised regimen
CI, confidence interval; CR, complete response;
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; ORR, overall
response rate; PR, partial response; SD, stable
disease.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
93
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Results: Response by Regimen
Response by regimen
n (%)
Original regimen only (n = 17)
11 (65)
Revised regimen only (n = 12)
8 (67)
Original + revised (n = 3)
1 (33)
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
94
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Results: Drug Exposure
• Median dose intensity:
– NAB- paclitaxel: 56.9 mg/m2/week; 76% of the
planned dose
– Carboplatin: 47.6 mg/week, 62% of the planned dose
• Median number of cycles: 8 (range 2-39 cycles)
• Eight patients who responded and had at least 6 cycles of
NAB- paclitaxel and carboplatin continued to receive
trastuzumab alone until progression of disease
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
95
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Safety
Adverse Event, %
Grade 1
Grade 2
Grade 3
Grade 4
Hematologica,b
Neutropenia
Leukopenia
Anemia
Thrombocytopenia
13
22
25
38
34
28
63
34
41
44
3
3
9
3
3
0
Non-hematologic
Sensory neuropathy
Nausea
Diarrhea
Rash/Desquamation
Arthralgia
Fatigue
Stomatitis
Elevated ALT
Elevated AST
47
56
19
22
16
38
28
9
9
13
16
25
9
3
31
13
6
0
3
0
0
0
0
16
0
3
0
0
0
0
0
0
0
0
0
0
aBased
b1
on laboratory data graded by National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
episode of febrile neutropenia was observed.
ALT, alanine aminotransferase; AST, asparatate
aminotransferase; HER2, human epidermal
growth factor receptor 2; MBC, metastatic breast
cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
96
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Safety: Hypersensitivity Reactions
• Steroid premedication
– Cycle 1 for all patients treated with monthly carboplatin
(N = 15)
– Five patients continued premedication in subsequent cycles
– Two patients stopped premedication for subsequent cycles
without any hypersensitivity reactions
• Total of 9 hypersensitivity reactions
– Carboplatin: 5 patients (none during monthly regimen)
– Trastuzumab: 4 patients
– NAB- paclitaxel: none
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
97
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Safety: Dose Reductions
• Patients with ≥ 1 dose reduction
– NAB- paclitaxel: 22 (69%)
– Carboplatin: 19 (59%)
– Majority of dose reductions (95%) were for hematologic toxicity
(each drug)
• Patients with ≥ 1 dose delay
– Dose delays occurred in 22/32 (69%) patients
– Of those,18/22 (82%) were for hematologic toxicities
– None for peripheral neuropathy
• Patients with ≥ 1 dose interruption
– NAB- paclitaxel: 2 (9%)
– Carboplatin: 2 (9%)
– Trastuzumab: 6 (19%)
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
98
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2+ MBC
Conclusions
• Weekly NAB- paclitaxel + trastuzumab + carboplatin (weekly or
monthly) is active as first-line therapy for
HER2+ MBC
• Hypersensitivity reactions to weekly carboplatin, generally
occurring on infusions 6-8, make monthly carboplatin dosing
preferable
• This combination may be the preferred regimen for patients
with HER2+ MBC who need or want to avoid premedication
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.
99
Safety Results of Lapatinib Plus NABPaclitaxel in Women With First- or
Second-Line HER2-Overexpressing
Metastatic Breast Cancer
D.A. Yardley, R. Wholf, L. D. Bosserman,
M. Saleh, D. Waterhouse, S. Lahiri,
J. M. Mahoney, Y. Nagarwala, P. Richards
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
100
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Background
• Lapatinib is an orally active, reversible, small-molecule tyrosine
kinase inhibitor of both ErbB1 (EGFR) and ErbB2 (HER2) that
is approved for combination with capecitabine in patients with
HER2+ MBC1
• NAB- paclitaxel was found to be more efficacious than Cremophor®
EL paclitaxel in a phase III study of patients with MBC2
EGFR, epidermal growth factor receptor; HER2,
human epidermal growth factor receptor 2; MBC,
metastatic breast cancer.
Yardley DA, et al. ASCO Breast. 2009 [Abstract 245].
1. Lapatinib [package insert]. Research
Triangle Park, NC: GlaxoSmithKline; 2007.
2. Gradishar WJ et al, J Clin Oncol
2005;23(31):7794-7803.
101
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Objectives
• Primary endpoint
– Overall tumor response rate (CR + PR)
• Secondary endpoints
– Progression-free survival
– Overall survival
– Duration of response
– Time to response
– Time to tumor progression
– Toxicities
CR, complete response; HER2, human
epidermal growth factor receptor 2; MBC,
metastatic breast cancer; PR, partial response.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
102
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Key Eligibility Criteria
• Key inclusion criteria
– RECIST-defined measurable disease
– HER2 overexpressing MBC (FISH+ or IHC 3+)
– ≤ 1 prior chemotherapeutic regimen in the metastatic setting
– Prior therapy with trastuzumab in the neoadjuvant, adjuvant, or
metastatic setting was permitted
– Prior endocrine therapy was permitted in the neoadjuvant,
adjuvant, or metastatic setting
FISH, fluorescence in situ hybridization; HER2,
human epidermal growth factor receptor 2; IHC,
immunohistochemistry; MBC, metastatic breast
cancer; RECIST, Response Evaluation Criteria in
Solid Tumors.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
103
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Study Design and Treatment
• A planned safety analysis was to occur after the first 10
patients completed at least 1 cycle of treatment
• As of July 31, 2009, 26 of the expected 60 patients were
enrolled
N = 60
Lapatinib 1250 mg po daily +
NAB- paclitaxel 125 mg/m2
IV qw 3/4a
a
b
Continued until disease progression or
withdrawal from the study due to unacceptable
toxicity or withdrawal of consent, or lost to
follow-upb
Dose reduced to lapatinib 1000 mg daily + NAB- paclitaxel 100 mg/m2 IV weekly based on safety data from the first 5 patients
treated.
Patients will be treated with NAB- paclitaxel and lapatinib for a minimum of 6 cycles; if complete response (CR) is obtained prior to
6 cycles, patient is to receive 2 additional cycles beyond CR.
HER2, human epidermal growth factor receptor
2; IV, intravenous; MBC, metastatic breast
cancer; po, by mouth; qw 3/4, first 3 of 4 weeks.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
104
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Baseline Patient Characteristics
Baseline characteristic (N = 26)a
Age in years, median (range)
Value
56.5 (37-80)
HER2 status, n (%)
IHC 3+
FISH+
IHC 3+ and FISH+
10 (38)
8 (31)
8 (31)
First-line metastatic treatment, n (%)
20 (77)
Second-line metastatic treatment, n (%)
6 (23)
aAll
patients were female
FISH, fluorescence in situ hybridization; HER2,
human epidermal growth factor receptor 2; IHC,
immunohistochemistry; MBC, metastatic breast
cancer.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
105
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Preliminary Efficacy Results
Treatment response (N = 26)
n (%)
ORR (CR + PR)
CRa
PRb
4 (15)
1 (4)
3 (12)
SD
8 (31)
PD
2 (8)
Unknown
a
b
12 (46)
Patient was being treated in the 2nd-Line MBC setting.
2 patients were being treated in 1st-Line MBC and 1 patient in 2nd-Line MBC.
• Of the 12 unknown patients, 11 had not yet met a time point after baseline
for the measurement of a response
CR, complete response; HER2, human
epidermal growth factor receptor 2; MBC,
metastatic breast cancer; ORR, overall response
rate, PD, progressive disease; PR, partial
response; SD, stable disease.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
106
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Select Safety Results
• Grade 3 toxicities were observed in the first 5 patients treated
with NAB- paclitaxel 125 mg/m2 and lapatinib 1250 mg
– This prompted an early protocol-specified safety analysis
– Consequently, protocol amendment and dose modification
occurred for all subsequent treatments
• NAB- paclitaxel reduced to 100 mg/m2
• Lapatinib reduced to 1000 mg
• Thirty-three percent of the subsequent 21 patients treated with
reduced doses demonstrated at least one grade 3 event
– No grade 4 events occurred
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
107
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Select Safety Results (cont.)
Maximum toxicity
Adverse Event
Neutropenia
Diarrhea
Rash
aDose
bn
cn
AB-Pac/Lapatinib
dosea
Grade 1
(%)
Grade 2
(%)
Grade 3
(%)
125/1250b
1 (20)
0
3 (60)
100/1000c
0
2 (10)
3 (14)
125/1250b
2 (40)
1 (20)
2 (40)
100/1000c
7 (33)
4 (19)
4 (19)
125/1250b
0
3 (60)
1 (20)
100/1000c
5 (24)
3 (14)
2 (10)
given for AB-Pac in mg/m2 the first 3 of 4 weeks; lapatinib dose given in mg daily.
= 5.
= 21; numbers and percentages reflect number of patients experiencing the event.
• No grade 4 adverse events were reported
AB-Pac, NAB- paclitaxel; HER2, human
epidermal growth factor receptor 2; MBC,
metastatic breast cancer.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
108
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Select Safety Results (cont.)
All patients
(N = 26)
Dose of ABPac/Lap
125/1250
(n = 5)
Dose of ABPac/Lap
100/1000
(n = 21)
Diarrhea
20 (77)
5 (100)
15 (71)
Fatigue
13 (50)
3 (60)
10 (48)
Nausea
12 (46)
5 (100)
7 (33)
Rash
12 (46)
3 (60)
9 (43)
Anemia
9 (35)
3 (60)
6 (29)
Neutropenia
8 (31)
3 (60)
5 (24)
Anorexia
6 (23)
1 (20)
5 (24)
Pyrexia
6 (23)
2 (40)
4 (19)
Vomiting
6 (23)
4 (80)
2 (10)
Alopecia
5 (19)
2 (40)
3 (14)
Constipation
5 (19)
3 (60)
2 (10)
Dehydration
5 (19)
3 (60)
2 (10)
Peripheral neuropathy
5 (19)
2 (40)
3 (14)
Adverse event occurring in > 15% of
patients, n (%)
AB-Pac, NAB- paclitaxel; HER2, human
epidermal growth factor receptor 2; lap, lapatinib;
MBC, metastatic breast cancer.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
109
NAB- Paclitaxel Plus Lapatinib as First- or Second-Line
Treatment for HER2+ MBC
Conclusions
• Grade 3 toxicities were evident with the initial doses of 125
mg/m2 NAB- paclitaxel qw 3/4 and 1250 mg
lapatinib daily
• This led to a 20% dose modification for both agents to 100 mg/m2
NAB- paclitaxel qw 3/4 and 1000 mg lapatinib daily
• With the dose modification, the incidence of grade 3 events
decreased from 100% in the first 5 patients to 33% in the next
21 patients
• Accrual to this trial is ongoing, with complete safety and
efficacy data to be reported
HER2, human epidermal growth factor receptor
2; MBC, metastatic breast cancer; qw 3/4, first 3
of 4 weeks.
Yardley DA et al. ASCO Breast. 2009 [Abstract 245].
110
NAB-Paclitaxel combination studies
Update from San Antonio Breast Cancer
Symposium 2011
111
Phase II Study Evaluating Lapatinib in
Combination With nab®-Paclitaxel in
Women Who Have Received ≤1
Chemotherapy Regimen for HER2Overexpressing Metastatic Breast Cancer
Denise A. Yardley, Lowell Hart, Linda Bosserman, Mansoor
N. Saleh, David M. Waterhouse, Maura K. Hagan, Paul
Richards, Michelle L. DeSilvio, Janine M. Mahoney, Yasir
Nagarwala
Yardley DA et al. SABCS 2011 [Poster P1-12-10].
112
NAB- Paclitaxel and Lapatinib in MBC with HER2+
Study Design and Treatment
Author
Phase
N
Regimen
Green et al. (2006)
II
43
nab-paclitaxel 260 mg/m2 q3w
Rizvi et al. (2008)
I/II
40
nab-paclitaxel 100 / 125 / 140 mg/m2 days 1,8,15 q4w
COMBINATION STUDIES
Yardley DA et al. SABCS 2011 [Poster P1-12-10].
113
NAB- Paclitaxel and Lapatinib in MBC with HER2+
Study Characteristics
Patient Population
• Women with HER2-overexpressing MBC who received ≤1 prior chemotherapeutic regimen in
the metastatic setting
• Prior therapy with trastuzumab in the neoadjuvant, adjuvant, or metastatic setting was
permitted
• Prior endocrine therapy was permitted in the neoadjuvant, adjuvant, or metastatic setting
Primary Objective
• Overall tumor response rate (CR and PR) of lapatinib in nab®-paclitaxel
Secondary Objectives
•
•
•
•
•
•
Progression-free survival (PFS)
Overall survival (OS)
Duration of response (DOR)
Time to response (TTR)
Time to progression (TTP)
To determine the qualitative and quantitative toxicities combination of oral lapatinib and IV
nab®-paclitaxel
Yardley DA et al. SABCS 2011 [Poster P1-12-10].
NAB- Paclitaxel and Lapatinib in MBC with HER2+
Patient characteristics
Yardley DA et al. SABCS 2011 [Poster P1-12-10].
114
115
NAB- Paclitaxel and Lapatinib in MBC with HER2+
Results
Yardley DA et al. SABCS 2011 [Poster P1-12-10].
116
NAB- Paclitaxel and Lapatinib in MBC with HER2+
Serious adverse events and treatment discontinuation
Yardley DA et al. SABCS . 2011 [Poster P1-12-10].
117
NAB- Paclitaxel and Lapatinib in MBC with HER2+
Conclusions
• The ORR primary endpoint of 53% compares favorably with other
HER2-based combinations in this setting and warrants further
exploration
• Lapatinib 1000 mg with nab®-paclitaxel 100 mg/m2 IV is feasible with
manageable and predictable toxicity
• Lapatinib dose interruption or reduction was primarily due to
nonhematologic toxicities.
• nab®-paclitaxel dose delays/missed doses were primarily due to
nonhematologic toxicities; dose delays were primarily due to
hematologic toxicities
• At the time of this presentation, there are 5 patients still on singleagent lapatinib
Yardley DA et al. SABCS . 2011 [Poster P1-12-10].
118
Randomized Phase 2 Trial of Weekly vs Q 2Weekly vs Q 3-Weekly NAB- Paclitaxel
With Bevacizumab as First-Line Therapy
for Metastatic Breast Cancer
AD Seidman, AK Conlin, A Bach, A Forero-Torres, G
Wright, MH Hackney, A Clawson, D Schofield, J
Iglesias, and CA Hudis
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
119
NAB- Paclitaxel and Bevacizumab in MBC
Study Design
Purpose: multicenter, open-label, randomized, phase 2 study to evaluate
antitumor activity and safety of weekly NAB-paclitaxel vs q2w vs standard q3w
infusion regimens, all in combination with bevacizumab, for first-line treatment of
MBC
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
120
NAB- Paclitaxel and Bevacizumab in MBC
Methods
Inclusion criteria
•
•
•
•
Parenchymal brain metastases
Adjuvant taxane ≤ 12 months or any chemotherapy ≤ 6 months
Congestive heart failure (New York Heart Association grade ≥ 2)
Uncontrolled hypertension, proteinuria, vascular disease, or coagulopathy
Dose Modification
• NAB-Paclitaxel could be delayed or reduced for neutropenia or for grade ≥ 3
nonhematologic toxicity
• The dose of NAB-paclitaxel given q3w, q2w, or qw could be reduced up to 2 times by
40, 40, or 20 mg/m2 at each dose level, respectively.
• Once reduced, doses could not be re-escalated
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
121
NAB- Paclitaxel and Bevacizumab in MBC
Patient Characteristics
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
122
NAB- Paclitaxel and Bevacizumab in MBC
Results: Tumor Response
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
123
NAB- Paclitaxel and Bevacizumab in MBC
Results: Time To Progression by Schedule
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
124
NAB- Paclitaxel and Bevacizumab in MBC
Results: Overall Survival by Schedule
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
125
NAB- Paclitaxel and Bevacizumab in MBC
Treatment Related Adverse Events
Seidman AD et al. SABCS 2011 [Poster P1-14-01].
126
NAB- Paclitaxel and Bevacizumab in MBC
Conclusions
• NAB-paclitaxel + bevacizumab regimens studied demonstrated
antitumor activity in women with MBC
• Neutropenia, sensory neuropathy, and fatigue were the most
common grade ≥ 3 treatment-emergent adverse events observed.
Sensory neuropathy was a common reason for treatment
discontinuation
• Weekly NAB-paclitaxel + bevacizumab led to the longest, albeit nonsignificant, TTP and OS. Thus, this regimen appears to have the
highest therapeutic index. However, sensory neuropathy was
treatment-limiting, suggesting a 3 weeks-on and 1-week-off schedule
may be preferred
Seidman AD et al. SABCS 2011 [Poster P1-14-01].