Transcript Slide 1

1
Albumin-Bound Paclitaxel
for the Treatment of
Non-small Cell Lung Cancer
Clinical data
2
Albumin-Bound Paclitaxel Trials in NSCLC:
Monotherapy
Trial Description
Phase
AB-paclitaxel dosed every-3-weeks as first-line therapy for
patients with advanced NSCLC1
II
AB-paclitaxel dosed weekly as initial chemotherapy for patients
with stage IV NSCLC2
I/II
AB, albumin-bound; NSCLC, non-small cell lung cancer.
1. Green MR, et al. Ann Oncol. 2006;17:1263-1268.
2. Rizvi NA, et al. J Clin Oncol. 2008;26:639-643.
3
Albumin-Bound Paclitaxel Trials in NSCLC:
Combination Therapy
Trial Description
Phase
Combination Therapy with Carboplatin
Weekly AB-paclitaxel + carboplatin as first-line therapy for advanced NSCLC1
II
Dose-finding study of weekly and q3w AB-paclitaxel + carboplatin as first-line therapy for advanced
NSCLC2
II
AB-paclitaxel + carboplatin vs CrEL paclitaxela + carboplatin as first-line therapy for advanced
NSCLC3,4
III
AB-Paclitaxel + carboplatin for patients at risk of bleeding from VEGF-directed therapies5
II
AB-paclitaxel + carboplatin in 2 different schedules for patients with ES-SCLC6
II
Combination Therapy with Carboplatin and Bevacizumab
AB-paclitaxel + carboplatin + bevacizumab as first-line therapy for advanced nonsquamous
NSCLC7
II
In vivo assessment of the effects of bevacizumab in advanced NSCLC8
II
Combination with Carboplatin and Radiotherapy
AB-paclitaxel + carboplatin + thoracic radiation in locally advanced NSCLC9
®
Cremophor is a registered trademark of BASF.
AB, albumin-bound; CrEL, Cremophor® EL; ESSCLC, extensive stage small cell lung cancer;
NSCLC, non-small cell lung cancer; q3w, every 3
weeks; VEGF, vascular endothelial growth factor.
I
1. Allerton JP, et al. ASCO. 2006. [Abstract 7127].
2. Socinski MA, et al. J Thoracic Oncol. 2010;5(5):852-861.
3. Socinski MA, et al. ASCO. 2010 [Abstract LBA7511].
4. Socinski MA et al. ASCO. 2011 [Abstract 7551].
5. Otterson GA et al. IASLC. 2011 [Abstract 2230].
6. Grilley-Olson JE et al. IASLC. 2011 [Abstract 2221].
7. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
8. Heist RS, et al. ASCO. 2010. [Abstract 7612].
9. Keedy VL et al. ASCO. 2011 [Abstract 7046].
4
Albumin-Bound Paclitaxel
as First-line Treatment for
Non-Small Cell Lung Cancer
Monotherapy Studies
5
Summary of Albumin-Bound Paclitaxel Monotherapy
Studies in Non-Small Cell Lung Cancer
Trial Description
Phase
Albumin-bound paclitaxel as first-line treatment in
advanced NSCLC1
II
Albumin-bound paclitaxel as first-line treatment in stage
IV NSCLC2
I/II
NSCLC, non-small cell lung cancer.
1. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
2. Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
6
Summary of Albumin-Bound Paclitaxel Monotherapy
Studies in Non-Small Cell Lung Cancer
Trial Description
Albumin-bound paclitaxel
as first-line treatment in
advanced NSCLC1
Albumin-bound paclitaxel
as first-line treatment in
stage IV NSCLC2
Phase
Main Idea
II
q3w albumin-bound paclitaxel at
260 mg/m2 showed considerable
activity and a favorable therapeutic
index in advanced NSCLC
I/II
qw 3/4 albumin-bound paclitaxel at
125 mg/m2 demonstrated encouraging
clinical efficacy in stage IV NSCLC
NSCLC, non-small cell lung cancer; q3w, every 3 weeks; qw 3/4, first 3 of 4 weeks.
1. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
2. Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
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nab-paclitaxel®, a Novel, Cremophor® ELFree
Albumin-Bound Particle Form of Paclitaxel
for the Treatment of
Advanced Non-Small Cell Lung Cancer
M.R. Green, G.M. Manikhas, S. Orlov, B. Afanasyev,
A.M. Makhson, P. Bhar, M.J. Hawkins
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
8
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Background
• Cremophor® ELa paclitaxel plays a role in first-line therapy for
advanced NSCLC1
– Cremophor EL, the solvent vehicle2, is associated with severe
hypersensitivity reactions2,3
– To prevent severe hypersensitivity reactions, all patients should be
premedicated prior to administration of Cremophor EL paclitaxel2
• Albumin-bound paclitaxel is a solvent-free formulation4
– Use of albumin as a vehicle eliminates solvent-related toxicities5
– No premedication to prevent hypersensitivity reactions is required prior
to administration4
• Due to the limitations of treatments for NSCLC, Green et al.
explored efficacy/safety of albumin-bound paclitaxel for NSCLC5
a
Cremophor is a registered trademark of BASF;
NSCLC, non-small cell lung cancer.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
3. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
4. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
5. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Objective
• Objective
– Evaluate the efficacy and safety of albumin-bound paclitaxel 260 mg/m2
q3w as first-line treatment for patients with advanced NSCLC
• Primary efficacy endpoint
– ORR
• Secondary endpoints
– TTP
– OS
– Toxicity
• Other endpoints assessed
– Overall disease control rate (confirmed responders + patients with
SD ≥ 16 weeks)
NSCLC, non-small cell lung cancer; ORR, overall
response rate; OS, overall survival; q3w, every 3
weeks; SD, stable disease; TTP, time to tumor
progression.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
10
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Key Eligibility Criteria
• Key inclusion criteria
– Men and non-pregnant women ≥ 18 years of age
– Histologically or cytologically confirmed advanced NSCLC
(at least 1 measurable stage IIIB or IV lesion)
– Evidence of inoperable local recurrence or metastasis, but no
other active malignancy
– No prior therapy for metastatic disease
– Expected survival of > 12 weeks
– Adequate hematologic, hepatic, and renal function
NSCLC, non-small cell lung cancer.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Key Eligibility Criteria (cont.)
• Key exclusion criteria
– Clinical evidence of brain metastasis
– Serious concurrent illness
– ECOG PS of ≥ 2
– Peripheral neuropathy ≥ grade 2
– Prior radiotherapy
ECOG, Eastern Cooperative Oncology Group;
NSCLC, non-small cell lung cancer; PS,
performance status.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Phase II Study Design
Albumin-bound paclitaxel
260 mg/m2 IV
over 30 minutes
Treatment repeated q3w
until disease progression
or unacceptable toxicity
• Dose reduction (from 260 to 200 mg/m2) was permitted for:
– Grade 4 hematologic toxicity
– Neutropenic fever or sepsis
– Grade 3 or 4 non-hematologic toxicity
• Dose reduction (to 130 mg/m2) was recommended for all
subsequent cycles if:
– Adverse events listed above recurred after the initial resolution
and reinitiation of albumin-bound paclitaxel dosing
IV, intravenous; NSCLC, non-small cell lung
cancer; q3w, every 3 weeks.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
13
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Baseline Patient Characteristics
Baseline characteristic (N = 43)
Value
Sex, n (%)
Men
Women
33 (77)
10 (23)
Age, years
Median
Range
< 65, n (%)
≥ 65, n (%)
58
43 - 75
34 (79)
9 (21)
ECOG PS, n (%)
0
1
9 (21)
34 (79)
Dominant lesion site, n (%)
Visceral
Nonvisceral
36 (84)
7 (16)
Total number of lesions, n (%)
1
2-3
>3
5 (12)
13 (30)
25 (58)
Stage at primary diagnosis
I
II
III
IV
Unknown
1 (2)
2 (5)
14 (33)
24 (56)
2 (5)
ECOG, Eastern Cooperative Oncology Group; NSCLC,
non-small cell lung cancer; PS, performance status. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Results: Overall Response and Response by Histology
Subgroup/variable
Overall responseb
Response by histology
Carcinoma/adenocarcinoma
Squamous cell carcinoma
Otherc
Baseline,
n
Confirmed
ORR,
n (%)
Disease
control,a
n (%)
Death,
n (%)
43
7 (16)
21 (49)
23 (53)
11
29
3
1 (9)
5 (17)
1 (33)
5 (45)
14 (48)
2 (67)
5 (45)
16 (55)
2 (67)
ORR, overall response rate.
a Includes responders + patients with stable disease ≥ 16 weeks.
b Includes all partial responses.
c Other categories of NSCLC include large-cell carcinoma, undifferentiated NSCLC, and mixed squamous and adenocarcinoma.
NSCLC, non-small cell lung cancer.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Results: Time to Disease Progression (treated population)
• Median TTP: 6 months (95% CI: 3.9 - 6.5)
• Probability of not having progressed: 50% at 6 months,13% at 1 year
CI, confidence interval; NSCLC, non-small cell
lung cancer; q3w, every 3 weeks; TTP, time to
tumor progression.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Results: Overall Survival (treated population)
• Median survival was 11 months (95% CI: 9.5 - 16.2)
• Probability of surviving 1 year was 45%
CI, confidence interval; NSCLC, non-small cell
lung cancer; q3w, every 3 weeks.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Results: Dose Adjustments and Discontinuations Due to AEs
Dose adjustments and discontinuations due to
treatment-related AEs (N = 43)
n (%)
Dose reductiona
2 (5)
Dose interruption
0
Discontinuation of therapy
2 (5)
AE, adverse event.
aTwo dose reductions were permitted: from 260 to 200 mg/m 2 and from 200 to 130 mg/m 2.
• Treatment was well-tolerated
•
95% of patients received albumin-bound paclitaxel at the protocol-specified dose
•
98% of all cycles were administered at the full dose
•
Patients received a median of 6 treatment cycles
•
63% of patients received ≥ 6 treatment cycles
AE, adverse event; NSCLC, non-small
cell lung cancer.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
18
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Results: Treatment-Related Toxicities/Adverse Events
Maximum grade, n (%) of patients
Toxicity/AEa
Patients with ≥ 1
treatment-related AE
Hematologicb
Anemia
Neutropenia
Leukopenia
Thrombocytopenia
Non-hematologic
Alopecia
Sensory neuropathy
Arthralgia
Fatigue
Myalgia
Fever
All
1
2
3
4
40 (93)
7 (16)
24 (56)
9 (21)
0
32 (74)
21 (49)
10 (23)
6 (14)
24 (56)
9 (21)
7 (16)
6 (14)
8 (19)
8 (19)
3 (7)
0
0
4 (9)
0
0
0
0
0
0
33 (77)
28 (65)
15 (35)
14 (33)
8 (19)
7 (16)
4 (9)
21 (49)
10 (23)
3 (7)
5 (12)
2 (5)
29 (67)
5 (12)
4 (9)
8 (19)
3 (7)
5 (12)
NA
2 (5)
1 (2)
3 (7)
0
0
NA
0
0
0
0
0
AE, adverse event; NA, not applicable.
aReported in ≥ 10% of patients (N = 43).
bBased on central laboratory values.
NSCLC, non-small cell lung cancer.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Conclusions
• Albumin-bound paclitaxel 260 mg/m2 administered IV over 30
minutes without premedication was well tolerated
• Significant tumor responses and prolonged disease control
were documented in these patients with NSCLC
• Exploration of higher doses of albumin-bound paclitaxel alone
and in combination with other drugs in NSCLC is warranted
IV, intravenous; NSCLC, non-small cell lung
cancer.
Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
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Phase I/II Trial of Weekly Intravenous
Albumin-Bound Paclitaxel as
Initial Chemotherapy in Patients with
Stage IV Non-Small Cell Lung Cancer
N.A. Rizvi, G.J. Riely, C.G. Azzoli,
V.A. Miller, K.K. Ng, J. Fiore, G. Chia,
M. Brower, R. Heelan, M.J. Hawkins,
M.G. Kris
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
21
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Advanced NSCLC
Background
• Cremophor® ELa paclitaxel plays a role in first-line therapy for
advanced NSCLC1
– Cremophor EL, the solvent vehicle2, is associated with severe
hypersensitivity reactions2,3
– To prevent severe hypersensitivity reactions, all patients should be
premedicated prior to administration of Cremophor EL paclitaxel2
• Albumin-bound paclitaxel is a solvent-free formulation4
– Use of albumin as a vehicle eliminates solvent-related toxicities5
– No premedication to prevent hypersensitivity reactions is required prior
to administration4
aCremophor
EL is a registered trademark of
BASF; NSCLC, non-small cell lung cancer.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
3. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
4. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
5. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
22
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Background (cont.)
• In a phase II study of albumin-bound paclitaxel 260 mg/m2 IV
q3w as first-line therapy for advanced NSCLC1:
– ORR 16%; median TTP 6 months; median survival 11 months
– No severe hypersensitivity reactions reported
• In a phase I/PK dose-ranging study of weekly albumin-bound
paclitaxel in patients with solid tumors2:
– MTD in lightly pretreated patients was 150 mg/m2
– DLTs were grade 3 peripheral neuropathy and grade 4 neutropenia
– PR in 1 patient with lung cancer previously treated with Cremophor® EL
paclitaxel
• Rizvi et al. explored the MTD of weekly albumin-bound
paclitaxel in patients with untreated stage IV NSCLC3
DLT, dose-limiting toxicity; IV, intravenous; MTD,
maximum-tolerated dose; NSCLC, non-small cell
lung cancer; ORR, overall response rate; PK,
pharmacokinetics; PR, partial response; q3w, every
3 weeks; TTP, time to tumor progression.
1. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
2. Nyman DW, et al. J Clin Oncol. 2005; 23(31):7785-7793.
3. Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
23
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Objective
• Objective
– Determine MTD and single-agent activity of albumin-bound paclitaxel
administered weekly as first-line therapy for patients with stage IV NSCLC
• Primary endpoints
– ORR* (CR and PR determined using RECIST)
– Safety
• Secondary efficacy endpoints
– TTP
– OS
*Responses had to be confirmed at least 4
weeks after initial documentation; CR, complete
response; MTD, maximum tolerated dose;
NSCLC, non-small cell lung cancer; ORR, overall
response rate; OS, overall survival; PR, partial
response; RECIST, Response Evaluation Criteria
in Solid Tumors; TTP, time to tumor progression.
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
24
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Key Eligibility Criteria
• Key inclusion criteria
– Stage IV or recurrent NSCLC
– Laboratory requirements
•
•
•
•
•
•
AST and ALT ≤ 2.5X the upper limit of normal range
Total bilirubin within the normal range
Creatinine ≤ 1.5 mg/dL
ANC ≥ 1.5  109 cells/L
Platelets ≥ 100  109 cells/L
Hemoglobin ≥ 9 g/dL
• Key exclusion criteria
– Prior chemotherapy for advanced NSCLC
– Peripheral neuropathy > grade 1
– Radiotherapy received ≤ 3 weeks before study entry
ALT, alanine aminotransferase; ANC, absolute
neutrophil count; AST, aspartate aminotransferase;
NSCLC, non-small cell lung cancer.
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
25
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Study Design
• Open-label, single-arm, phase I/II trial
Phase I
(N =15)
Albumin-bound paclitaxel
100 → 125 → 150 mg/m2 IV
qw 3/4
Phase II
(N = 40)
Albumin-bound paclitaxel
125 mg/m2 IV
qw 3/4
IV, intravenous; NSCLC, non-small cell lung cancer;
q8w, every 8 weeks; qw 3/4, first 3 of 4 weeks.
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
Radiologic tumor
assessment q8w
26
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Baseline Characteristics of Patients in Phase II Portion
Baseline characteristic (N = 40)
Value
Sex, n (%)
Men
Women
19 (47)
21 (53)
Age, years
Median
Range
70
43 - 84
Karnovsky PS, n (%)
90%-100%
70%-80%
10 (25)
30 (75)
Prior chemotherapy, n (%)
Neoadjuvant
Adjuvant
Prior gefitinib or erlotinib
3 (8)
6 (15)
5 (13)
Histology, n (%)
Adenocarcinoma
Squamous cell carcinoma
32 (80)
8 (20)
EGFR TKI—epidermal growth factor tyrosine kinase inhibitor
NSCLC, non-small cell lung cancer; PS,
performance status.
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
27
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Results: Phase II
Outcome (N = 40)
Value
ORR (PR + CR)*
%
95% CI
30
16 - 44
SD ≥ 16 weeks
n
%
8
20
Median TTP
months
95% CI
5
3-8
Median OS
months
95% CI
11
7 - NR
One-year OS
%
41
*Responses had to be confirmed at least 4 weeks after initial documentation.
CI, confidence interval; CR, complete response; NR, not reached; ORR, overall response rate; OS, overall survival; PR, partial
response; SD, stable disease; TTP, time to tumor progression.
NSCLC, non-small cell lung cancer.
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
28
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Results: Treatment-Related Adverse Events
Maximum grade, %
AE*
(N = 40)
All
1
2
3
4
Hematologic
Anemia
Leukopenia
Neutropenia
92
62
60
63
23
13
23
20
28
8
20
15
0
0
5
Non-hematologic
Fatigue
Neuropathy
Alopecia
Constipation
Diarrhea
Nausea
Rash
Edema
Myalgia
Anorexia
Hypersensitivity
75
73
70
58
48
45
40
30
28
28
0
28
35
10
38
25
38
35
18
18
18
0
30
23
60
20
10
8
5
13
10
10
0
18
15
0
0
13
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
*Most frequent treatment-related AEs in patients treated with albumin-bound paclitaxel 125 mg/m2.
AE, adverse event.
NSCLC, non-small cell lung cancer.
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
29
Albumin-Bound Paclitaxel Monotherapy as First-Line
Treatment for Stage IV NSCLC
Conclusions
• Albumin-bound paclitaxel 125 mg/m2 administered qw 3/4 was
well tolerated
– No corticosteroid premedication was administered and
no hypersensitivity reactions were seen
• Albumin-bound paclitaxel 125 mg/m2 demonstrated
encouraging single-agent activity
• Additional studies of single-agent albumin-bound paclitaxel
as well as platinum-based combinations are warranted
NSCLC, non-small cell lung cancer; qw 3/4, first
3 of 4 weeks.
Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
30
Albumin-Bound Paclitaxel
for the Treatment of
Non-Small Cell Lung Cancer
Combination Therapy Studies
31
Summary of Albumin-Bound Paclitaxel Combination
Therapy Studies in NSCLC
Trial Description
Phase
Combination Therapy with Carboplatin
Weekly AB-paclitaxel + carboplatin as first-line therapy for advanced NSCLC1
II
Dose-finding study of weekly and q3w AB-paclitaxel + carboplatin as first-line
therapy for advanced NSCLC2
II
AB-paclitaxel + carboplatin vs CrEL paclitaxel + carboplatin as first-line therapy for
advanced NSCLC3,4
III
AB-Paclitaxel + carboplatin for patients at risk of bleeding from VEGF-directed
therapies5
II
Combination Therapy with Carboplatin and Bevacizumab
AB-paclitaxel + carboplatin + bevacizumab as first-line therapy for advanced
nonsquamous NSCLC6
II
In vivo assessment of the effects of bevacizumab in advanced NSCLC7
II
Combination with Carboplatin and Radiotherapy
AB-paclitaxel + carboplatin + thoracic radiation in locally advanced NSCLC8
I
Combination Therapy in SCLC
AB-paclitaxel + carboplatin in 2 different schedules for patients with ES-SCLC9
II
AB, albumin-bound; CrEL, Cremophor® EL; ES-SCLC, extensive stage small cell lung cancer; NSCLC, non-small cell lung cancer; q3w, every 3
weeks; VEGF, vascular endothelial growth factor.
®
Cremophor is a registered trademark of BASF.
References in slide notes.
32
Summary of Albumin-Bound Paclitaxel Combination
Therapy Studies in NSCLC
Trial Description
Phase
Main Idea
Combination Therapy with Carboplatin
Weekly AB-paclitaxel + carboplatin as first-line therapy for
advanced NSCLC1
II
AB-paclitaxel + carboplatin has a high degree of
antitumor activity and an acceptable safety profile1
Dose-finding study of weekly and q3w ab-pac +
carboplatin as first-line therapy for advanced NSCLC2
II
AB-paclitaxel 100 mg/m2 weekly + carboplatin AUC = 6
q3w is an optimal dose and schedule for treating
NSCLC2
AB-paclitaxel + carboplatin vs CrEL paclitaxel +
carboplatin as first-line therapy for advanced NSCLC3,4
III
AB-paclitaxel + carboplatin demonstrated a higher
response rate than CrEL paclitaxel + carboplatin3,4
AB-paclitaxel + carboplatin for NSCLC patients at risk of
bleeding from VEGF directed therapies5
II
AB-paclitaxel + carboplatin showed a high ORR in
NSCLC patients ineligible for VEGF directed therapies5
Combination Therapy with Carboplatin and Bevacizumab
AB-paclitaxel + carboplatin + bevacizumab as first-line
therapy for advanced nonsquamous NSCLC6
II
PFS and OS were higher than previously reported in
patients with advanced nonsquamous NSCLC and
toxicity was generally acceptable5
In vivo assessment of the effects of bevacizumab in
advanced NSCLC7
II
PD and imaging biomarker studies in bevacizumabtreated NSCLC patients are feasible and may predict
tumor response6
I
Weekly AB-paclitaxel at 40 mg/m2 + carboplatin +
thoracic radiation appears to be safe and well tolerated7
II
qw and q3w schedules of AB-paclitaxel + carboplatin
produced high ORRs in patients with ES-SCLC6
Combination with Carboplatin and Radiotherapy
AB-paclitaxel + carboplatin + thoracic radiation in locally
advanced NSCLC8
Combination Therapy in SCLC
AB-paclitaxel + carboplatin in 2 different schedules for
patients with ES-SCLC9
AB, albumin-bound; AUC, area under the curve; CrEL, Cremophor® EL; ES-SCLC, extensive stage small cell lung cancer; NSCLC, non-small cell lung
cancer; OS, overall survival; PD, pharmacodynamic; PFS, progression-free survival; q3w, every 3 weeks; qw, weekly.
References in slide notes.
33
Albumin-Bound Paclitaxel
for the First-Line Treatment of
Non-Small Cell Lung Cancer
Combination Therapy
with Carboplatin
34
A Phase II Evaluation of the Combination of
Albumin-Bound Paclitaxel + Carboplatin in
the First-Line Treatment of
Advanced Non-Small Cell Lung Cancer
J.P. Allerton, C.T. Hagenstad, T.R. Webb, G.B. Smith,
R. Birch, T.F. Goggins, S.B. Katakkar, W. Khan,
N.D. Mehta, F.A. Greco, Online Collaborative
Oncology Group
Allerton JP, et al. ASCO. 2006 [abstract 7127].
35
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Background
• Cremophor® EL paclitaxela + platinum agents are recommended
as first-line chemotherapy for advanced NSCLC1
– In phase III trials, CrEL paclitaxel + carboplatin showed efficacy
• Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4
– CrEL use is associated with severe hypersensitivity reactions6
• All patients should be premedicated prior to CrEL paclitaxel administration to
prevent severe hypersensitivity reactions5
• Albumin-bound paclitaxel is a solvent-free formulation of
paclitaxel7
– Use of albumin as a vehicle eliminates solvent-related toxicities8
– No premedication to prevent hypersensitivity reactions is required prior
to administration7
a
Cremophor® EL is a registered trademark of
BASF; CrEL, Cremophor EL; NSCLC, non-small
cell lung cancer; RR, response rates.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Kelly K, et al. J Clin Oncol. 2001;19:3210-3218.
3. Scagliotti GV, et al. J Clin Oncol. 2002;20:4282-429.
4. Lilenbaum RC, et al. J Clin Oncol. 2005;23:190-196.
5. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
6. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
7. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
8. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
36
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Background (cont.)
• Belani et al. studied weekly Cremophor® EL paclitaxel 100 mg/m2
qw 3/4 + carboplatin for advanced NSCLC1
– ORR 32%
– Median TTP 30 weeks
– Median survival time 49 weeks
– 1-year survival rate 47%
• Allerton et al. examined whether substituting albumin-bound
paclitaxel for Cremophor® EL paclitaxel at an identical dose
would improve ORR2
NSCLC, non-small cell lung cancer; ORR,
objective response rate; qw3/4, weekly for 3 of 4
weeks; TTP, time to tumor progression.
1. Belani CP, et al. J Clin Oncol. 2003;21(15):2933-2939.
2. Allerton JP, et al. ASCO. 2006 [abstract 7127].
37
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Objective
• Objective
– Determine efficacy and safety of albumin-bound paclitaxel +
carboplatin as first-line therapy for advanced NSCLC
• Efficacy endpoints
– Response rate
– Response duration
– TTP
• Safety endpoints
– Toxicities
NSCLC, non-small cell lung cancer ; TTP,
time to tumor progression.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
38
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Key Eligibility Criteria
• Key inclusion criteria
– Inoperable stage IIIB or IV NSCLC
• ≥ 1 measurable indicator lesion
• > 4 weeks from previous radiation therapy
– ECOG PS of 0, 1, or 2 at screening and on first day of treatment
– Life expectancy > 12 weeks
• Key exclusion criteria
– Previous treatment with chemotherapy
– Peripheral neuropathy ≥ grade 2
ECOG, Eastern Cooperative Oncology Group;
NSCLC, non-small cell lung cancer; PS,
performance status.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
39
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Study Design
• Open-label, phase II study
Albumin-bound paclitaxel
100 mg/m2 IV
on days 1, 8, and 15 q28 days
Carboplatin
AUC = 6 IV
on day 1
AUC, area under the curve; IV, intravenous;
NSCLC, non-small cell lung cancer; q28, every
28 days.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
40
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Baseline Patient Characteristics
Baseline characteristic (N = 56)
Value
Age, years
Median
Range
66
37 - 83
Sex, n (%)
Men
Women
39 (70)
17 (30)
Disease stage, n (%)
Stage IIIB
14 (25)
Stage IV with metastasis to, n
Bone
Liver
Brain
Lymph nodes
17
7
2
17
ECOG PS
Median
0, n
1, n
2, n
1
18
33
2
ECOG, Eastern Cooperative Oncology Group; PS, performance status.
NSCLC, non-small cell lung cancer.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
41
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Response Rate
Response rate, n (%)
Patients
CR
PR
SD > 12 weeks
All evaluable patients (N = 50)
1 (2)
24 (48)
18 (36)
Stage IIIB (n = 12)
0
4 (33)
4 (33)
Stage IV (n = 38)
1 (3)
20 (53)
14 (37)
CR, complete response; PR, partial response; SD, stable disease.
• Of 18 patients with SD
– Stable at 12-29 weeks, n = 14
– Progressed at 20, 21, 23, and 28 weeks, n = 4
NSCLC, non-small cell lung cancer.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
42
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Time to Tumor Progression
• Median TTP, 28 weeks; maximum follow-up, 39 weeks
a
Albumin-bound paclitaxel 100 mg/m2 was
administered IV qw 3/4 and carboplatin AUC = 6
was administered on day 1 only of a 28-day cycle.
AUC, area under the curve; NSCLC, non-small cell
lung cancer; qw 3/4 weekly on 3 of 4 weeks; TTP,
time to tumor progression.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
43
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Toxicities
Grade 3 or 4 toxicitiesa
n (%)
Neutropenia
24 (44)
Thrombocytopenia
14 (25)
Anemia
5 (9)
Neuropathy
0
Arthralgia
0
Myalgia
0
Nausea
1 (2)
Vomiting
1 (2)
Diarrhea
0
a
Toxicities associated with albumin-bound paclitaxel followed by carboplatin.
NSCLC, non-small cell lung cancer.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
44
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Conclusions
• Efficacy conclusions
– In first-line treatment of advanced NSCLC, albumin-bound paclitaxel +
carboplatin had a high degree of objectively-defined antitumor activity
• ORR 50%
• Median TTP 28 weeks
• Safety conclusions
– Acceptable safety profile
– Neutropenia was the most common severe toxicity
– No patients had grade 3/4 peripheral neuropathy
NSCLC, non-small cell lung cancer;
ORR, overall response rate; TTP, time
to tumor progression.
Allerton JP, et al. ASCO. 2006 [abstract 7127].
45
A Dose Finding Study of Weekly and Every 3
Week Albumin-Bound Paclitaxel Followed by
Carboplatin as First-Line Therapy in Patients
with Advanced Non-Small Cell Lung Cancer
M.A. Socinski, G.M. Manikhas, D.L. Stroyakovsky,
A.N. Makhson, S.V. Cheporov, S.V. Orlov, P.K.
Yablonsky, P.H. Bhar, and J. Iglesias
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
46
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Background
• Cremophor® EL paclitaxela + platinum agents are recommended
as first-line chemotherapy for advanced NSCLC1
– In phase III trials, CrEL paclitaxel + carboplatin showed efficacy:
• Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4
– CrEL use is associated with severe hypersensitivity reactions6
• All patients should be premedicated prior to CrEL paclitaxel administration to
prevent severe hypersensitivity reactions5
• Albumin-bound paclitaxel is a solvent-free formulation of
paclitaxel7
– Use of albumin as a vehicle eliminates solvent-related toxicities8
– No premedication to prevent hypersensitivity reactions is required prior
to administration7
a
Cremophor® EL is a registered trademark of
BASF; CrEL, Cremophor EL; NSCLC, non-small
cell lung cancer; RR, response rates.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Kelly K, et al. J Clin Oncol. 2001;19:3210-3218.
3. Scagliotti GV, et al. J Clin Oncol. 2002;20:4282-429.
4. Lilenbaum RC, et al. J Clin Oncol. 2005;23:190-196.
5. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
6. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
7. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
8. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
47
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Background
Phase
Patients,
n
ORR,
%
Median
TTP,
months
CrEL paclitaxel monotherapy1
III
157
16
4
6.8
CrEL paclitaxel + carboplatin2
NA
290
17
3.1
8.1
q3w AB-paclitaxel monotherapy3
II
43
16
6
11
weekly AB-paclitaxel monotherapy4
II
40
30
5
11
weekly AB-paclitaxel + carboplatin5
II
50
50
7
NA
NSCLC treatment studied
Median
OS,
months
AB, albumin-bound; CrEL, Cremophor EL; NA, not available; ORR overall response rate; OS, overall survival; q3w, every 3 weeks;
TTP, time to tumor progression.
• Based on the efficacy of ab-paclitaxel vs CrEL paclitaxel, Socinski et al. aimed to
identify the optimal dose of ab-paclitaxel + carboplatin as first-line therapy in
advanced NSCLC6
NSCLC, non-small cell lung cancer.
1. Ranson M, et al. J Natl Cancer Inst. 2000;92:1074-1080.
2. Schiller JH, et al. N Engl J Med. 2002;346:92-98.
3. Green MR, et al. Ann Oncol. 2006;17:1263-1268.
4. Rizvi NA, et al. J Clin Oncol. 2008;26:639-643.
5. Allerton JP, et al. ASCO. 2006 [abstract 7127].
6. Socinski MA, et al. J Thoracic Oncol. 2010;5(5):852-861.
48
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Objective
• Objective
– Identify optimal dose and schedule of albumin-bound paclitaxel + carboplatin as
first-line therapy for advanced NSCLC
• Primary efficacy endpoints
– CR or PR based on RECIST
• Secondary efficacy endpoints
– SD ≥ 16 weeks
– PFS
– OS
• Safety endpoints
–
–
–
–
Serious AEs
Treatment-related AEs
Laboratory abnormalities
Dose modifications, dose interruptions, premature discontinuation of study drug
AE, adverse event; CR, complete response;
NSCLC, non-small cell lung cancer; OS, overall
survival; PFS, progression-free survival; PR,
partial response; q3w, every 3 weeks; RECIST,
Response Evaluation Criteria in Solid Tumors;
SD, stable disease.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
49
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Key Eligibility Criteria
• Key inclusion criteria
– Men and nonpregnant, nonlactating women ≥ 18 years of age
– Stage IIIB or IV NSCLC
• Histologically or cytologically confirmed
• Pleural effusion or evidence of inoperable local recurrence or metastasis
• Measurable disease as defined by RECIST guidelines
– No previous treatment for metastatic disease
– Life expectancy > 12 weeks
– ECOG PS of 0 or 1
– Adequate hematologic, hepatic and renal function
ECOG, Eastern Cooperative Oncology Group;
NSCLC, non-small cell lung cancer; PS,
performance status; RECIST, Response
Evaluation Criteria in Solid Tumors.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
50
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Key Eligibility Criteria
• Key exclusion criteria
– Evidence of active brain metastasis
– Any other clinically serious concurrent illness
– Radiotherapy or chemotherapy in the previous 4 weeks
– Peripheral neuropathy > grade 1
– History of allergy or hypersensitivity to either of the study drugs
NSCLC, non-small cell lung cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
51
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Study Design
• Open-label, multicenter, phase II study
• AB-paclitaxel dosing schedule shown below
• All patients also received q3w carboplatin AUC = 6
q3w AB-paclitaxel dosing
weekly AB-paclitaxel dosing
Cohort 1
Patients 1-25
225 mg/m2 on day 1 q3w
Cohort 5
Patients 101-125
140 mg/m2 on day 1, 8 q3w
Cohort 2
Patients 26-50
260 mg/m2 on day 1 q3w
Cohort 6
Patients 126-150
100 mg/m2 on day 1, 8, 15 q3w
Cohort 3
Patients 51-75
300 mg/m2 on day 1 q3w
Cohort 7
Patients 151-175
125 mg/m2 on day 1, 8, 15 q3w
Cohort 4
Patients 76-100
340 mg/m2 on day 1 q3w
AB-paclitaxel, albumin-bound paclitaxel; AUC,
area under the curve; NSCLC, non-small cell
lung cancer; q3w, every 3 weeks.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
52
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Baseline Patient Characteristics
Weekly
(days 1, 8)
q3w
Baseline
characteristic
(N = 175)
Weekly
(days 1, 8, 15)
Cohortsa
225
mg/m2
260
mg/m2
300
mg/m2
340
mg/m2
140
mg/m2
100
mg/m2
125
mg/m2
Age, years
Mean
59.7
63.1
60.1
61.3
61.6
59.9
58.8
Sex, n (%)
Men
23 (92)
18 (72)
17 (68)
20 (80)
22 (88)
21 (84)
20 (80)
Stage, n (%)
IIIB
IV
10 (40)
15 (60)
8 (32)
17 (68)
4 (16)
21 (84)
3 (12)
22 (88)
4 (16)
21 (84)
4 (16)
21 (84)
7 (28)
18 (72)
Histology, n (%)
Nonsquamous
Squamous
Otherb
9 (36)
11 (44)
5 (20)
7 (28)
18 (72)
0
9 (36)
14 (56)
2 (8)
9 (36)
16 (64)
0 (0)
10 (40)
15 (60)
0
9 (36)
16 (64)
0
13 (52)
10 (40)
2 (8)
ECOG PS, n (%)
0
1
1 (4)
24 (96)
0
25 (100)
3 (12)
22 (88)
7 (28)
18 (72)
5 (20)
20 (80)
4 (16)
21 (84)
3 (12)
22 (88)
Preexisting
peripheral
neuropathy, n (%)
Grade 0
Grade 1
23 (92)
2 (8)
23 (92)
2 (8)
24 (96)
1 (4)
21 (84)
4 (16)
25 (100)
0
24 (96)
1 (4)
25 (100)
0
AUC, area under the curve; ECOG PS, Eastern Cooperative Oncology Group performance status; q3w, every 3 weeks.
a 25 patients per cohort; all patients received carboplatin AUC = 6.
b Poorly differentiated or non-differentiated NSCLC.
NSCLC, non-small cell lung cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
53
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Response Rates and DCR for All Treated Patients
Weekly
(days 1, 8)
q3w
Clinical
response
(N = 175)
Weekly
(days 1, 8, 15)
Cohortsa
225
mg/m2
260
mg/m2
300
mg/m2
340
mg/m2
140
mg/m2
100
mg/m2
125
mg/m2
10 (40)
20.8-59.2
6 (24)
7.3-40.7
6 (24)
7.3-40.7
8 (32)
13.7-50.3
14 (56)
36.5-75.5
12 (48)
28.4-67.6
9 (36)
17.2-54.8
CR, n (%)
0
1 (4)
0
0
0
1 (4)
1 (4)
PR, n (%)
10 (40)
5 (20)
6 (24)
8 (32)
14 (56)
11 (44)
8 (32)
SD ≥ 16 wks,
n (%)
5 (20)
8 (32)
3 (12)
0
2 (8)
2 (8)
3 (12)
15 (60)
40.8-79.2
14 (56)
36.5-75.5
9 (36)
17.2-54.8
8 (32)
13.7-50.3
16 (64)
45.2-82.8
14 (56)
36.5-75.5
12 (48)
28.4-67.6
ORR,
n (%)
95% CI
DCRb
n (%)
95% CI
AUC, area under the curve; CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response
rate; PR, partial response; q3w, every 3 weeks; SD, stable disease.
a 25 patients per cohort, all patients received carboplatin at AUC = 6..
b DCR = CR + PR + SD ≥ 16 weeks.
NSCLC, non-small cell lung cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
54
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: PFS and OS for All Treated Patients
Weekly
(days 1, 8)
q3w
Weekly
(days 1, 8, 15)
Clinical
response
(N = 175)
225
mg/m2
260
mg/m2
300
mg/m2
340
mg/m2
140
mg/m2
100
mg/m2
125
mg/m2
Median PFS,
months
95% CI
6.9
4.2-9.6
6.5
4.3-9.1
5.3
2.2-8.5
4.8
3.9-7.8
5.6
3.9-7.7
6.2
4.2-9.7
6.4
4.2-7.9
Median OS,
months
95% CI
10.7
8.7-17.0
12.2
8.5-21.9
8.3
4.2-15.4
14.6
7.6-17.2
12.0
6.5-17.1
11.3
7.8- >20.1
15.0
10- >18.4
Cohortsa
AUC, area under the curve; CI, confidence interval; OS, overall survival; PFS, progression-free survival; q3w, every 3 weeks.
a 25 patients per cohort, all patiente received carboplatin AUC = 6.
NSCLC, non-small cell lung cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
55
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Progression-Free Survival
AUC, area under the curve; NSCLC, non-small
cell lung cancer; q3w, every 3 weeks.
Note: all patients received carboplatin AUC = 6.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
56
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Overall Survival
AUC, area under the curve; NSCLC, non-small
cell lung cancer; q3w, every 3 weeks.
Note: all patients received carboplatin AUC = 6.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
57
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Efficacy Results by Histologic Subtype, SCC
Weekly
(days 1, 8)
q3w
Weekly
(days 1, 8, 15)
Cohortsa
225 mg/m2
(n = 11 )
260 mg/m2
(n = 18)
300 mg/m2
(n = 14)
340 mg/m2
(n = 16)
140
mg/m2
(n = 15)
100
mg/m2
(n= 16)
125
mg/m2
(n = 10)
ORR,
n (%)
95% CI
5 (45)
16.8-76.6
5 (28)
9.7-53.5
5 (36)
12.8-64.9
6 (38)
13.8-61.2
8 (53)
28.1-78.6
5 (31)
11.0-58.7
3 (30)
6.7-65.2
CR, n (%)
0
1 (6)
0
0
0
0
0
PR, n (%)
5 (45)
4 (22)
5 (36)
6 (38)
8 (53)
5 (31)
3 (30)
SD ≥ 16 weeks,
n (%)
2 (18)
6 (33)
1 (7)
0
1 (7)
1 (6)
1 (10)
DCRb
n (%)
95% CI
7 (64)
35.2-92.1
11 (61)
38.6-83.6
6 (43)
16.9-68.8
6 (37)
13.8-61.2
9 (60)
35.2-84.8
6 (38)
13.8-61.2
4 (40)
12.2-73.8
Median PFS,
months
95% CI
8.1
4.2-10.4
8.4
5.7-21.7
5.3
1.9-15.5
6.0
4.4-7.8
5.0
3.9-6.1
4.5
2.1-9.7
4.2
4.1-7.9
Median OS,
months
95% CI
13.2
5.4-18.5
12.2
8.5-23.9
8.0
3.1-17.8
15.1
10.5-18.5
9.4
7.8-14.0
12.6
5.3->18.8
10.9
9.2-16.3
Clinical
response
AUC, area under the curve; CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate;
OS, overall survival; PFS, progression-free survival; PR, partial response; q3w, every 3 weeks; SCC, squamous cell carcinoma; SD,
stable disease.
a All patients received carboplatin AUC = 6.
b DCR = CR + PR + SD ≥ 16 weeks.
NSCLC, non-small cell lung cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
58
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Efficacy Results by Histologic Subtype, Non-SCC
Weekly
(days 1, 8)
q3w
Weekly
(days 1, 8, 15)
Cohorts
225
mg/m2
(n = 9)
260
mg/m2
(n = 7)
300
mg/m2
(n = 9)
340
mg/m2
(n = 9)
140
mg/m2
(n = 10)
100
mg/m2
(n = 9)
125
mg/m2
(n = 13)
4 (44)
13.7-78.8
1 (14)
0.4-57.9
1 (11)
0.3-48.2
2 (22)
2.8-60.0
6 (60)
29.6-90.4
7 (78)
50.6-100
6 (46)
19.1-73.2
CR, n (%)
0
0
0
0
0
1 (11)
1 (8)
PR, n (%)
4 (44)
1 (14)
1 (11)
2 (22)
6 (60)
6 (67)
5 (38)
SD ≥ 16 weeks,
n (%)
1 (11)
2 (29)
2 (22)
0
1 (10)
1 (11)
1 (8)
5 (56)
21.2-86.3
3 (43)
9.9-81.6
3 (33)
7.5-70.1
2 (22)
2.8-60.0
7 (70)
41.6-98.4
8 (89)
68.4-100
7 (54)
26.8-80.1
PFS in months,
median
95% CI
5.8
4.0-9.6
5.5
2.5-10.2
5.3
3.5-7.0
4.4
3.7-8.7
7.7
3.5-15.9
6.6
5.7-17.0
18.3
4.6-18.3
OS in months,
median
95% CI
12.4
10.3-21.0
10.7
7.3->22.0
10.5
7.3->25.1
11.9
4.4->22.3
13.1
4.8->18.4
9.8
7.8-11.3
>18.4
15.0->18.4
Clinical
response
ORR,
n (%)
95% CI
DCRa
n (%)
95% CI
AUC, area under the curve; CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate;
OS, overall survival; PFS, progression-free survival; PR, partial response; q3w, every 3 weeks; SD, stable disease.
a All patients received carboplatin AUC = 6.
b DCR = CR + PR + SD ≥ 16 weeks.
Non-SCC, nonsquamous cell carcinoma;
NSCLC, non-small cell lung cancer;
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
59
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: ORR and DCR by Histologic Subtype
DCR, disease control rate; Non-SCC,
nonsquamous cell carcinoma; NS, not
statistically significant; NSCLC, non-small cell
lung cancer; ORR, overall response rate; q3w,
every 3 weeks; SCC, squamous cell carcinoma.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
60
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: PFS and OS by Histologic Subtype
Non-SCC, nonsquamous cell carcinoma; NS,
not statistically significant; NSCLC, non-small
cell lung cancer; OS, overall survival; PFS,
progression-free survival; q3w, every 3 weeks;
SCC, squamous cell carcinoma.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
61
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Treatment-Related Hematologic ≥ Grade 3 AEs in
≥ 5% of Patients
Weekly
(days 1, 8)
q3w
Weekly
(days 1, 8, 15)
Adverse event,
n (%)
(N = 175)
225
mg/m2
260
mg/m2
300
mg/m2
340
mg/m2
140
mg/m2
100
mg/m2
125
mg/m2
Neutropenia
Grade 3
Grade 4
8 (32)
8 (32)
9 (36)
6 (24)
9 (36)
3 (12)
7 (28)
5 (20)
8 (32)
11 (44)
9 (36)
7 (28)
7 (28)
8 (32)
Leukopenia
Grade 3
Grade 4
8 (32)
1 (4)
6 (24)
0 (0)
7 (28)
0 (0)
9 (36)
1 (4)
12 (48)
0 (0)
6 (24)
0 (0)
5 (20)
1 (4)
Thrombocytopenia
Grade 3
Grade 4
7 (28)
3 (12)
5 (20)
1 (4)
5 (20)
2 (8)
5 (20)
1 (4)
5 (20)
3 (12)
4 (16)
1 (4)
5 (20)
4 (16)
Anemia
Grade 3
Grade 4
4 (16)
1 (4)
6 (24)
0 (0)
3 (12)
1 (4)
2 (8)
1 (4)
4 (16)
1 (4)
4 (16)
0 (0)
10 (40)
1 (4)
Cohortsa
AUC, area under the curve; q3w, every 3 weeks.
a 25 patients per cohort, all patients received carboplatin AUC = 6.
AE, adverse event; NSCLC, non-small cell lung
cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
62
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Treatment-Related Non-Hematologic ≥ Grade 3 AEs
in ≥ 5% of Patients
Weekly
(days 1, 8)
q3w
Weekly
(days 1, 8, 15)
Adverse event,
n (%)
(N = 175)
225
mg/m2
260
mg/m2
300
mg/m2
340
mg/m2
140
mg/m2
100
mg/m2
125
mg/m2
Peripheral
neuropathy
Grade 3
Grade 4
3 (12)
0 (0)
4 (16)
0 (0)
6 (24)
0 (0)
12 (48)
0 (0)
2 (8)
0 (0)
2 (8)
0 (0)
4 (16)
0 (0)
Fatigue
Grade 3
Grade 4
3(12)
0 (0)
1 (4)
0 (0)
4 (16)
0 (0)
3 (12)
0 (0)
1 (4)
0 (0)
0 (0)
0 (0)
4 (16)
0 (0)
Myalgia
Grade 3
Grade 4
0
0
1 (4)
0
1 (4)
0
6 (24)
0
0
0
0
0
0
0
Arthralgia
Grade 3
Grade 4
0
0
1 (4)
0
1 (4)
0
2 (8)
0
0
0
0
0
0
0
Cohortsa
AUC, area under the curve; q3w, every 3 weeks.
a 25 patients per cohort, all patients received carboplatin AUC = 6.
AE, adverse event; NSCLC, non-small cell lung
cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
63
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Time to Improvement of Peripheral Neuropathy
Weekly
(days 1, 8)
q3w
Weekly
(days 1, 8, 15)
Cohortsa
Improvement of
peripheral
neuropathy
225
mg/m2
(n = 3)
260
mg/m2
(n = 4)
300
mg/m2
(n = 6)
340
mg/m2
(n = 12)
140
mg/m2
(n = 2)
100
mg/m2
(n = 2)
125
mg/m2
(n = 4)
Improved to grade ≤ 2,
n (%)
2 (67)
4 (100)
2 (33)
7 (58)
1 (50)
2 (100)
1 (25)
Time to improvement,
Median daysa
95% CI
15.0
9.0-> 21.0
14.5
6.0-34.0
> 48.0
6.0-> 48.0
23.0
17.0-> 66.0
8.0
---
15.5
13.0-18.0
> 24.0
8.0-> 24.0
AUC, area under the curve; CI, confidence interval; q3w, every 3 weeks.
a All patients received carboplatin AUC = 6.
b Time to improvement was defined as the time from first occurrence of grade 3 peripheral neuropathy to improvement of at least to grade 2.
NSCLC, non-small cell lung cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
64
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Results: Dose Modifications and Dose Interruptions
• Dose modifications
– Albumin-bound paclitaxel:
• In the q3w cohorts, 40% of patients had ≥ 1 dose reduction
• In the weekly cohorts, 51% of patients had ≥ 1 dose reduction
• Hematologic toxicity was the most common reason for dose reductions
– Carboplatin:
• In the q3w cohorts, 6% of patients had a dose reduction
• In the weekly cohorts, 16% of patients had a dose reduction
• Dose interruptions
– Albumin-bound paclitaxel:
• None
– Carboplatin:
• In the q3w cohorts, 2 patients had a dose interruption because of a
hypersensitivity reaction
NSCLC, non-small cell lung cancer.
q3w, every 3 weeks.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
65
First-Line Albumin-Bound Paclitaxel + Carboplatin in
Advanced NSCLC
Conclusions
• Albumin-bound paclitaxel + carboplatin demonstrated
antitumor activity in all cohorts and was well tolerated
– 100 mg/m2 dose of albumin-bound paclitaxel, although not showing the
highest DCR of all doses tested, provided the best clinical benefit-risk
ratio
– Weekly vs q3w albumin-bound paclitaxel was associated with improved
clinical outcomes and less serious AEs
• 100 mg/m2 weekly albumin-bound paclitaxel + carboplatin AUC
= 6 q3w is an optimal dose and schedule for treating NSCLC
– Based on the these results, a phase III study comparing 100 mg/m2
albumin-bound paclitaxel + carboplatin AUC = 6 q3w with standard
dose Cremophor® EL paclitaxel + carboplatin for NSCLC was initiated
AE, adverse event; AUC, area under the curve;
DCR, disease control rate; NSCLC, non-small
cell lung cancer; q3w, every 3 weeks.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
66
Survival Results of a Randomized, Phase III
Trial of Albumin-Bound Paclitaxel and
Carboplatin Compared With Cremophor-Based
Paclitaxel and Carboplatin as First-Line Therapy
in Advanced Non-Small Cell Lung Cancer
M.A. Socinski, I. Bondarenko,
N.A. Karaseva, A.M. Makhson,
I.O. Vynnychenko, I. Okamoto, J. Hon,
V. Hirsh, P. Bhar, G.I. Berks, J.L. Iglesias
aCremophor
BASF.
is a registered trademark of
Socinski MA et al. ASCO. 2011 [Abstract 7551].
67
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Background
• Cremophor® EL paclitaxela + platinum agents are recommended
as first-line chemotherapy for advanced NSCLC1
– In phase III trials, CrEL paclitaxel + carboplatin showed efficacy:
• Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4
– CrEL use is associated with severe hypersensitivity reactions6
• All patients should be premedicated prior to CrEL paclitaxel administration to
prevent severe hypersensitivity reactions5
• Albumin-bound paclitaxel is a solvent-free formulation of
paclitaxel7
– Use of albumin as a vehicle eliminates solvent-related toxicities8
– No premedication to prevent hypersensitivity reactions is required prior
to administration7
a
Cremophor® EL is a registered trademark of
BASF; CrEL, Cremophor EL; NSCLC, non-small
cell lung cancer; RR, response rates.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Kelly K, et al. J Clin Oncol. 2001;19:3210-3218.
3. Scagliotti GV, et al. J Clin Oncol. 2002;20:4282-429.
4. Lilenbaum RC, et al. J Clin Oncol. 2005;23:190-196.
5. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
6. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
7. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
8. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
68
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Background (cont.)
• Weekly CrEL paclitaxel 100 mg/m2 qw 3/4 + carboplatin AUC = 6 on
day 1 achieved ORR of 32% in advanced NSCLC1
• Substituting AB-paclitaxel for CrEL paclitaxel at an identical dose
achieved response rates of 50%2
• Based on the efficacy of AB-paclitaxel vs CrEL paclitaxel observed in
these studies, a phase II trial was conducted3
– Showed that 100 mg/m2 weekly AB-paclitaxel + carboplatin AUC = 6
q3w is the optimal dose/schedule for treatment of advanced NSCLC3
• Based on these phase II results, a phase III regulatory pathway trial
was designed4
– Investigated the efficacy and safety of AB-paclitaxel + carboplatin vs
CrEL paclitaxel + carboplatin as first-line therapy in advanced NSCLC4
• Final survival outcomes are also presented here
AB, albumin-bound: AUC, area under the curve;
CrEL, Cremophor EL; NSCLC, non-small cell lung
cancer; ORR, objective response rate; q3w, every 3
weeks; qw 3/4, weekly for 3 of 4 weeks.
1. Belani CP, et al. J Clin Oncol. 2003;21(15):2933-2939.
2. Allerton JP, et al. ASCO. 2006 [abstract 7127].
3. Socinski MA, et al. J Thoracic Oncol. 2010;5(5):852-861.
4. Socinski MA, et al. ASCO. 2010 [abstract LBA7511].
69
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Objective
• Objective
– Investigate efficacy and safety of AB-paclitaxel + carboplatin vs
CrEL paclitaxel + carboplatin as first-line therapy for advanced NSCLC
• Primary endpoint
– ORR (CR + PR) by independent radiologic review based on RECIST
• Secondary endpoints
– PFS and OS
– DCRa
– Safety
a DCR
= CR + PR + SD ≥ 16 weeks.
AB, albumin-bound ; CR, complete response;
CrEL, Cremophor ® EL; DCR, disease control
rate; NSCLC, non-small cell lung cancer;
ORR, objective response rate; OS, overall
survival; PFS, progression-free survival; PR,
partial response; RECIST, Response
Evaluation Criteria in Solid Tumors; SD,
stable disease.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
70
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Key Eligibility Criteria
• Key inclusion criteria
– Adult patients with histologically/cytologically confirmed
stage IIIB or IV NSCLC
– Measurable disease by RECIST
– No prior treatment for metastatic disease
• Adjuvant therapy was allowed if it was > 1 year prior to study entry
– ECOG PS of 0 or 1
– Adequate hematologic, hepatic, and renal function
• Key exclusion criteria
– Active brain metastases
• Treated, controlled metastases were allowed
– Baseline peripheral neuropathy ≥ grade 2
ECOG, Eastern Cooperative Oncology Group;
NSCLC, non-small cell lung cancer; PS,
performance status; RECIST, Response
Evaluation Criteria in Solid Tumors.
Socinski MA, et al. ASCO. 2010 [abstract LBA7511].
71
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Study Design
Chemotherapy-naïve
ECOG PS 0-1
Stage IIIB/IV NSCLC
(N = 1052)
Randomized 1:1
mg/m2
AB-paclitaxel 100
days 1, 8, 15
Carboplatin AUC = 6 day 1
Cycles of 21 days
No Premedication
(n = 521)
AB, albumin-bound; AUC, area under the
curve; CrEL, Cremophor® EL; ECOG, Eastern
Cooperative Oncology Group; NSCLC, nonsmall cell lung cancer; PS, performance
status.
CrEL paclitaxel 200 mg/m2 day 1
Carboplatin AUC = 6 day1
Cycles of 21 days
Premedication with
Dexamethasone + Antihistamines
(n = 531)
Socinski MA et al. ASCO. 2011 [Abstract 7551].
72
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Baseline Patient Characteristics
Baseline characteristic
Age, years
Median
Range
< 70 years, n (%)
≥ 70 years, n (%)
Sex, n (%)
Male
Female
Stage, n (%)a
III
IV
Histology, n (%)a
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other
ECOG PS, n (%)
0
1
Prior chemotherapy, n (%)
Smoking status, n (%)
Never smoked
Smoked and quit
Smoked and still smokes
AB-paclitaxel +
carboplatin
(n = 521)
CrEL paclitaxel +
carboplatin
(n = 531)
60
28 - 81
448 (86)
73 (14)
60
24 - 84
449 (85)
82 (15)
392 (75)
129 (25)
397 (75)
134 (25)
99 (19)
421 (81)
107 (20)
424 (80)
254 (49)
228 (44)
9 (2)
29 (6)
264 (50)
221 (42)
13 (2)
33 (6)
133 (26)
385 (74)
12 (2)
113 (21)
416 (78)
8 (2)
138 (27)
165 (32)
210 (41)
144 (28)
146 (28)
231 (44)
AB, albumin-bound; CrEL, Cremophor EL ; ECOG PS, Eastern Cooperative Oncology Group performance status.
a Data were missing for 1 patient at the time of this analysis.
NSCLC, non-small cell lung cancer.
Socinski MA, et al. ASCO. 2010 [abstract LBA7511].
73
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Results: ORR, Stratified by Histologya
a
Not a pre-specified endpoint.
AB, albumin-bound; CrEL Cremophor EL; NSCLC,
non-small cell lung cancer; ORR, objective
*response
Not a pre-specified
endpoint
rate.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
74
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Primary Endpoint: Objective Responses -ITT
AUC, area under the curve; CrEL,
Cremophor EL; NSCLC, non-small cell lung
cancer.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
75
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Results: Progression-Free Survival
AB, albumin-bound; AUC, area under the curve;
CI, confidence interval; CrEL, Cremophor EL;
HR, hazard ratio; PFS, progression-free
* Not a pre-specified endpoint
survival.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
76
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Results: Progression-Free Survival
AB, albumin-bound; Carbo, carboplatin; CI,
confidence interval; CrEL, Cremophor EL; HR,
*hazard
Not a
pre-specified
endpoint
ratio;
PFS, progression-free
survival.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
77
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Results: Overall Survival
AB, albumin-bound; AUC, area under the curve; CI,
confidence interval; CrEL, Cremophor EL; HR,
ratio;
OS, overall survival.
*hazard
Not a
pre-specified
endpoint
Socinski MA et al. ASCO. 2011 [Abstract 7551].
78
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Results: Overall Survival
AB, albumin-bound; Carbo, carboplatin; CI,
confidence interval; CrEL, Cremophor EL; HR,
*hazard
Not a
pre-specified
endpoint
ratio;
OS, overall survival.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
79
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Results: Safety
Treatment-related grade 3/4 AEsa
Hematologic, %
Neutropenia
Thrombocytopenia
Anemia
Febrile neutropenia
Nonhematologic, %
Fatigue
Sensory neuropathy
Anorexia
Nausea
Myalgia
Time in days to improvement of sensory
neuropathy to grade 1, median
AB-paclitaxel
+ carboplatin
(n = 514)
CrEL
paclitaxel +
carboplatin
(n = 524)
P-value
42
18
24
1
48
7
6
1
.081
< .001
< .001
NS
5
3
2
<1
<1
6
12
<1
<1
2
NS
< .001
NS
NS
.011
38
104
.238
AB, albumin-bound; AE, adverse event; CrEL, Cremophor EL; NS, not statistically significant;.
a By National Cancer Institute Common Terminology Criteria for Adverse Events.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
80
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor®
EL Paclitaxel + Carboplatin in Advanced NSCLC
Conclusions
• The primary endpoint of a higher ORR albumin-bound paclitaxel plus
carboplatin compared with Cremophor® EL palictaxel plus carboplatin
was met
-
Overall: 33% vs. 25% (P = .005)
• Within the squamous cell subset, the ORR of albumin-bound
paclitaxel plus carboplatin was higher than Cremophor EL paclitaxel
plus carboplatin: 41% vs. 24% (P < .001)
• There was no significant difference in PFS or OS between the 2 arms
- HRs trended in favor of the albumin-bound paclitaxel arm,
particularly in the elderly and in patients with squamous cell
histology
• The albumin-bound paclitaxel arm exhibited higher rates of grade 3/4
anemia and thrombocytopenia and lower rates of grade 3/4 myalgia
and sensory neuropathy
HR, hazard ratio; NSCLC, non-small cell lung
cancer; ORR, overall response rate; OS, overall
survival; PFS, progression-free survival.
Socinski MA et al. ASCO. 2011 [Abstract 7551].
81
Phase II Trial of Albumin-Bound Paclitaxel
Plus Carboplatin in Patients With Advanced
NSCLC at Risk of Bleeding From VEGF
Directed Therapies
G. A. Otterson, E. M. Bertino, N. A. Karim,
K. Donthireddy, A. M. Ghany, R. Rupert,
S. Cantrell, M. Rahmani, M. Lynn,
S. P. Nana-Sinkam, G. S. Phillips,
M. A. Villalona-Calero
NSCLC, non-small cell lung cancer; VEGF,
vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
82
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Background
• A phase II trial of albumin-bound paclitaxel plus carboplatin and
bevacizumab in patients with advanced NSCLC produced an ORR of
31% and a median OS of 16.8 months1
• Albumin-bound paclitaxel plus carboplatin produced a higher ORR vs
Cremophor® EL paclitaxel plus carboplatin in a phase III trial of
patients with advanced NSCLC2
– Difference particularly pronounced in patients with squamous histology (ORR =
41% vs 24%; P < .001)
• Albumin-bound paclitaxel plus carboplatin may be a viable option for
patients who can not receive bevacizumab due to characteristics
such as squamous histology or risk of bleeding
®
Cremophor is a registered trademark of BASF.
NSCLC, non-small cell lung cancer; ORR, overall
response rate; OS, overall survival; VEGF,
vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
1. Reynolds C, et al. J Thorac Oncol.
2009;4(12):1537-1543.
2. Socinski MA et al. ASCO. 2011 [Abstract 7551].
83
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Objective
• Objective: to determine the efficacy of albumin-bound
paclitaxel plus carboplatin in patients who are ineligible for
treatment with bevacizumab
• Primary endpoint: overall response rate by RECIST
• Secondary endpoints
–
–
–
–
Safety/toxicity
OS
PFS
Exploratory
• Tumor SPARC expression
• Serum micro RNA expression profiles
NSCLC, non-small cell lung cancer; OS, overall
survival; PFS, progression-free survival;
RECIST, Response Evaluation Criteria in Solid
Tumors; SPARC, Secreted Protein Acidic and
Rich in Cysteine; VEGF, vascular endothelial
growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
84
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Key Eligibility Criteria
• Inclusion criteria
– Advanced NSCLC
• Stage IIIB with pleural effusion
• Stage IV
• Recurrent
– Not eligible to receive bevacizumab because of
•
•
•
•
Squamous histology
Thrombotic or embolic events within 6 months
History of controlled, non-life–threatening hemoptysis
Cavitary lung lesions
NSCLC, non-small cell lung cancer; VEGF,
vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
85
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Key Eligibility Criteria (cont.)
• Exclusion criteria
– Prior treatment of advanced NSCLC
– Pre-existing ≥ grade 2 neuropathy
– Uncontrolled brain metastases
– Major surgery within 4 weeks
– Nonhealing wounds
– Uncontrolled cardiac disease
– HIV
– Hepatitis B or C
NSCLC, non-small cell lung cancer; VEGF,
vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
86
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Study Design
• Study design: phase II, single-arm, 2-stage Simon model
-
First stage: 27 patients
Second stage: 36 patients
Twenty-one day cycles
Patients allowed to receive up to 6 cycles of therapy
Albumin-bound paclitaxela
300 mg/m2
Day 1
a The
dose of albumin-bound paclitaxel was reduced
from 300 mg/m2 for the first 40 patients to 260 mg/m 2
for the subsequent patients due to excessive grade 3
neuropathy.
AUC, area under the curve; NSCLC, non-small
cell lung cancer; VEGF, vascular endothelial
growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
Carboplatin
AUC = 6
Day 1
87
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Baseline Patient Characteristics
Baseline characteristic
N = 52
Age in years, mean
64
Race, n (%)
White
Black
Other
42 (81)
9 (17)
1 (2)
Tobacco pack years, mean
Histology, n (%)
Squamous
Adenocarcinoma
Adenosquamous
Poorly differentiated NSCLC
49
37 (71)
8 (15)
2 (4)
5 (10)
ECOG PS, n (%)
0
1
2
18 (35)
24 (46)
10 (19)
ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small cell lung cancer.
VEGF, vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
88
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Results: Clinical Outcomes
Clinical response, n (%)
N = 52
Partial response
16 (31)a
Stable disease
18 (35)
Progressive disease
10 (19)
Not evaluable
8 (15)
a
Thirteen (25%) of the 16 partial responses were confirmed responses.
NSCLC, non-small cell lung cancer; VEGF,
vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
89
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Results: Adverse Events
Grade 3 or 4 adverse events in > 5% of patientsa
(N = 52)
Grade 3
Grade 4
Hematologic, n (%)
Anemia
Neutropenia
Thrombocytopenia
2 (4)
4 (8)
5 (10)
1 (2)
8 (15)
1 (2)
Nonhematologic, n (%)
Sensory neuropathy
Febrile neutropenia
Infection in the absence of neutropenia
Hyponatremia
Hypoxia
Dyspnea
Dehydration
Fatigue
13 (25)
7 (13)
5 (10)
7 (13)
1 (2)
7 (13)
6 (12)
10 (20)
0
2 (4)
5 (10)
0
2 (4)
2 (4)
3 (6)
0
a
Adverse events per Common Terminology Criteria for Adverse Events, version 3.0.
NSCLC, non-small cell lung cancer; VEGF,
vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
90
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With
NSCLC at Risk of Bleeding From VEGF Directed Therapies
Conclusions
• This treatment regimen offers a reasonable first-line treatment
option for patients with advanced squamous NSCLC who are
not eligible to receive bevacizumab
• Fifty-two patients have been enrolled in this ongoing study; 11
more patients are required to complete accrual
• The clinical response data from the first stage of this trial (30%
of the 27 patients exhibited partial responses) allowed for
continuation to the second stage
• Exploratory endpoints examining tumoral SPARC and serum
micro RNA profiles are pending
NSCLC, non-small cell lung cancer; SPARC,
Secreted Protein Acidic and Rich in Cysteine;
VEGF, vascular endothelial growth factor.
Otterson GA, et al. IASLC 2011 [Abstract P3.183].
91
Albumin-Bound Paclitaxel
for the Treatment of
Non-Small Cell Lung Cancer
Combination Therapy with
Carboplatin and Bevacizumab
92
Phase II Trial of Albumin-Bound Paclitaxel +
Carboplatin + Bevacizumab in First-Line
Patients With Advanced Nonsquamous
Non-Small Cell Lung Cancer
C. Reynolds, D. Barrera, R. Jotte, A. I. Spira, C.
Weissman, K. A. Boehm, S. Pritchard,
L. Asmar
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
93
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Background
• Cremophor® EL paclitaxela + platinum agents are recommended as
first-line chemotherapy for advanced NSCLC1
– In phase III trials, CrEL paclitaxel + carboplatin showed efficacy:
• Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4
– CrEL use is associated with severe hypersensitivity reactions6
• All patients should be premedicated prior to CrEL paclitaxel administration to
prevent severe hypersensitivity reactions5
• Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel7
– Use of albumin as a vehicle eliminates solvent-related toxicities8
– No premedication to prevent hypersensitivity reactions is required prior
to administration7
a
Cremophor® EL is a registered trademark of
BASF; CrEL, Cremophor EL; NSCLC, non-small
cell lung cancer; RR, response rates.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Kelly K, et al. J Clin Oncol. 2001;19:3210-3218.
3. Scagliotti GV, et al. J Clin Oncol. 2002;20:4282-429.
4. Lilenbaum RC, et al. J Clin Oncol. 2005;23:190-196.
5. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
6. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
7. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
8. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
94
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Background (cont.)
• Bevacizumab is a VEGF-specific angiogenesis inhibitor1
– Indicated with CrEL paclitaxel + carboplatin as first-line treatment of
patients with unresectable, locally advanced, recurrent, or metastatic
nonsquamous NSCLC1
• In a phase III trial, AB-paclitaxel + carboplatin achieved a
higher ORR than CrEL paclitaxel + carboplatin in advanced
NSCLC2
– 33% vs 25%, P = .0052
• A phase II trial was designed to evaluate AB-paclitaxel +
carboplatin + bevacizumab in advanced nonsquamous
NSCLC3
AB-paclitaxel, albumin-bound paclitaxel; CrEL,
Cremophor EL; NSCLC, non-small cell lung
cancer; ORR, objective response rate; VEGF,
vascular endothelial growth factor.
1. Avastin (bevacizumab) package insert. San Francisco, CA, Genentech, Inc., 2011.
2. Socinski MA, et al. ASCO. 2010 [abstract LBA7511].
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
95
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Objective
• Objective
– Evaluate the safety and antitumor activity of AB-paclitaxel + carboplatin
+ bevacizumab q21d in advanced stage IIIB/IV NSCLC
• Primary endpoint
– Response rate based upon RECIST criteria
• Secondary endpoints
– TTP
– Duration of response
– Safety
– 1- and 2-year survival
– Proportion of patients with SD ≥ 16 weeks
– Changes in QOL using FACT-Taxane questionnaires
AB, albumin-bound: FACT, Functional
Assessment of Cancer Therapy; NSCLC, nonsmall cell lung cancer; q21d, every 21 days;
QOL, quality of life; RECIST, Response
Evaluation Criteria In Solid Tumors; SD, stable
disease; TTP, time to disease progression.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
96
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Key Eligibility Criteria
• Key inclusion criteria
– Histologically or cytologically confirmed advanced stage IIIB (wet)/IV
nonsquamous NSCLC
– Evidence of inoperable local recurrence or metastasis
– Measurable disease by RECIST
– No prior chemotherapy
– Prior RT permitted as long as the measurable disease
• Was outside the field of radiation
• Had progressed since completion of radiation
– ECOG PS of 0-1
ECOG, Eastern Cooperative Oncology Group;
NSCLC, non-small cell lung cancer; PS,
performance status; RECIST, response
evaluation criteria in solid tumors ; RT, radiation
therapy.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
97
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Key Eligibility Criteria (cont.)
• Key exclusion criteria
– Another active malignancy
– Pre-existing peripheral neuropathy of NCI grade > 1
• Exclusion criteria related to the administration of bevacizumab
– Presence of CNS metastases
– Gross hemoptysis
– Unstable angina
– Use of therapeutic anticoagulation
CNS, central nervous system; NSCLC, non-small
cell lung cancer; NCI, National Cancer Institute.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
98
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Study Design
• Open-label, single arm, phase II study
Albumin-bound paclitaxel 300 mg/m2 IV
+
Carboplatin AUC = 6 IV
+
Bevacizumab 15 mg/kg
On day 1 of each 21 day cycle
• Patients did not receive maintenance bevacizumab
• Patients were to receive a minimum of 4 cycles of treatment
AUC, area under the curve; IV, intravenous;
NSCLC, non-small cell lung cancer .
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
99
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Baseline Patient Characteristics
Baseline characteristic (N = 50)
Age, years
Median
Range
Sex, n (%)
Male
Female
Histology, n (%)
Adenocarcinoma
Bronchioalveolar
Large cell
NOS
ECOG PS, n (%)
0
1
Prior treatment, n (%)
Surgery
Radiation
Number of metastatic sites per patient, n (%)
1
2
3
4
ECOG, Eastern Cooperative Oncology Group; NOS, not otherwise specified; PS, performance status.
NSCLC, non-small cell lung cancer.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
Value
67
32 - 83
22 (48)
28 (56)
43 (86)
1 (2)
4 (8)
2 (4)
26 (52)
24 (48)
19 (30)
4 (8)
19 (38)
15 (30)
9 (18)
1 (2)
100
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Results: Response After Treatment
Response (N = 48)
Value
ORR, %
31
Clinical benefit rate (CR + PR + [SD ≥ 6 months]), %
54
CR, n
0
PR, n (%)
SD, n (%)
≥ 6 months, n
< 6 months, n
15 (31)
26 (54)
11
15
PD, n (%)
2 (4)
CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
• Median time to response: 1.3 months (range, 1.2 – 2.6)
• Median duration of response: 8.9 months (range, 2.9 – 19.1)
NSCLC, non-small cell lung cancer.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
101
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Results: Overall Survival
NSCLC, non-small cell lung cancer; OS, overall
survival.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
102
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Results: Progression-Free Survival
NSCLC, non-small cell lung cancer; PFS,
progression-free survival.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
103
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Results: Time to Progression
NSCLC, non-small cell lung cancer; TTP, time to
progression.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
104
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Results: Safety
Treatment-related AEs occurring in
> 1 patient (N = 48)
Grade 3
Grade 4
Hematologic, n (%)
Leukopenia
Neutropenia
Thrombocytopenia
2 (4)
8 (17)
4 (8)
0
18 (38)
1 (2)
Nonhematologic, n (%)
Anorexia
Constipation
Diarrhea
Fatigue
Febrile neutropenia
Neuropathy
Peripheral neuropathy
2 (4)
3 (6)
2 (4)
6 (13)
3 (6)
5 (10)
2 (4)
0
0
0
2 (4)
2 (4)
0
0
AE, adverse event.
NSCLC, non-small cell lung cancer.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
105
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Results: Quality of Life
• QOL was assessed using the FACT-Taxane scale1
• Over the course of the study, QOL decreased significantly with
the exception of emotional well-being
• Emotional well-being increased throughout cycles 1-5 and was
significantly higher than baseline at cycle 3 (P = 0.05)
FACT, Functional Assessment of Chronic Illness
Therapy; NSCLC, non-small cell lung cancer;
QOL, quality of life.
1. FACIT Functional Assessment of Chronic Illness
Therapy, FACT-Taxane Questionnaire v4. Available at
http://www.facit.org/FACITOrg/Questionnaires .
Accessed May 20, 2011.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
106
First-Line Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced Nonsquamous NSCLC
Conclusions
• Efficacy conclusions
– PFS and OS rates were higher than previously reported in patients with
advanced NSCLC
– PR occurred in 31% of patients
– SD in 54% of patients
• Safety conclusions
– Toxicity was generally acceptable
– Low incidence of grade 3 peripheral neuropathy
– Absence of any obvious exacerbation of chemotherapy-induced
myelosuppression by the addition of bevacizumab
• Phase III evaluation of this combination would determine
whether it is more efficacious than previous regimens
NSCLC, non-small cell lung cancer; PFS,
progression-free survival; PR, partial response;
SD, stable disease; OS, overall survival.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
107
In Vivo Assessment of the Effects of
Bevacizumab in Advanced
Non-Small Cell Lung Cancer
R. Suk Heist, D.G. Duda, D.V. Sahani,
N.Pennell, J. Neal, M. Ancukiewicz,
J. Engelman, T.J. Lynch, R.K. Jain
Heist RS, et al. ASCO. 2010 [abstract 7612].
108
Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced NSCLC
Background
• Cremophor® EL paclitaxela + platinum agents are recommended as
first-line chemotherapy for advanced NSCLC1
– In phase III trials, CrEL paclitaxel + carboplatin showed efficacy:
• Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4
– CrEL use is associated with severe hypersensitivity reactions6
• All patients should be premedicated prior to CrEL paclitaxel administration to
prevent severe hypersensitivity reactions5
• Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel7
– Use of albumin as a vehicle eliminates solvent-related toxicities8
– No premedication to prevent hypersensitivity reactions is required prior
to administration7
a
Cremophor® EL is a registered trademark of
BASF; CrEL, Cremophor EL; NSCLC, non-small
cell lung cancer; RR, response rates.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Kelly K, et al. J Clin Oncol. 2001;19:3210-3218.
3. Scagliotti GV, et al. J Clin Oncol. 2002;20:4282-429.
4. Lilenbaum RC, et al. J Clin Oncol. 2005;23:190-196.
5. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
6. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
7. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
8. Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
109
Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced NSCLC
Background (cont.)
• Bevacizumab is a VEGF-specific angiogenesis inhibitor1
– Indicated with CrEL paclitaxel + carboplatin as first-line treatment of
patients with locally advanced, recurrent, or metastatic nonsquamous
NSCLC1
• Phase II trial evaluated the antitumor activity of AB-paclitaxel +
carboplatin + bevacizumab2
– Demonstrated higher PFS and OS than previously reported in advanced
nonsquamous NSCLC2
• Phase II trial was designed to identify biomarkers for
bevacizumab in NSCLC patients treated with AB-paclitaxel +
carboplatin + bevacizumab3
AB, albumin-bound; CrEL, Cremophor EL;
NSCLC, non-small cell lung cancer; OS, overall
survival; PFS, progression-free survival; VEGF,
vascular endothelial growth factor.
1. Avastin (bevacizumab) package insert. San Francisco, CA, Genentech, Inc., 2011.
2. Reynolds C, et al. J Thorac Oncol. 2009;4:1-7.
3. Heist RS, et al. ASCO. 2010 [abstract 7612].
110
Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced NSCLC
Objective
• Objective
– Identify biomarkers for bevacizumab in patients with NSCLC
• Primary endpoint
– 6-month PFS rate
• Secondary endpoints
– RR and OS
– Safety
• Exploratory correlative endpoints
– Effect of bevacizumab on
• Tumor perfusion
• Serum levels of angiogenic cytokines and CECs
– Relationship between tumor response and changes in
• Tumor perfusion
• Serum levels of angiogenic cytokines and CECs
CECs, circulating endothelial cells; NSCLC, nonsmall cell lung cancer; OS, overall survival; PFS,
progression-free survival; RR, response rate.
Heist RS, et al. ASCO. 2010 [abstract 7612].
111
Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced NSCLC
Study Design
• Open-label, phase II study
Day -14:
Bevacizumab 15 mg/kg
Day 1:
Albumin-bound paclitaxel 100 mg/m2
+
Carboplatin AUC = 6
+
Bevacizumab 15 mg/kg
Days 8 and 15:
Albumin-bound paclitaxel 100 mg/m2
AUC, area under the curve; CECs, circulating
endothelial cells; CT, computed tomography;
FDG-PET, fluorodeoxyglucose positron emission
tomography; NSCLC, non-small cell lung cancer.
• Correlative studies included
– Perfusion CT
– FDG-PET
– CECs
– Angiogenic cytokines
• Correlative studies performed
– On day -14
– On day -2 (except FDG-PET)
– After cycles 2 and 4
– At time of progression
Heist RS, et al. ASCO. 2010 [abstract 7612].
112
Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced NSCLC
Results: Preliminary Analysis of Correlative Studies
Bev, bevacizumab; NSCLC, non-small cell lung
cancer; RECIST, response evaluation criteria in
solid tumors.
Heist RS, et al. ASCO. 2010 [abstract 7612].
113
Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab
in Advanced NSCLC
Results: Preliminary Analysis of Correlative Studies
CT, computed tomography; FDG-PET,
fluorodeoxyglucose positron emission
tomography; NSCLC, non-small cell lung cancer;
RECIST, response evaluation criteria in solid
tumors; SUV, standardized uptake value.
Heist RS, et al. ASCO. 2010 [abstract 7612].
114
Albumin-Bound Paclitaxel + Carboplatin +
Bevacizumab in Advanced NSCLC
Conclusions
• Pharmacodynamic blood and imaging biomarker studies in
bevacizumab-treated NSCLC patients are feasible
• Preliminary data suggest that such studies may predict tumor
response
• Enrollment and biomarker analyses are ongoing
NSCLC, non-small cell lung cancer.
Heist RS, et al. ASCO. 2010 [abstract 7612].
115
Albumin-Bound Paclitaxel
for the Treatment of
Non-Small Cell Lung Cancer
Combination Therapy with
Carboplatin and Radiation
116
A Phase I Study of Albumin-Bound Paclitaxel
With Carboplatin and Thoracic Radiation in
Patients With Locally Advanced NSCLC
V. L. Keedy, B. Lu, L. Horn, Y. Shyr, W. Conkright,
D.P. Carbone, A. Sandler
Keedy VL et al. ASCO. 2011 [Abstract 7046].
117
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Background
• In selected patients with unresectable stage III NSCLC, concurrent
chemoradiation is superior to sequential therapy1,2
– NCCN-preferred1: cisplatin + etoposide3 and cisplatin + vinblastine4
– NCCN category 2B1,a: carboplatin + Cremophor® EL paclitaxel5,b
• CrEL use is associated with severe hypersensitivity reactions7
– All patients should be premedicated prior to CrEL paclitaxel administration to
prevent severe hypersensitivity reactions6
• Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel8
– No premedication to prevent hypersensitivity reactions is required prior
to administration8
• Phase I trial was designed to evaluate carboplatin + albumin-bound
paclitaxel + thoracic radiation in unresectable stage III NSCLC9
a Recommendation
is based on lower-level
evidence and there is nonuniform NCCN
consensus but no major disagreement.
b Cremophor® is a registered trademark of BASF.
CrEL, Cremophor EL; NCCN, National
Comprehensive Cancer Network; NSCLC, nonsmall cell lung cancer.
1. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v3.2011.
2. Auperin A, et al. J Clin Oncol. 2010;28:2181-2190.
3. Albain KS, et al. J Clin Oncol. 2002;20:3454-3460.
4. Curran WJ, et al. Proc Am Soc Clin Oncol. 2003;22:621[abstract 2499].
5. Belani CP, et al. J Clin Oncol. 2005;23:5883-5891.
6. Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010.
7. Gelderblom H, et al. Eur J Cancer. 2001;37:1590-1598.
8. nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation, 2010.
9. Keedy VL, et al. J Clin Oncol. 2010;28(suppl):abstract e17504.
118
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Objective
• Objective
– Determine the MTD of weekly albumin-bound paclitaxel + carboplatin +
concurrent thoracic radiation followed by consolidation therapy with
albumin-bound paclitaxel plus carboplatin in patients with unresectable
stage III NSCLC
• Endpoints
– Safety and tolerability
NSCLC, non-small cell lung cancer.
Keedy VL et al. ASCO. 2011 [Abstract 7046].
119
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Key Eligibility Criteria
• Inclusion criteria
– Nonmetastatic, inoperable Stage IIIA or IIIB NSCLC without pleural effusion
– Measurable disease
– Patients ≥ years of age
– ECOG performance status = 0 or 1
– Adequate hepatic, renal, and bone marrow function
– Force Expiratory volume in 1 second > 800 mL
• Exclusion criteria
– Known hypersensitivity to carboplatin or albumin-bound paclitaxel
– Prior systemic chemotherapy, thoracic radiotherapy, or surgical resection
– Peripheral neuropathy ≥ grade 2
– Concomitant malignancy
– Pregnant or nursing women
ECOG, Eastern Cooperative Oncology Group;
NSCLC, non-small cell lung cancer.
Keedy VL et al. ASCO. 2011 [Abstract 7046].
120
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Study Design
• Dose-escalating 3 + 3 phase I trial of inoperable, stage III NSCLC
patients receiving albumin-bound paclitaxel plus carboplatin plus XRT
Consolidation period: 21-day cycle Χ 2
DLT period: 7 weeks
Albumin-bound paclitaxel
40 – 60 mg/m2
qw
Carboplatin
AUC = 2
qw
21 days rest
Albumin-bound paclitaxel
100 mg/m2
qw
Restaging
Carboplatin
AUC = 6
Day 1
Concurrent radiation therapy
2 Gy
qd Χ 33 days
AUC, area under the curve; DLT, dose-limiting
toxicity; MTD, maximum tolerated dose; NSCLC,
non-small cell lung cancer; qd, daily; qw, weekly;
XRT, radiation therapy.
Keedy VL et al. ASCO. 2011 [Abstract 7046].
121
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Results: Baseline Patient Characteristics
Baseline characteristic
N = 11
Age in years, median (range)
67 (45 – 75)
Smoker, n (%)
11 (100)
Male, n (%)
9 (82)
Race, n (%)
White
Black
10 (91)
1 (9)
ECOG PS, n (%)
0
1
5 (45)
6 (55)
Histology
Adenocarcinoma
Squamous
Not otherwise specified
5 (45)
4 (36)
2 (18)
Disease stage, n (%)
IIIA
IIIB
7 (64)
4 (36)
ECOG PS, Eastern Cooperative Oncology Group performance status.
NSCLC, non-small cell lung cancer.
Keedy VL et al. ASCO. 2011 [Abstract 7046].
122
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Results: Antitumor Activity
n = 9a
Best response, n
Partial response
9
Stable disease
0
a Of
the 11 enrolled patients, 1 withdrew and 1 was not evaluable for response
• Two dose-limiting toxicities occurred in the 60 mg/m2 arm
-
40 mg/m2 determined to be the MTD of albumin-bound paclitaxel
• Seven patients have progressed
-
At 3, 5, 6 (2 patients), 7, 8, and 20 months after enrollment
Two patients remain progression-free at 10 and 34 months
NSCLC, non-small cell lung cancer.
Keedy VL et al. ASCO. 2011 [Abstract 7046].
123
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Results: Safety and Tolerability
≥ grade 2 AEs during
concurrent
chemoradiotherapy, n
Albumin-bound paclitaxel dosea
40 mg/m2 (n = 6)
60 mg/m2 (n = 4)
Grade 2
Grade 3
Grade 2
Grade 3
Esophagitis
2
0
1
1b
Fatigue
1
0
3
0
Dehydration
2
0
1
0
Neutropenia
1
1
1
0
Hypoxia
1
1
0
0
Anemia
2
0
0
0
Febrile neutropenia
0
0
0
1
Thrombocytopenia
1
0
0
0
Chest pain
0
1
0
0
Nausea
1
0
0
0
Dermatitis
0
0
0
1b
Dyspnea
1
0
0
0
AE, adverse event.
a No grade 4 toxicities were observed.
b Dose-limiting toxicity.
Keedy VL et al. ASCO. 2011 [Abstract 7046].
124
Albumin-Bound Paclitaxel + Carboplatin + Thoracic
Radiation in Unresectable Stage III NSCLC
Conclusions
• The recommended phase II dose of weekly albumin-bound
paclitaxel + weekly carboplatin AUC = 6 + radiation therapy for
patients with stage III NSCLC is 40 mg/m2
• A phase II study to evaluate this treatment is currently ongoing
NSCLC, non-small cell lung cancer.
Keedy VL et al. ASCO. 2011 [Abstract 7046].
125
Albumin-Bound Paclitaxel
for the Treatment of
Small Cell Lung Cancer
Combination Therapy with
Carboplatin
126
A Randomized Phase II Study of Carboplatin
and Albumin-Bound Paclitaxel With 2 Different
Schedules in Patients With Extensive Stage
Small Cell Lung Cancer
J. E. Grilley-Olson, V. L. Keedy, A. Sandler,
D. Moore, M. A. Socinski, T. E. Stinchcombe
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
127
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Background
• The NCCN considers etoposide plus a platinum agent to be
the standard treatment regimen for patients with SCLC1
• Clinicians often prescribe carboplatin over cisplatin in an effort
to reduce the risk of emesis, neuropathy, and nephropathy1
• Etoposide treatment is associated with substantial toxicity,
including myelosuppression, nausea, and vomiting2
• Albumin-bound paclitaxel given weekly or every 3 weeks in
combination with carboplatin may lead to improved tolerability
and acceptable efficacy in patients with ES-SCLC
ES-SCLC, extensive stage small cell lung
cancer; NCCN, National Comprehensive Cancer
Network; SCLC, small cell lung cancer.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
1. NCCN Clinical Practice Guidelines in
OncologyTM, Small Cell Lung Cancer, v2.2012.
2. Spira A, et al. N Engl J Med. 2004;
350(4):379-392.
128
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Objective
• Objective: to evaluate the efficacy of 2 different dosing
regimens of albumin-bound paclitaxel plus carboplatin in
patients with ES-SCLC
• Endpoints
– Primary: ORR per RECIST
– Secondary
•
•
•
•
DoR
PFS
OS
Toxicity profile per CTCAE version 3.0
CTCAE, Common Terminology Criteria for
Adverse Events; DoR, duration of response; ESSCLC, extensive stage small cell lung cancer;
ORR, overall response rate; OS, overall survival;
PFS, progression-free survival; RECIST,
Response Evaluation Criteria in Solid Tumors.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
129
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Key Eligibility Criteria
• Inclusion criteria
– Histologically or cytologically confirmed ES-SCLC
– ECOG PS 0 - 2
– Adequate organ function
– Patients ≥ 18 years of age
– If brain metastases are present, they must be stable
ECOG PS, Eastern Cooperative Oncology Group
performance status; ES-SCLC, extensive stage
small cell lung cancer.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
130
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Key Eligibility Criteria (cont.)
• Exclusion criteria
– Prior systemic chemotherapy, immunotherapy, or biologic
therapy for ES-SCLC
– Prior malignancies within 5 years
– Serious concomitant illness
– Grade ≥ 2 neuropathy
– Previous anaphylactic reaction to carboplatin, paclitaxel, or
docetaxel
– Severe or uncontrolled cardiac disease
ES-SCLC, extensive stage small cell lung
cancer.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
131
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Study Design
• Study design: randomized (1:1) phase II study of 2 different
schedules of albumin-bound paclitaxel plus carboplatin in
patients with ES-SCLC
– Twenty-one day cycles
– Response assessments were performed after cycles 2 and 4
Albumin-bound paclitaxela
240 - 300 mg/m2 IV
Day 1
OR
Albumin-bound paclitaxela
80 - 100 mg/m2 IV
Days 1, 8, and 15
Carboplatin
AUC = 6 IV
Day 1
a
Doses of albumin-bound paclitaxel were originally planned to be 300 mg/m 2 and 100 mg/m2 in the q3w and qw schedules,
respectively, but excessive toxicity required reductions to 240 mg/m 2 and 80 mg/m2, respectively.
AUC, area under the curve; ES-SCLC, extensive
stage small cell lung cancer; IV, intravenous;
q3w, every 3 weeks; qw, weekly.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
132
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Baseline Patient Characteristics
Carbo + AB-Paclitaxel
q3w
(n = 14)
Carbo + AB-Paclitaxel
qw
(n = 13)
60 (45 - 80)
67 (52 - 72)
ECOG PS, n (%)
0
1
2
5 (36)
8 (57)
1 (7)
2 (15)
11 (85)
0
Male, n (%)
10 (71)
8 (62)
White, n (%)
13 (93)
11 (85)
Baseline Characteristic
Age in years, median (range)
AB, albumin-bound; carbo, carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; q3w, every 3 weeks; qw,
weekly.
EGFR TKI—epidermal growth factor tyrosine kinase inhibitor
ES-SCLC, extensive stage small cell lung
cancer.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
133
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Results: Clinical Outcomes
Carbo + AB-Paclitaxel
q3w
(n = 14)
Carbo + AB-Paclitaxel
qw
(n = 13)
11 (79)
11 (85)
PFS in months, median (95% CI)
5.8 (2.8 - 7.1)
5.2 (3.0 - 6.7)
OS in months, median (95% CI)
8.6 (3.6 - 15.6)
11.6 (5.8 - 17.8)
36 (13 - 59)
42 (15 - 67)
Clinical Outcome
Partial response, n (%)
1-year survival, % (95% CI)
AB, albumin-bound; carbo, carboplatin; CI, confidence interval; OS, overall survival; PFS, progression-free survival; q3w, every 3 weeks; qw,
weekly.
ES-SCLC, extensive stage small cell lung
cancer.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
134
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Results: Adverse Events
Carbo + AB-Paclitaxel
q3w
(n = 14)
Carbo + AB-Paclitaxel
qw
(n = 13)
Hematologic
Neutropeniaa
Anemia
Thrombocytopenia
8 (57)
4 (29)
3 (21)
5 (38)
4 (31)
3 (23)
Nonhematologic
Sensory neuropathy
Pain
Fatigue
Nausea
Vomiting
Diarrhea
3 (21)
4 (29)
0
0
0
1 (7)
0
0
1 (8)
3 (23)
2 (15)
1 (8)
Grade 3 or 4 AEs, n (%)
AB, albumin-bound; AE, adverse event; carbo, carboplatin; q3w, every 3 weeks; qw, weekly.
a No cases of febrile neutropenia were reported in either arm.
ES-SCLC, extensive stage small cell lung
cancer.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
135
Carboplatin and Albumin-Bound Paclitaxel at 2
Different Schedules in Patients With ES-SCLC
Conclusions
• Response rates of 79% and 85% in the q3w and qw schedules
of albumin-bound paclitaxel, respectively, demonstrate clinical
activity of this combination therapy in patients with ES-SCLC
• The majority of grade 3 or 4 adverse events were hematologic
in both arms
• Protocol dose reductions in both arms were necessary due to
excessive toxicities at the originally specified doses
ES-SCLC, extensive stage small cell lung
cancer; q3w, every 3 weeks; qw, weekly.
Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
136
BACK UP
NSCLC
Clinical Data
137
nab-paclitaxel in Advanced NSCLC
Trial
CA031
Socinski1
Patients
Advanced, 1st Line
N=1052
Treatment
ABX 100 mg/m2 qw +
carboplatin
paclitaxel + carboplatin
ORR
Median
Survival
Neuropathy
Neutropenia
Anemia
Gr 3
Gr 4
Gr 3
Gr 4
Gr 3
Gr 4
33%
OS: 12.1 mo
3%
0
33%
12%
22%
5%
25%
OS: 11.2 mo
10%
0
33%
23%
6%
21%
CA028
Socinski2
Advanced, 1st Line
N=250
(dose-finding study)
ABX 100 mg/m2 qw+
carboplatin
48%
PFS: 6.2
OS: 11.3
8%
0
36%
28%
16%
0
CA015
Rizvi3
Advanced, 1st Line,
N=40
ABX 125 mg/m2 qw
30%
TTP: 5 mo
OS: 11 mo
15%
0
15%
5%
8%
0
CA018
Green4
Advanced, metastatic
1st-line
N=43
ABX 260 mg/m2 q3w
16%
TTP: 6mo
OS: 11 mo
5%
0
9%
0
0
0
ABX014
Allerton, Greco5
Advanced; 1st-line
NSCLC
N=50
ABX 100 mg/m2 qw +
carboplatin
50%
TTP: 28 wks
0
0
44% (Gr 3 or 4)
9% (Gr 3 or 4)
ABX036
Reynolds6
Advanced nonsquamous; 1st-line
N=48
ABX 300 mg/m2 q3w +
carboplatin + BEV
31%
PFS: 9.8 mo
OS: 16.8 mo
10%
0
17%
37%
NR
NR
ABX255
Otterson7
BEV-ineligible;
advanced, 1st-line
NSCLC
N=52 (safety)
N=27 (efficacy)
ABX 260 mg/m2 q3w +
carboplatin
30%
NR
25%
0
8%
15%
4%
2%
1. Socinski IASCL 2011 2. Socinski JTO 2010. 3. Rizvi JCO 2008 4. Green Ann Onc 2006 5. Allerton ASCO 2006
6. Reynolds JTO 2009
7. Otterson IASLC 2011.
137
138
CA031 vs Historical Phase 3 Data with
Taxol/Carboplatin
Trial
CA031
Socinski
Patients
Advanced, 1st Line
N=1052
Treatment
ABX 100 mg/m2 qw +
carboplatin
Taxol+ carboplatin
Belani 2003
N=390
ORR
Median
Survival
Anemia
Gr 3
Gr 4
Gr 3
Gr 4
Gr 3
Gr 4
OS: 12.1 mo
3%
0
33%
12%
22%
5%
25%
OS: 11.2 mo
10%
0
33%
23%
6%
21%
TTP: 30 wks
Taxol 100 mg/m2 qw +
Carbo
32%
Taxol 225 mg/m2 q3w +
Carbo
17%
5%
22%
OS: 49 wks
7%
TTP: 3.1 mo
N=1207
ECOG 4599
Sandler 2005
N=878
Taxol 200 mg/m2 q3w +
Carbo
15%
PFS: 4.5 mo
OS: 10.3 mo
N=1037
Taxol 225 mg/m2 q3w +
Carbo
29%
TTP: 5.0 mo
OS: 9.9 mo
N=926
Taxol 200 mg/m2 q3w +
Carbo
24%
PFS 5.4 mo
OS: 10.6 mo
ESCAPE
Scagliotti 2010
Neutropenia
33%
ECOG 1594
Schiller 2002
INTACT2
Herbst 2004
Neuropathy
10%
0
20%
43%
8%
2%
0
0S
NR0
17%
NR
1%
OS: 8.1 mo
0.9%
0
5.9%
0
3%
0.6%
3%
1%
0%
138