Transcript Stem Cell Mobilization and Collection in Patients With

1
Albumin-Bound Paclitaxel
for the Treatment of
Non-small Cell Lung Cancer
Combination Therapy Studies
2
Summary of Albumin-Bound Paclitaxel Combination
Therapy Studies in Non-small Cell Lung Cancer
Title
Phase
Combination Therapy with Carboplatin
Phase II study of albumin-bound paclitaxel + carboplatin for first-line advanced NSCLC
(weekly dosing) 1
II
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 cancer2
II
Phase II trial of albumin-bound paclitaxel plus carboplatin for advanced NSCLC in
patients at risk of bleeding from VEGF directed therapies3
II
Ongoing phase III study
Phase III study of albumin-bound paclitaxel + carboplatin vs paclitaxel + carboplatin for
first-line advanced NSCLC4
III
Combination Therapy with Carboplatin and Bevacizumab
Phase II study albumin-bound paclitaxel + carboplatin + bevacizumab for treatment of
advanced NSCLC5
II
Combination with carboplatin and radiotherapy
A phase I study of albumin-bound paclitaxel with carboplatin and thoracic radiation in
patients with locally advanced NSCLC6
NSCLC, non-small cell lung cancer
I
1. Allerton et al. ASCO. 2006
2. Socinski et al. J Thoracic Oncol. 2010
3. Bertino et al. ASCO. 2010
4. Socinski et al. ASCO. 2010
5. Reynolds et al. J Thoracic Oncol. 2009
6. Keedy et al. ASCO. 2010
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Albumin-Bound Paclitaxel
in Non-small Cell Lung Cancer
Combination Therapy with Carboplatin
4
A Phase II Evaluation of the Combination of
Albumin-Bound Paclitaxel and Carboplatin in
the First-line Treatment of Advanced Non-Small
Cell Lung Cancer
J.P. Allerton, C.T. Hagenstad, R.T. 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. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
5
First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Study Rationale and Objectives
• The Belani et al. study of solvent-based paclitaxel followed by
carboplatin in the treatment of patients with advanced nonsmall cell lung cancer (NSCLC)1:
– Twenty-eight day cycle
– Solvent-based paclitaxel 100 mg/m2 administered on Days 1, 8,
and 15
– Carboplatin AUC = 6 administered on Day 1 only
– Favorable therapeutic index in 390 evaluable patients in
comparison to other dosing schedules
• Albumin-bound paclitaxel has shown a clinical advantage over
solvent-based paclitaxel in patients with metastatic breast
cancer2-4
• Primary objective: to determine the antitumor activity of the
combination of albumin-bound paclitaxel and carboplatin in
patients with advanced, previously-untreated NSCLC
• Secondary objective: to describe the side effects and safety
1. Belani et al, J Clin Oncol, 2003
profile
2. Gradishar et al, J Clin Oncol, 2005
NSCLC, non-small cell lung cancer;
AUC, area under the curve
3. Ibrahim et al, J Clin Oncol, 2005
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006 4. Ibrahim et al, Clin Cancer Res, 2002
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First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Study Endpoints
• Open-label, phase II study
• Twenty-eight day treatment cycle
– Albumin-bound paclitaxel 100 mg/m2 intravenously over 30
minutes
• Days 1, 8, and 15
– Carboplatin AUC = 6 over 30 minutes
• Day 1 only
• Primary endpoints
– Overall response rate (ORR)
• Secondary endpoints
– Response duration
– Time to progression (TTP)
– Adverse events (AEs)
NSCLC, non-small cell lung cancer;
AUC, area under the curve
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
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First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Patient Eligibility Criteria
• Key inclusion criteria
– Inoperable stage IIIB or IV NSCLC
– Eastern Cooperative Oncology Group performance status
(ECOG PS) of ≥ 2 at screening and on the first day of treatment
– Life expectancy > 12 weeks
– Blood counts
• Neutrophils > 1500/mm3
• Platelets > 100,000/mm3
– Clinical chemistry/liver function tests (normal limit defined by
institution)
• Key exclusion criteria
– Grade 2 or greater peripheral neuropathy
NSCLC, non-small cell lung cancer
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
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First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Select Patient Demographics
Baseline characteristic (N = 56)
Median age, years (range)
Male sex
n (%)
66 (37-83)
39 (70)
Disease stage, n
Stage IIIB
Stage IV
14
42
Median ECOG performance score
1
ECOG, Eastern Cooperative Oncology Group
• Forty-two of 56 (75%) patients in this study had stage IV disease
• The median age was 66 years
• Seventy percent of patients were male
NSCLC, non-small cell lung cancer
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
9
First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Results
• Six of 56 patients removed from study after < 2 cycles due to:
– Death due to progression (n = 3)
– Adverse events
• Thrombocytopenia (n = 1)
• Neutropenia (n = 1)
– Therapy refused (n = 1)
• Fifty patients evaluable
– Twelve with stage IIIB
– Thirty-eight with stage IV
• Six patients experienced progressive disease
• A total of 258 cycles were administered; 228 (88%) were at the
full planned dose of albumin-bound paclitaxel
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
10
First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Results
• ORR: 25/50 patients (50%)
– One patient had a complete response (CR)
– Twenty-four patients exhibited partial responses (PR)
• Stable disease ≥ 12 weeks: 18/50 patients
• Median TTP: 28 weeks
TTP, time to tumor progression
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
11
First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Results: TTP
Albumin-bound
paclitaxel (N = 43)
• Median TTP: 28 weeks
• Maximum follow-up: 39 weeks
TTP, time to tumor progression
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
12
First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Safety: Adverse Events
Grade 3/4 adverse event (n = 50)
n (%)
Neutropenia
24 (44)
Thrombocytopenia
14 (25)
Anemia
5 (9)
Neuropathy
1 (2)
Arthralgia
0
Myalgia
0
Nausea
1 (2)
Vomiting
1 (2)
Diarrhea
0
• Twenty-four patients (44%) experienced grade 3/4 neutropenia
• Grade 3/4 neuropathy occurred in 14 patients (25%)
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
13
First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Protocol Amendment: 125 mg/m2
• Based on preliminary safety data, the protocol was amended
to increase the weekly albumin-bound paclitaxel dose (9/2005)
– Twenty-eight day cycle
• Albumin-bound paclitaxel 125 mg/m2 IV over 30 minutes
– Days 1, 8, and 15
• Carboplatin AUC = 6 over 30 minutes
– Day 1 only
• Forty patients enrolled
– Median age: 65 years (range 47-82)
– Thirteen women; 26 men
• Thirty-two patients evaluable
– Stage IIIB: n = 3
– Stage IV: n = 29
AUC, area under the curve
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
14
First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Results: Amended Protocol
• Data cutoff was October 10, 2006
• Overall response: 12/40 patients (30%, 95% CI 17-46%)
– Complete response: n = 2
– Partial response: n = 10
• Stable disease ≥ 12 weeks: 15/40 patients
• Median projected TTP = 30 weeks
CI, confidence interval; TTP, time to
tumor progression
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
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First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Safety: Amended Protocol
Adverse event (N = 40)
Grade 3, n (%)
Grade 4, n (%)
Neutropenia
7 (18)
12 (30)
Neuropathy
3 (8)
1 (3)
• Grade 4 neutropenia occurred in 12/40 (30%) patients
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
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First-Line Albumin-Bound Paclitaxel and Carboplatin in
Advanced NSCLC
Conclusions
• Combining albumin-bound paclitaxel and carboplatin is
tolerable and active in the treatment of advanced, newly
diagnosed NSCLC
• Results of this study compare favorably to previously reported
results with solvent-based paclitaxel and carboplatin in a study
of similar design1
1) Belani et al, J Clin Oncol, 2003
NSCLC, non-small cell lung cancer
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
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A Dose Finding Study of Weekly and Every-3Week 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 et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Study Rationale
• Solvent-based paclitaxel 175–225 mg/m2 every-3-week (q3w)
combined with carboplatin AUC = 6 demonstrated a 17% to
32% overall response rate (ORR) in patients with advanced
non-small cell lung cancer (NSCLC)1-4
• In a phase I/II study with a similar patient population, weekly
albumin-bound paclitaxel alone as monotherapy demonstrated
a 30% ORR and an overall survival (OS) of 11 months5
• This study presents the final efficacy and safety results of
weekly or q3w albumin-bound paclitaxel combined with
carboplatin AUC = 6 q3w as first-line therapy for patients with
advanced NSCLC
AUC, area under the curve
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
1. Kelly et al. JCO. 2001
2. Lilenbaum et al. JCO. 2005
3. Scagliotti et al. JCO. 2002
4. Schiller et al. NEJM. 2002
5. Rizvi et al. JCO. 2008
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Study Objective
• To identify the optimal dose of albumin-bound paclitaxel plus
carboplatin AUC = 6 q3w as first-line therapy in patients with
advanced NSCLC
AUC, area under the curve; q3w, every-3weeks; NSCLC, non-small cell lung cancer
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Study Design
• Treatment
– Open-label, multicenter, phase II study
– Sequential enrollment in escalating dose cohorts of 25 patients
– Patients received q3w or weekly albumin-bound paclitaxel
followed by q3w carboplatin AUC = 6 as first-line treatment
Albumin-bound paclitaxel doses and schedules
Weekly
(Days 1, 8 every
21 days)
Q3W
Cohort 1
225 mg/m2
Cohort 2
260 mg/m2
AUC, area under the curve; q3w, every-3weeks
Cohort 3
300 mg/m2
Cohort 4
340 mg/m2
Cohort 5
140 mg/m2
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
Weekly
(Days 1, 8, 15 every 21
days)
Cohort 6
100 mg/m2
Cohort 7
125 mg/m2
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Objectives
• Primary endpoint: Complete response (CR) or partial response
(PR) based on Response Evaluation Criteria In Solid Tumors
(RECIST)
• Secondary endpoints:
–
–
–
–
Disease control rate (DCR)
Progression-free survival (PFS)
Overall survival (OS)
Safety
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Patient Eligibility Criteria
• Key inclusion criteria
– ≥ 18 years old
– Previously untreated
– Histologically or cytologically confirmed advanced NSCLC with
pleural effusion or evidence of inoperable local recurrence or
metastasis (stages IIIB and IV)
– Eastern Cooperative Oncology Group (ECOG) performance status
of 0 or 1
• Key exclusion criteria
–
–
–
–
Peripheral neuropathy, grade > 1
Other concurrent malignancy
History of allergy or hypersensitivity to either of the study drugs
Brain metastases
NSCLC, non-small cell lung cancer
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Baseline Patient Characteristics
Q3W
Weekly (D1, 8)
Weekly (D1, 8, 15)
Baseline
characteristic
(N = 175)
C1
225
mg/m2
(n = 25)
C2
260
mg/m2
(n = 25)
C3
300
mg/m2
(n = 25)
C4
340
mg/m2
(n = 25)
C5
140
mg/m2
(n = 25)
C6
100
mg/m2
(n= 25)
C7
125
mg/m2
(n = 25)
Mean age (years)
59.7
63.1
60.1
61.3
61.6
59.9
58.8
Men, n (%)
23 (92)
18 (72)
17 (68)
20 (80)
22 (88)
21 (84)
20 (80)
Histology, n (%)
Adenocarcinoma
Squamous cell
Large cell
Other*
8 (32)
11 (44)
1 (4)
5 (20)
7 (28)
18 (72)
0
0
9 (36)
14 (56)
0
2 (8)
7 (28)
16 (64)
2 (8)
0 (0)
10 (40)
15 (60)
0 (0)
0 (0)
9 (36)
16 (64)
0
0
13 (52)
10 (40)
0
2 (8)
ECOG, 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)
Disease stage, n (%)
IIIB
IVB
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)
*Poorly differentiated or non-differentiated NSCLC;
ECOG, Eastern Cooperative Oncology Group; q3w, every-3-week
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: Efficacy
Q3W
Weekly (D1, 8)
Weekly (D1, 8, 15)
Clinical
response
(N = 175)
C1
225
mg/m2
(n = 25)
C2
260
mg/m2
(n = 25)
C3
300
mg/m2
(n = 25)
C4
340
mg/m2
(n = 25)
C5
140
mg/m2
(n = 25)
C6
100
mg/m2
(n= 25)
C7
125
mg/m2
(n = 25)
ORR, n (%)
95% CI
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 (0)
1 (4)
0 (0)
0 (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 (0)
2 (8)
2 (8)
3 (12)
15 (60)
40.8-79.2
14 (56)
36.575.5
9 (36)
17.254.8
8 (32)
13.7-50.3
16 (64)
45.2-82.8
14 (56)
36.5-75.5
12 (48)
28.4-67.6
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
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
10.0->18.4
DCR*
95% CI
*DCR = CR + PR + SD ≥ 16 wks
ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate; PFS, progressionfree survival; OS, overall survival; CI, confidence interval; q3w, every-3-week
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
25
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: PFS
1.00
1.00
140 mg/m2 (c5, n = 25)
100 mg/m2 (c6, n = 25)
125 mg/m2 (c7, n = 25)
225
(c1, n = 25)
2
260 mg/m (c2, n = 25)
300 mg/m2 (c3, n = 25)
340 mg/m2 (c4, n = 25)
0.75
0.50
0.25
0.00
0
3
6
9
12 15 18 21 24
27
Proportion Not Progressed
Proportion Not Progressed
mg/m2
0.75
0.50
0.25
0.00
0
3
6
Months
9
12 15
18 21
24
27
Months
• Median PFS ranged from 4.8 to 6.9 months in the q3w cohorts and 5.6 to 6.4
months in the weekly cohorts
PFS, progression-free survival; q3w, every3-weeks
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
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First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: OS
1.00
1.00
140 mg/m2 (c5, n = 25)
100 mg/m2 (c6, n = 25)
125 mg/m2 (c7, n = 25)
225
(c1, n = 25)
2
260 mg/m (c2, n = 25)
300 mg/m2 (c3, n = 25)
340 mg/m2 (c4, n = 25)
0.75
0.50
0.25
0.00
0
3
6
9
12
15 18
21
24 27
Probability of Survival
Probability of Survival
mg/m2
0.75
0.50
0.25
0.00
0
3
6
Months
9
12
15 18
21
24 27
Months
• Median OS ranged from 8.3 to 14.6 months in the q3w cohorts and from 11.3 to
15.0 months in the weekly cohorts
OS, overall survival; q3w, every-3-weeks
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
27
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: Efficacy (Squamous Cell Carcinoma)
Albumin-Bound Paclitaxel Doses and Schedules
Q3W
Weekly (D1, 8)
Weekly (D1, 8, 15)
Clinical
response
(N = 175)
C1
225
mg/m2
(n = 25)
C2
260
mg/m2
(n = 25)
C3
300
mg/m2
(n = 25)
C4
340
mg/m2
(n = 25)
C5
140
mg/m2
(n = 25)
C6
100
mg/m2
(n= 25)
C7
125
mg/m2
(n = 25)
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 wks, n (%)
2 (18)
6 (33)
1 (7)
0
1 (7)
1 (6)
1 (10)
DCR*
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
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
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
*DCR = CR + PR + SD ≥16 wks; ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease
control rate; PFS, progression-free survival; OS, overall survival; CI, confidence interval; q3w, every-3-weeks
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
28
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: Efficacy Stratified by Histologic Status
P = 0.003
P = 0.013
N/S
N/S
N/S
N/S
P = 0.014
N/S
Non-squamous
Squamous
q3w, every-3-weeks; NS, not statistically significant
ORR, overall response rate; PFS,
progression-free survival
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
29
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: Select Adverse Events
Grade 3/4 adverse
event occurring in
≥ 5% of patients
(N = 175)
Neutropenia
Grade 3
Grade 4
Leukocytopenia
Grade 3
Grade 4
Neuropathy
Grade 3
Grade 4
Fatigue
Grade 3
Grade 4
Thrombocytopenia
Grade 3
Grade 4
Anemia
Grade 3
Grade 4
Myalgia
Grade 3
Grade 4
Arthralgia
Grade 3
Grade 4
Q3W
Weekly (D1, 8)
Weekly (D1, 8, 15)
C1
225 mg/m2
(n = 25)
C2
260 mg/m2
(n = 25)
C3
300 mg/m2
(n = 25)
C4
340 mg/m2
(n = 25)
C5
140 mg/m2
(n = 25)
C6
100 mg/m2
(n= 25)
C7
125 mg/m2
(n = 25)
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)
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)
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)
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)
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)
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)
0
0
1 (4)
0
1 (4)
0
6 (24)
0
0
0
0
0
0
0
0
0
1 (4)
0
1 (4)
0
2 (8)
0
0
0
0
0
0
0
q3w, every-3-weeks
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
30
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: Peripheral Neuropathy Improvement
Q3W
Improvement in
treatment-related
peripheral
neuropathy
(n = 118)
Weekly (D1, 8)
Weekly (D1, 8, 15)
C1
225
mg/m2
(n = 25)
C2
260
mg/m2
(n = 25)
C3
300
mg/m2
(n = 25)
C4
340
mg/m2
(n = 25)
C5
140
mg/m2
(n = 25)
C6
100
mg/m2
(n= 25)
C7
125
mg/m2
(n = 25)
Improved to grade ≤
2, n (%)
2 (67)
4 (100)
2 (33)
7 (58)
1 (50)
2 (100)
1 (25)
Median time to
improvement, days*
15.0
14.5
>48.0
23.0
8.0
15.5
>24.0
9.0 >21.0
6.0 - 34.0
6.0 >48.0
17.0 >66.0
---
13.0 - 18.0
8.0 - >24.0
95% CI
Time to improvement defined as time from first occurrence of grade 3 to improvement to at least grade 2. Patients were followed for 30 days
from time of most recent occurrence.
CI, confidence interval; q3w, every-3-weeks
• Peripheral neuropathy was the most common nonhematologic treatmentrelated AE: 118 (67%) patients
– All grades: 80 (80%) in the q3w cohorts and 38 (51%) in the weekly cohorts
– Grade 3: 25 (25%) in the q3w cohorts and 8 (11%) in the weekly cohorts
AE, adverse event
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
31
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Results: Efficacy (Non-Squamous Cell Carcinoma)
Q3W
Weekly (D1, 8)
Weekly (D1, 8, 15)
Clinical
response
(N = 175)
C1
225
mg/m2
(n = 25)
C2
260
mg/m2
(n = 25)
C3
300
mg/m2
(n = 25)
C4
340
mg/m2
(n = 25)
C5
140
mg/m2
(n = 25)
C6
100
mg/m2
(n= 25)
C7
125
mg/m2
(n = 25)
ORR, n (%)
95% CI
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 wks, 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, months
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, months
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
DCR*
95% CI
*DCR = CR + PR + SD ≥ 16 weeks
ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate; PFS, progressionfree survival; OS, overall survival; CI, confidence interval
NSCLC, non-small cell lung cancer
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
32
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Conclusions
• The albumin-bound paclitaxel and carboplatin combination
demonstrated efficacy across treatment regimens and was well
tolerated
• Based on descriptive statistics, weekly treatments with albuminbound paclitaxel demonstrated improved clinical outcomes
compared with q3w regimens
• Patients receiving weekly treatment with albumin-bound
paclitaxel vs q3w experienced fewer incidences of peripheral
neuropathy, alopecia, myalgia, and arthralgia
q3w, every-3-weeks
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
33
First-Line Sequential Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLC
Conclusions (cont.)
• Incidence of peripheral neuropathy was lowest in the 100
mg/m2 and 140 mg/m2 weekly arms
– In the 100 mg/m2 arm, all severe neuropathy cases improved to
grade 2 or better within 15.5 days
• The 100 mg/m2 weekly arm demonstrated the optimal
combination of safety and efficacy
• As a result, a phase III, randomized, multicenter study
comparing 100 mg/m2 albumin-bound paclitaxel weekly and
carboplatin AUC = 6 q3w to solvent-based paclitaxel and
carboplatin has been initiated
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
34
Phase II Trial of Albumin-Bound Paclitaxel Plus
Carboplatin for Advanced NSCLC in Patients at
Risk of Bleeding From VEGF-Directed Therapies
E.M. Bertino, M.A. Villalona-Calero,
S.P. Nana-Sinkam, A.M. Ghany,
K. Donthireddy, N.A. Karim, S. Cantrell,
M. Rahmani, G.S. Phillips, G.A. Otterson
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
35
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Background
• Non-small cell lung cancer (NSCLC) accounts for
approximately 85% of lung cancers diagnosed
• In advanced NSCLC, a platinum-based doublet remains the
standard of care for front-line therapy
• Bevacizumab, an anti-angiogenic agent, is approved for use in
first-line therapy of advanced NSCLC in combination with
chemotherapy
• The addition of bevacizumab results in improved response
rates and survival, but pulmonary hemorrhage is a significant
toxicity
• In phase II/III clinical trials, an increased risk of life-threatening
or fatal bleeding was identified in patients with squamous
histology1,2
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
1. Johnson et al. JCO. 2004
2. Sandler et al. NEJM. 2006
36
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Background (cont.)
• Theoretical safety concerns also exist for patients with brain
metastases and those on anticoagulation therapy, although
recent trials have not identified increased risk1,2
• At this time, patients with squamous histology and/or
hemoptysis are excluded from bevacizumab therapy due to
increased bleeding risk
• Albumin-bound paclitaxel is a novel formulation, composed of
a nanometer-sized albumin bound to a paclitaxel particle
• The albumin particle improves intracellular transport of the
paclitaxel molecule into tumor cells, as demonstrated by in vivo
murine tumor models5,6
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
1. Reck et al. JCO. 2009
2. Socinski et al. JCO. 2009
5. Rizvi et al. JCO. 2008
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 6. Reynolds et al J Thorac Oncol 2009
37
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Background (cont. 2)
• The albumin-bound formulation also demonstrates higher dose
tolerability and decreased hypersensitivity reactions
• In NSCLC patients, albumin-bound paclitaxel was safe and
effective in phase I/II studies, producing 16-30% response
rates (RR)7-9
• A recent phase II trial evaluated carboplatin, albumin-bound
paclitaxel, and bevacizumab in non-squamous NSCLC with
promising results: toxicity was tolerable and partial response
rate was 31% with a median survival of 16.8 months10
• Similarly, it was recently announced that a phase III trial
comparing albumin-bound paclitaxel plus carboplatin to
paclitaxel plus carboplatin in advanced NSCLC met its primary
endpoint of improved ORR
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor; ORR, overall response rate
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
38
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Hypothesis
• The combination of albumin-bound paclitaxel and carboplatin
in patients with advanced NSCLC who are not eligible for
bevacizumab therapy may have superior efficacy and
tolerability compared with the standard approach of a platinum
agent plus a third generation non-platinum agent (paclitaxel,
docetaxel, gemcitabine, or vinorelbine)
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
39
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Study Design
• Phase II, single arm, non-randomized, 2-stage Simon model
– First stage: 27 patients
– Second stage: 36 patients
• Treatment plan
– Albumin-bound paclitaxel 300 mg/m2 and carboplatin AUC = 6
on Day 1 of a 21-day cycle for up to 6 cycles
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
40
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Select Patient Inclusion Criteria
• Inclusion criteria
– Adults with advanced NSCLC (stage IIIB with pleural effusion,
stage IV, or recurrent) who are ineligible for bevacizumab
therapy due to:
•
•
•
•
Squamous histology
Thrombotic or embolic events within 6 months
History of hemoptysis (controlled, non-life threatening)
Cavitary lung lesions
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
41
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Select Patient Exclusion Criteria
• Exclusion criteria
–
–
–
–
–
–
–
Prior treatment for advanced NSCLC
Pre-existing neuropathy ≥ grade 2
Uncontrolled brain metastases
Major surgery within 4 weeks of study drug
Non-healing wounds
Uncontrolled cardiac disease
HIV or hepatitis B or C
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
42
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Trial Endpoints
• Primary endpoint:
– Overall response rate (complete and partial responses)
– A response rate of at least 35% will be considered acceptable for
further study of this combination
• Secondary endpoints:
–
–
–
–
Evaluation of safety/toxicity
Overall and progression-free survival
Tumor SPARC expression (exploratory)
Serum micro RNA expression profiles (exploratory)
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor; SPARC; secreted protein acidic
and rich in cysteine
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
43
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Study Population
Baseline characteristic (N = 35)
Mean age, years (range)
Caucasian, %
Tobacco use, mean pack years
(min, max)
n (%)
63.9 (36-82)
82.8
46.4 (4, 150)
Histology, n
Squamous
Adenocarcinoma
Adenosquamous
Poorly differentiated
Large cell
23
7
1
3
1
Eligibility criteria, n
Hemoptysis
Squamous histology
Thrombotic event
Anticoagulation
7
19
2
1
• Twenty-three patients (66%) had squamous histology, while 12 patients
(34%) had non-squamous histology
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
44
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Safety: Adverse Events (AEs)
Adverse event (n = 35)
Grade 3 (%)
Grade 4 (%)
Hematologic
Anemia
Neutropenia
Thrombocytopenia
0
3
6
3
14
3
Neurologic
Sensory neuropathy
Motor neuropathy
Confusion
Seizure
Muscle weakness
31
3
3
3
3
3
0
0
0
0
14
6
6
6
3
0
3
17
6
0
0
3
0
0
0
3
Infectious
Neutropenic fever/infection
Infection without
neutropenia
NSCLC, non-small cell lung
cancer; VEGF, vascular
endothelial growth factor
Metabolic
Alkalosis
Hyperglycemia
Hypokalemia
Hyponatremia
Hypophosphatemia
Hypermagnesemia
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
45
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
Safety: Adverse Events (AEs)
Adverse event (n = 35)
Grade 3 (%)
Grade 4 (%)
Pulmonary
Hypoxia
Respiratory failure
Airway obstruction
Dyspnea
Pulmonary hemorrhage
Bronchospasm/wheezing
3
0
0
14
3
3
6
6
3
6
0
0
Cardiac
Hypertension
Hypotension
3
3
0
3
Gastrointestinal
Dehydration
Diarrhea
Nausea
11
3
3
3
0
0
Renal
Renal failure
3
3
Other
Anorexia
Fatigue
3
20
0
0
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
46
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients
at Risk of Bleeding from VEGF-Directed Therapies
References
1. Gradishar WJ, et al. J Clin Oncol 2005;23:7794-803.
2. Nyman DW, et al. J Clin Oncol 2005;23:7785-93.
3. Green MR, et al. Ann Oncol 2006;17:1263-8.
4. Stinchcombe TE, et al. Cancer Chemother Pharmacol 2007;60:759-66.
5. Rizvi NA, et al. J Clin Oncol 2008;26:639-43.
6. Reynolds CD, et al. J Thorac Oncol 2009;4:1537-43.
NSCLC, non-small cell lung cancer;
VEGF, vascular endothelial growth
factor
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
47
Results of a Randomized, Phase III Trial of
Albumin-bound Paclitaxel Plus Carboplatin
Compared With Cremophor-based Paclitaxel
Plus 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, J. Iglesias
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
48
Background
• Platinum-based doublets have reached a therapeutic plateau
in advanced NSCLC
• Paclitaxel plus carboplatin produces 15-25% overall response
and survival outcomes comparable to all other doublets1-3
• The solvent polyoxyethylated castor oil (cremophor) decreases
efficacy and contributes to the toxicities observed with
paclitaxel including hypersensitivity reactions and neuropathy
• Albumin-bound paclitaxel has been shown to be more
efficacious than solvent-based paclitaxel in MBC4
NSCLC, non-small cell lung cancer;
MBC, metastatic breast cancer
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
1. Kelly 2001
2. Sandler 2006
3. Schiller 2002
4. Gradishar et al. JCO. 2005
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
49
Rationale
• Albumin-bound paclitaxel leverages the gp60 / caveolin-1 /
SPARC transcytosis pathway to establish a portal to the tumor
microenvironment resulting in high intratumoral drug
concentration1
• Overexpression of caveolin-1 and SPARC occurs in NSCLC
and is associated with poor prognosis2-4
NSCLC, non-small cell lung cancer;
SPARC, secreted protein acidic and rich
in cysteine
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
1. Desai et al. 2008
2. Yoo et al. 2002
3. Chin et al. 2005
4. Koukorakis et al. 2003
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
50
Background
• A 7-arm trial investigated the safety and efficacy of albuminbound paclitaxel plus carboplatin at both weekly and q3w
dosing schedules:
– Weekly albumin-bound paclitaxel (100 mg/m2 D1, 8, 15) plus
carboplatin AUC = 6 q3w demonstrated optimal therapeutic
index
•
•
•
•
Overall response rate = 48%
Median PFS = 6.2 months
Median OS = 11.3 months
Grade 3/4 toxicities: neutropenia 64%, neuropathy 8%,
thrombocytopenia 20%, anemia 16%
• Based on the phase II results, a phase III trial was designed to
investigate the efficacy / safety of albumin-bound paclitaxel plus
carboplatin vs paclitaxel plus carboplatin as first-line therapy in
advanced NSCLC
NSCLC, non-small cell lung cancer; q3w,
every-3-weeks; AUC, area under the curve;
PFS, progression-free survival; OS, overall
survival
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
1. Socinski et al. JTO. 2010
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Study Design
Chemo-naive
PS 0-1
Stage IIIb/IV
NSCLC
N = 1,050
Albumin-bound paclitaxel
100 mg/m2 d1, 8 15
Carboplatin AUC 6 d1
No Premedication
n = 525
1:1 Randomization
Stratification factors:
• Stage (IIIb vs IV)
• Age (< 70 vs > 70)
• Sex
• Histology (squamous vs nonsquamous)
• Geographic region
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
With Premedication of
Dexamethasone + Antihistamines
n = 525
NSCLC, non-small cell lung cancer; PS, Eastern Cooperative Oncology
Group performance status; AUC, area under the curve
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
51
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Study Endpoints
• Primary endpoints:
– Objective response rate by independent radiologic review based
on RECIST
• Complete + partial responses (CR, PR)
• Secondary endpoints:
– Progression-free and overall survival
– Disease control rate: CR + PR + stable disease (SD) ≥ 16 weeks
– Safety (based on the National Cancer Institute’s common
terminology criteria for adverse events [CTCAE] version 3)
NSCLC, non-small cell lung cancer;
RECIST, Response Evaluation Criteria in
Solid Tumors
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
52
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Selected Patient Eligibility Criteria
• Major inclusion criteria
– Adult patients with histologically / cytologically confirmed stage
IIIB/IV NSCLC
– ECOG performance status of 0 or 1
– Measurable disease by RECIST
– Adequate hematologic, hepatic, and renal function
• Major exclusion criteria
– Prior treatment for metastatic disease (adjuvant therapy was
allowed if it was > 1 year prior to study entry)
– Active brain metastases (treated, controlled metastases allowed)
– Baseline peripheral neuropathy > grade 2
NSCLC, non-small cell lung cancer;
RECIST, Response Evaluation Criteria in
Solid Tumors; ECOG, Eastern Cooperative
Oncology Group
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
53
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Statistical Considerations
• Objective response rate of paclitaxel plus carboplatin therapy
in ECOG 1594 = 17%
• Based on the activity of albumin-bound paclitaxel in MBC, a
relative improvement of ~40% for albumin-bound paclitaxel
plus carboplatin over paclitaxel plus carboplatin was assumed
– The predicted overall response rate would, therefore, be 24%
• Based on this assumption, 525 patients in each arm provides
80% power with a two-sided type I error of 0.049 to reject the
null hypothesis
NSCLC, non-small cell lung cancer; MBC,
metastatic breast cancer; ECOG, Eastern
Cooperative Oncology Group
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
54
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Patient Accrual
Canada
4% (6 sites)
Ukraine
24% (16 sites)
Russia
45% (29 sites)
US
12% (25 sites)
Japan
14%
(21 sites)
Australia
1%
(5 sites)
Planned enrollment: from Dec 14 2007 to Aug 1, 2009
Actual enrollment: from Dec 14 2007 to July 14, 2009
Planned follow-up: 18 months
# of patients enrolled: 1052
# of patients evaluable for efficacy: 1052
# of patients evaluable for toxicity: 1038
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
55
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Baseline Patient Characteristics
Baseline characteristic
Median age, years (range)
< 70 years, n (%)
≥ 70 years, n (%)
Female sex, n (%)
ECOG, n (%)
0
1
Histology of primary diagnosis, n (%)*
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other
Stage at current diagnosis, n (%)*
Stage III
Stage IV
Prior chemotherapy, n (%)
Smoking status, n (%)
Never smoked
Smoked and quit
Smoked and still smokes
AB-P/C (n = 521)
P/C (n = 531)
All patients (N = 1052)
60 (28, 81)
448 (86)
73 (14)
129 (25)
60 (24, 84)
449 (85)
82 (15)
134 (25)
60 (24, 84)
897 (85)
155 (15)
263 (25)
133 (26)
385 (74)
113 (21)
416 (78)
246 (23)
801 (76)
254 (49)
228 (44)
9 (2)
29 (6)
264 (50)
221 (42)
13 (2)
33 (6)
518 (49)
449 (43)
22 (2)
62 (6)
99 (19)
421 (81)
12 (2)
513
138 (27)
165 (32)
210 (41)
107 (20)
424 (80)
8 (2)
521
144 (28)
146 (28)
231 (44)
206 (20)
845 (80)
20 (2)
1034
282 (27)
311 (30)
441 (43)
* Data were missing for 1 patient at the time of this analysis
AB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin; ECOG, Eastern Cooperative Oncology Group
NSCLC, non-small cell lung cancer
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
56
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Results: Patient Responses, All Histologies
Response Ratio = 1.31
(1.082 – 1.593)
P = 0.005
Response Ratio = 1.26
(1.060 – 1.496)
P = 0.008
Percent Responses
(n = 521)
NSCLC, non-small cell lung cancer; ABP/C; albumin-bound paclitaxel plus
carboplatin; P/C, paclitaxel plus carboplatin
(n = 531))
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
57
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Results: Patient Responses by Histologic Stratification
Squamous
Nonsquamous
P = 0.060
n = 228
n = 221
P = 0.808
P = 0.069
Percent Responses
P < 0.001
NSCLC, non-small cell lung cancer; ABP/C; albumin-bound paclitaxel plus
*carboplatin;
Not a pre-specified
endpoint
P/C, paclitaxel plus
carboplatin
n = 292
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
n = 310
58
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Results: Dose Characteristics
Treatment characteristic
Taxane dose intensity (mg/m2/wk)
Median (min, max)
Cycles administered
Median (min, max)
AB-P/C
(n = 514)
P/C
(n = 524)
83 (26.7, 102.9)
66 (32.9, 88.9)
6 (1, 17)
6 (1, 22)
AB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin
•
•
There was no limitation on the number of cycles
Patients in the albumin-bound P/C arm received a higher median dose
intensity
NSCLC, non-small cell lung cancer
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
59
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Safety
P/C
(n = 531)
AB-P/C
(n = 521)
Adverse event, %
Hematologic
Neutropenia
Thrombocytopenia
Anemia
Febrile neutropenia
Nonhematologic
Fatigue
Sensory neuropathy
Anorexia
Nausea
Myalgia
Grade 3
Grade 4
Grade 3
Grade 4
P value
33
13
22
<1
12
4
5
<1
33
6
6
1
23
2
<1
<1
0.009*
< .001**
< .001**
NS
4
3
2
1
<1
<1
0
0
0
0
6
10
<1
<1
2
<1
0
0
<1
0
NS
< .001*
NS
NS
.011*
*Favors albumin-bound P/C; ** Favors P/C
AB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin
NSCLC, non-small cell lung cancer
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
60
Albumin-Bound Paclitaxel + Carboplatin vs. CremophorPaclitaxel + Carboplatin in Advanced NSCLC
Conclusions
• In this phase III randomized trial, albumin-bound paclitaxel plus
carboplatin demonstrated a statistically significant higher
response rate than paclitaxel plus carboplatin (33% vs 25%, P
< .001)
• The response rate in the squamous cell subset was 41% in the
albumin-bound paclitaxel plus carboplatin arm vs 24% in the
paclitaxel plus carboplatin arm (P < .001)
• Albumin-bound paclitaxel plus carboplatin was well tolerated
and associated with less sensory neuropathy, myalgia, and
neutropenia than paclitaxel plus carboplatin
• Albumin-bound paclitaxel plus carboplatin was associated with
more anemia and thrombocytopenia than paclitaxel plus
carboplatin
• Progression-free survival analysis is planned for later this year
NSCLC, non-small cell lung cancer
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
61
62
Albumin-Bound Paclitaxel
in Non-small Cell Lung Cancer
Combination Therapy with
Carboplatin and Bevacizumab
63
An Open-Label, Phase II Trial of Albumin-Bound
Paclitaxel, Carboplatin, and Bevacizumab in
First-Line Patients With Advanced NonSquamous Non-small Cell Lung Cancer
C. Reynolds, D. Barrera, D. Q. Vu, R. Jotte,
A. I. Spira, C. H. Weissman, K. A. Boehm,
D. Ilegbodu, S. Pritchard, L. Asmar
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Study Rationale
• The development of albumin-bound paclitaxel has
circumvented many of the infusion difficulties that are
associated with standard solvent-based paclitaxel
• In this phase II trial, patients with advanced (stage IIIB or IV)
non-small cell lung cancer (NSCLC) received the combination
of albumin-bound paclitaxel, carboplatin and bevacizumab
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
64
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Objectives
• Primary endpoint
– Antitumor activity, based upon RECIST criteria
• Secondary endpoints
–
–
–
–
–
–
Time to disease progression (TTP)
Duration of response
Stable disease (SD) ≥16 weeks)
1- and 2-year survival
Changes in quality of life (QOL)
Safety
RECIST, response evaluation criteria in solid
tumors
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
65
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Study Design
Open-label, single arm, phase II study
carboplatin  albumin-bound paclitaxel  bevacizumab
Cycle
Study days
Carboplatin
Albumin-bound
paclitaxel
1
AUC = 6
300 mg/m2
15 mg/kg
2-21
Rest
Rest
Rest
1
AUC = 6
300 mg/m2
15 mg/kg
2-21
Rest
Rest
Rest
1
2
AUC, area under the curve
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
Bevacizumab
66
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Patient Eligibility
• Key inclusion criteria
– Histologically or cytologically confirmed advanced stage IIIB/IV
non-squamous NSCLC with evidence of inoperable local
recurrence or metastasis
– Measurable disease as per RECIST criteria
– No prior chemotherapy for the treatment of metastatic disease
– Prior radiation therapy permitted;
• Measurable disease must not have been irradiated
• Prior irradiation of measurable disease permitted only if it had
progressed since radiation therapy
– Eastern Cooperative Oncology Group Performance Status
(ECOG PS) 0-1
– Adequate renal, hepatic, and hematological function
NSCLC, non-small cell lung cancer; RECIST,
response evaluation criteria in solid tumors
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
67
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Patient Eligibility (cont.)
• Key exclusion criteria
– Another concurrent active malignancy
– Pre-existing peripheral neuropathy of NCI grade >1
– Creatinine clearance <30 mL/min or urine protein: creatinine
ratio (UPC) > 1.0 at registration
– Uncontrolled blood pressure > 150/100 mmHg
– Unstable angina
– Clinically significant cardiac disease, symptomatic coronary
artery disease or cardiac arrhythmias not well controlled with
medication, or myocardial infarction within the last 6 months
NSCLC, non-small cell lung cancer; NCI,
National Cancer Institute
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
68
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Patient Eligibility (cont.)
• Key exclusion criteria (cont.)
–
–
–
–
–
–
–
–
Impaired pulmonary function
Clinically significant peripheral vascular disease
History of thrombosis or stroke within the past 6 months
History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 4 weeks
Uncontrolled coagulopathy
History of seizure activity
Current or recent use (within 2 weeks) of aspirin, anticoagulants
or thrombolytic agents
Evidence of active brain metastasis
NSCLC, non-small cell lung cancer; NCI,
National Cancer Institute
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
69
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Select Patient Demographics
Baseline characteristic (N = 50)
Median age, years
n (%)
67 (32-83)
Female sex
28 (56)
Histology
Adenocarcinoma
Bronchioalveolar
Large cell
NOS
43 (86)
1 (2)
4 (8)
2 (4)
Prior surgery
19 (30)
Prior radiation therapy
4 (8)
Number of metastatic sites
1
2
3
4
19 (38)
15 (30)
9 (18)
1 (2)
Baseline ECOG performance status
0
1
26 (52)
24 (48)
NOS, not otherwise specified; ECOG, Eastern Cooperative Oncology
Group
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
70
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Best Response After Treatment
Treatment characteristic (na = 43)
PR
SD
≥ 6 months
< 6 months
PD
Not evaluated
Clinical benefit rate (CR + PR + SD ≥ 6 months)
Non-evaluable due to discontinuation
Non-evaluable due to lack of baseline tumor value
n (%)
15 (35)
26 (60)
11 (26)
15 (35)
2 (4.7)
5 (12)
26 (60)
4 (9)
1 (2.3)
Reason for discontinuation
Normal study completion
Adverse event
Investigator request
PD
Consent withdrawal or treatment refusal
17 (40)
16 (37)
1 (2.3)
11 (26)
5 (12)
OS
20 (47)
a
Of 50 enrolled patients, 48 were treated, and 43 were evaluable. Two patients who enrolled were not treated; one patient withdrew consent
before treatment and the other ineligible due to brain metastasis
b Deaths were due to PD (26 patients, 87%), COPD, pulmonary embolus, pulmonary hemorrhage, and suicide (1 patient each)
PR, partial response; SD, stable disease; PD, progressive disease; OS, overall survival
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
71
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Median Progression-Free Survival
1.0
0.9
Estimated PFS Rate
0.8
0.7
0.6
Censored
0.5
0.4
0.3
0.2
Median
MedianPFS:
PFS:9.8
9.8(Range,
(Range,<1-22.3
<1-22.3Months)
Months)
0.1
0.0
0
3
6
9
12
15
Month
NSCLC, non-small cell lung cancer; PFS,
progression-free survival
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
18
21
72
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Median Time to Tumor Progression
1.0
0.9
0.8
Estimated TTP Rate
0.7
Censored
0.6
0.5
0.4
0.3
0.2
Median Survival Time: 16.8 (Range, <1-24.9 Months)
0.1
0.0
0
3
6
9
12
15
Month
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
18
21
73
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Median Overall Survival
1.0
0.9
Estimated OS Rate
0.8
0.7
0.6
0.5
0.4
Censored
0.3
0.2
Median Survival Time: 16.8 (Range, <1-24.9 Months)
0.1
0.0
0
3
6
9
12
15
Month
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
18
21
24
74
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Safety
Grade 3/4 adverse event occurring
in ≥ 1 patient (na = 48)
All grades (%)
Grade 3 (%)
Grade 4 (%)
Neutropenia
26 (54.2)
8 (16.7)
18 (37.5)
Thrombocytopenia
5 (10.4)
4 (8.3)
1 (2.1)
Leukopenia
2 (4.2)
2 (4.2)
0
Fatigue
8 (16.7)
6 (12.5)
2 (4.2)
Febrile neutropenia
5 (10.4)
3 (6.3)
2 (4.2)
Neuropathy
5 (10.4)
5 (10.4)
0
Constipation
3 (6.3)
3 (6.3)
0
Anorexia
2 (4.2)
2 (4.2)
0
Diarrhea
2 (4.2)
2 (4.2)
0
Peripheral neuropathy
2 (4.2)
2 (4.2)
0
a
Number of treated patients
• Grade 3/4 neutropenia occurred in 26/48 (54%) patients
• Grade 3 neuropathy in 5/28 (10%) patients (no grade 4)
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
75
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Conclusions
• Although response rate in this study was similar to that
previously reported for combination therapy for advanced
NSCLC, the PFS and OS results were higher than previously
reported in patients with advanced NSCLC
• After completion of this study, 54% of patients went on to
receive second-line therapy: 14% received pemetrexed, 8%
received docetaxel, 6% received paclitaxel, and 6% received
the combination of carboplatin and paclitaxel
• Subsequent trials have shown that pemetrexed may be
particularly active in non-squamous NSCLC, which may have
contributed to the positive OS results observed in this trial;
however, the prolonged PFS observed suggests that some of
the benefit was likely derived from the combination therapy
used in this trial
NSCLC, non-small cell lung cancer; PFS,
progression-free survival; OS, overall survival
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
76
First-Line Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced Non-Squamous NSCLC
Conclusions (cont.)
• In this study, toxicity was generally acceptable; the low
incidence of grade 3 peripheral neuropathy and the absence of
any obvious exacerbation of chemotherapy-induced
myelosuppression by the addition of bevacizumab to this
regimen are particularly noteworthy
• Phase III evaluation of this combination would determine
whether it is truly more efficacious than previous regimens
• The optimal dosing schedule of albumin-bound paclitaxel
(weekly versus q3w) and the role of maintenance bevacizumab
are important issues that should be addressed
NSCLC, non-small cell lung cancer; q3w, every3-week
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
77
78
The Effect of Adding Bevacizumab to
Albumin-Bound Paclitaxel/Carboplatin Therapy
for Patients With 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 et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
79
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
Background
• Addition of bevacizumab to chemotherapy for advanced
NSCLC patients improves survival and demonstrates the
benefit of antiangiogenic therapy
• Mechanism of antitumor activity is still poorly understood
• Studies are needed to understand the mechanism of action
and to identify biomarkers for the efficacy of bevacizumab in
NSCLC patients
• Preliminary analyses of correlative studies are presented
NSCLC, non-small cell lung cancer
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
80
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
Study Design
• Open-label phase II trial of carboplatin, albumin-bound
paclitaxel, and bevacizumab
• All patients receive bevacizumab 15 mg/kg at day -14
• Patients then receive carboplatin (AUC = 6) on day 1,
albumin-bound paclitaxel (100 mg/m2) on days 1, 8, and 15,
and bevacizumab (15 mg/kg) on day 1
• Planned enrollment: 36
• Primary endpoint: 6-month PFS rate
• Secondary endpoints: safety, RR, OS
NSCLC, non-small cell lung cancer;
AUC, area under the curve; PFS,
progression-free survival; RR, response
rate; OS, overall survival
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
81
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
Correlative Study Endpoints
• To examine the effect of bevacizumab monotherapy on tumor
perfusion, as assessed by CT scan before and after single
dose of bevacizumab
• To examine the effect of bevacizumab monotherapy on serum
levels of angiogenic cytokines and circulating endothelial cells
before and after single dose of bevacizumab
• To examine the relationship between tumor response and
changes in tumor perfusion, as assessed by perfusion CT
scan, before and after combination therapy with carboplatin,
albumin-bound paclitaxel, and bevacizumab
• To examine the relationship between tumor response and
changes in serum levels of angiogenic cytokines and
circulating endothelial cells, before and after combination
therapy with carboplatin, albumin-bound paclitaxel, and
bevacizumab
CT, commuted tomography
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
82
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
Study Design
Day
-14
BEV
Day
-2
CAB
After
Cycle 2
CAB
CAB CAB
After
Cycle 4
CAB CAB
At Time of
Progression
BEV
At each time point: perfusion CT, FDG-PET (except Day -2), CECs, angiogenic cytokines
BEV, bevacizumab 15 mg/kg; CAB,
carboplatin AUC = 6, albumin-bound
paclitaxel 100 mg /m2, bevacizumab 15
mg/kg; CT, commuted tomography;
FDG-PET, fludeoxyglucose positron
emission tomography; CEC, circulating
endothelial cells
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
83
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
1.0
0.9
0.8
P = 0.001
0.7
0.6
0.5
0.4
Day -14
Day -2
Blood Flow after Bev [mL/min/100g]
c-KIT at Day -2 Relative to Day -14
CPC at Day -2 Relative to Day -14
Results: Correlative Findings
1.1
1.0
0.9
P = 0.033
0.8
0.7
Day -14
Day -2
150
Kendall's tp = 0.58, P = 0.009
100
50
-10
0
10 20 30 40 50
RECIST Change (%)
Bevacizumab alone
significantly decreased
circulating CD34+
progenitor cells
RECIST, response evaluation criteria in
solid tumors
Bevacizumab alone
significantly
decreased
soluble c-KIT
Among those
evaluable for
response, blood flow
at Day -2 correlated
directly with best
percentage
change in RECIST
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
84
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
Results: Correlative Findings
Baseline
Post-Bevacizumab
Post-Treatment
Blood flow 23.33 mL/100g/min
Blood flow 13.78 mL/100g/min
Blood flow 7.59 mL/100g/min
SUV 7.62
SUV 4.01
SUV 2.1
Contrast CT
(RECIST)
CT Perfusion
Blood Flow
FDG PET
RECIST, response evaluation criteria in
solid tumors; FDG-PET, fludeoxyglucose
positron emission tomography; SUV,
standardized uptake value
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
85
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
Results: Correlative Findings
• Evaluation of imaging characteristics and tumor response is
ongoing
• Preliminary analysis of 12 evaluable patients shows no definite
correlation between RECIST change and change in blood flow
RECIST, response evaluation criteria in
solid tumors
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
86
Albumin-Bound Paclitaxel, Carboplatin, and
Bevacizumab in Advanced NSCLC
Conclusions
• Pharmacodynamic blood and imaging biomarker studies in
bevacizumab-treated NSCLC patients are feasible, and
preliminary data suggest they may predict for tumor response
• Enrollment and continued biomarker analyses are ongoing
NSCLC, non-small cell lung cancer
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
87
Albumin-Bound Paclitaxel
in Non-small Lung Cancer
Combination Therapy with
Carboplatin and Radiation
88
A Phase I Study of Albumin-Bound Paclitaxel
With Carboplatin and Thoracic Radiation (TRT)
in Patients With Locally Advanced NSCLC
V. L. Keedy, B. Lu, Y. Shyr, L. Horn, D. P. Carbone,
A. Sandler, D. H. Johnson
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
89
Albumin-Bound Paclitaxel, Carboplatin, and Radiation
in Locally-Advanced NSCLC
Background
• One third of patients with non-small cell lung cancer (NSCLC)
present with localized, unresectable disease
• Concurrent chemoradiotherapy (e.g. weekly paclitaxel +
radiotherapy) is well established, with median survival ≈ 14
months
• Albumin-bound paclitaxel is a cremophor-free formulation of
paclitaxel designed to improve solubility and intratumor
delivery of active drug
• This phase I trial evaluates weekly albumin-bound paclitaxel +
carboplatin + concurrent thoracic radiation (TRT) in patients
with unresectable stage III NSCLC
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
90
Albumin-Bound Paclitaxel, Carboplatin, and Radiation
in Locally-Advanced NSCLC
Study Design
• Patients were enrolled in escalating dose cohorts in a 3 + 3
design of albumin-bound paclitaxel weekly, beginning at 40
mg/m2 and increasing by 20 mg/m2, in combination with
carboplatin (AUC = 2) weekly for 7 weeks and concurrent
thoracic radiation therapy (TRT) at 66 Gy/33 fractions
• Patients received 2 cycles of consolidation therapy with full
dose albumin-bound paclitaxel (100 mg/m2 weekly for 3
weeks) plus carboplatin AUC = 6 on Day 1 of each cycle)
every 21 days
• The dose-limiting toxicity (DLT) period is defined as the
concurrent chemoradiation period
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
91
Albumin-Bound Paclitaxel, Carboplatin, and Radiation
in Locally-Advanced NSCLC
Patient Dispositions
• Eight patients have been treated at 2 dose levels of albuminbound paclitaxel:
– 40 mg/m2
– 60 mg/m2
•
•
•
•
One patient gave their consent and then withdrew it
Seven patients have completed all cycles of therapy
Three patients were treated at 40 mg/m2 with no DLT reported
The 40 mg/m2 cohort is expanded and 1 patient remains on
concurrent treatment
DLT, dose-limiting toxicity
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
92
Albumin-Bound Paclitaxel, Carboplatin, and Radiation
in Locally-Advanced NSCLC
Results: Safety
• Four patients treated at 60 mg/m2 had 2 grade 3 DLTs:
– Radiation dermatitis
– Esophagitis
• Grade 2-3 toxicities during concurrent treatment include:
neutropenia, neutropenic fever, anemia, thrombocytopenia,
fatigue, esophagitis, nausea, dermatitis, hypoxia, and
dehydration
• No grade 4 toxicities have emerged during concurrent
treatment
DLT, dose-limiting toxicity
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
93
Albumin-Bound Paclitaxel, Carboplatin, and Radiation
in Locally-Advanced NSCLC
Results: Efficacy
• Seven patients are evaluable for response, and all 7 achieved
partial responses
– Three patients have progressed at 5, 7, and 8 months after
enrollment
– Four patients remain stable at 5, 7, 13, and 18 months
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
94
Albumin-Bound Paclitaxel, Carboplatin, and Radiation
in Locally-Advanced NSCLC
Conclusions
• Weekly albumin-bound paclitaxel at 60 mg/m2 exceeds the
maximum tolerated dose, but appears to be safe and well
tolerated at 40 mg/m2 when used in combination with weekly
carboplatin and TRT
• Enrollment in this cohort is ongoing
TRT, thoracic radiation therapy
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504