1 albumin-bound paclitaxel for the treatment of non-small cell lung cancer combination therapy...
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Albumin-Bound Paclitaxel Albumin-Bound Paclitaxel for the Treatment of for the Treatment of
Non-small Cell Lung CancerNon-small Cell Lung Cancer
Combination Therapy Studies
2
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
I
Summary of Albumin-Bound Paclitaxel Combination Summary of Albumin-Bound Paclitaxel Combination Therapy Studies in Non-small Cell Lung CancerTherapy Studies in Non-small Cell Lung Cancer
NSCLC, non-small cell lung cancer
1. Allerton et al. ASCO. 20062. Socinski et al. J Thoracic Oncol. 2010
3. Bertino et al. ASCO. 20104. Socinski et al. ASCO. 2010
5. Reynolds et al. J Thoracic Oncol. 20096. Keedy et al. ASCO. 2010
3
Albumin-Bound Paclitaxel Albumin-Bound Paclitaxel in Non-small Cell Lung Cancerin Non-small Cell Lung Cancer
Combination Therapy with Carboplatin
4
A Phase II Evaluation of the Combination of A Phase II Evaluation of the Combination of Albumin-Bound Paclitaxel and Carboplatin in Albumin-Bound Paclitaxel and Carboplatin in
the First-line Treatment of Advanced Non-Small the First-line Treatment of Advanced Non-Small Cell Lung CancerCell 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 7127Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
5
• The Belani et al. study of solvent-based paclitaxel followed by carboplatin in the treatment of patients with advanced non-small 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 profile
1. Belani et al, J Clin Oncol, 20032. Gradishar et al, J Clin Oncol, 2005
3. Ibrahim et al, J Clin Oncol, 2005 4. Ibrahim et al, Clin Cancer Res, 2002
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCStudy Rationale and ObjectivesStudy Rationale and Objectives
NSCLC, non-small cell lung cancer; AUC, area under the curve
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
6
• 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)
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCStudy EndpointsStudy Endpoints
NSCLC, non-small cell lung cancer; AUC, area under the curve
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
7
• 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
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCPatient Eligibility CriteriaPatient Eligibility Criteria
NSCLC, non-small cell lung cancerAllerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
8
Baseline characteristic (N = 56) n (%)
Median age, years (range) 66 (37-83)
Male sex 39 (70)
Disease stage, nStage IIIBStage IV
1442
Median ECOG performance score 1
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCSelect Patient DemographicsSelect Patient Demographics
• 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
ECOG, Eastern Cooperative Oncology Group
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
9
• 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
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCResultsResults
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
10
• 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
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCResultsResults
TTP, time to tumor progressionAllerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
11
• Median TTP: 28 weeks• Maximum follow-up: 39 weeks
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCResults: TTPResults: TTP
TTP, time to tumor progressionAllerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
Albumin-bound paclitaxel (N = 43)
12
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
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCSafety: Adverse EventsSafety: Adverse Events
• 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 7127Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
13
• 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
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCProtocol Amendment: 125 mg/mProtocol Amendment: 125 mg/m22
AUC, area under the curveAllerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
14
• 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
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCResults: Amended ProtocolResults: Amended Protocol
CI, confidence interval; TTP, time to tumor progression
15
Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
Adverse event (N = 40) Grade 3, n (%) Grade 4, n (%)
Neutropenia 7 (18) 12 (30)
Neuropathy 3 (8) 1 (3)
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCSafety: Amended ProtocolSafety: Amended Protocol
• Grade 4 neutropenia occurred in 12/40 (30%) patients
16
• 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
Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006
First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCConclusionsConclusions
NSCLC, non-small cell lung cancer
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A Dose Finding Study of Weekly and Every-3-A Dose Finding Study of Weekly and Every-3-Week Albumin-BoundWeek Albumin-Bound Paclitaxel Followed by Paclitaxel Followed by Carboplatin as First-line Therapy in Patients Carboplatin as First-line Therapy in Patients with Advanced Non-Small Cell Lung Cancerwith 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.
18
• 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
1. Kelly et al. JCO. 2001 2. Lilenbaum et al. JCO. 2005
3. Scagliotti et al. JCO. 20024. Schiller et al. NEJM. 2002
5. Rizvi et al. JCO. 2008Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCStudy RationaleStudy Rationale
AUC, area under the curve
19
• To identify the optimal dose of albumin-bound paclitaxel plus carboplatin AUC = 6 q3w as first-line therapy in patients with advanced NSCLC
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCStudy ObjectiveStudy Objective
AUC, area under the curve; q3w, every-3-weeks; NSCLC, non-small cell lung cancer
20
• 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
Q3WWeekly (Days 1, 8 every
21 days)
Weekly (Days 1, 8, 15 every 21
days)
Cohort 1
225 mg/m2
Cohort 2
260 mg/m2
Cohort 3
300 mg/m2
Cohort 4
340 mg/m2
Cohort 5
140 mg/m2
Cohort 6
100 mg/m2
Cohort 7
125 mg/m2
Albumin-bound paclitaxel doses and schedules
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCStudy DesignStudy Design
AUC, area under the curve; q3w, every-3-weeks
21
• 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.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCObjectivesObjectives
22
• 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.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCPatient Eligibility CriteriaPatient Eligibility Criteria
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*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.
Baseline characteristic (N = 175)
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)
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)
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCBaseline Patient CharacteristicsBaseline Patient Characteristics
24
*DCR = CR + PR + SD ≥ 16 wksORR, objective 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-week
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
Clinical response(N = 175)
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)
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)
DCR*
95% CI
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
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
6.24.2-9.7
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
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: EfficacyResults: Efficacy
25
• 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
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: PFSResults: PFS
PFS, progression-free survival; q3w, every-3-weeks
1.00
0.75
0.50
0.25
0.000 3 6 9 12 15 18 21 24 27
Months
Pro
po
rtio
n N
ot
Pro
gre
ssed
1.00
0.75
0.50
0.25
0.000 3 6 9 12 15 18 21 24 27
Months
Pro
po
rtio
n N
ot
Pro
gre
ssed
225 mg/m2 (c1, n = 25)260 mg/m2 (c2, n = 25)300 mg/m2 (c3, n = 25)340 mg/m2 (c4, n = 25)
140 mg/m2 (c5, n = 25)100 mg/m2 (c6, n = 25)125 mg/m2 (c7, n = 25)
26
• 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
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: OSResults: OS
OS, overall survival; q3w, every-3-weeks
140 mg/m2 (c5, n = 25)100 mg/m2 (c6, n = 25)125 mg/m2 (c7, n = 25)
Months
1.00
0.75
0.50
0.25
0.000 3 6 9 12 15 18 21 24 27
Months
Pro
bab
ility
of
Su
rviv
al
Pro
bab
ility
of
Su
rviv
al
225 mg/m2 (c1, n = 25)260 mg/m2 (c2, n = 25)300 mg/m2 (c3, n = 25)340 mg/m2 (c4, n = 25)
1.00
0.75
0.50
0.25
0.000 3 6 9 12 15 18 21 24 27
27
Albumin-Bound Paclitaxel Doses and Schedules
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
*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
Clinical response(N = 175)
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)
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
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: Efficacy (Squamous Cell Carcinoma)Results: Efficacy (Squamous Cell Carcinoma)
28
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: Efficacy Stratified by Histologic StatusResults: Efficacy Stratified by Histologic Status
q3w, every-3-weeks; NS, not statistically significant
Non-squamous
Squamous
ORR, overall response rate; PFS, progression-free survival
N/S N/SP = 0.003 P = 0.013
P = 0.014 N/SN/S N/S
29
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
Grade 3/4 adverse event occurring in ≥ 5% of patients(N = 175)
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)
NeutropeniaGrade 3Grade 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)
LeukocytopeniaGrade 3Grade 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)
NeuropathyGrade 3Grade 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)
FatigueGrade 3Grade 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)
ThrombocytopeniaGrade 3Grade 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)
AnemiaGrade 3Grade 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)
MyalgiaGrade 3Grade 4
00
1 (4)0
1 (4)0
6 (24)0
00
00
00
ArthralgiaGrade 3Grade 4
00
1 (4)0
1 (4)0
2 (8)0
00
00
00
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: Select Adverse EventsResults: Select Adverse Events
q3w, every-3-weeks
30
• Peripheral neuropathy was the most common nonhematologic treatment-related 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
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
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
Improvement in treatment-related peripheral neuropathy(n = 118)
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)
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
95% CI 9.0 - >21.0
6.0 - 34.06.0 - >48.0
17.0 - >66.0
--- 13.0 - 18.0 8.0 - >24.0
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: Peripheral Neuropathy ImprovementResults: Peripheral Neuropathy Improvement
AE, adverse event
31
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
*DCR = CR + PR + SD ≥ 16 weeksORR, objective 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
Clinical response(N = 175)
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)
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)
DCR*
95% CI
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
First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCResults: Efficacy (Non-Squamous Cell Carcinoma)Results: Efficacy (Non-Squamous Cell Carcinoma)
NSCLC, non-small cell lung cancer
32
• The albumin-bound paclitaxel and carboplatin combination demonstrated efficacy across treatment regimens and was well tolerated
• Based on descriptive statistics, weekly treatments with albumin-bound 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
Socinski et al. J Thorac Oncol. 2010 Jun;5(6):852-61.
First-Line Sequential Albumin-Bound Paclitaxel and First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCConclusionsConclusions
q3w, every-3-weeks
33
• 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.
First-Line Sequential Albumin-Bound Paclitaxel and First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCConclusions (cont.)Conclusions (cont.)
34
Phase II Trial of Albumin-Bound Paclitaxel Plus Phase II Trial of Albumin-Bound Paclitaxel Plus Carboplatin for Advanced NSCLC in Patients at Carboplatin for Advanced NSCLC in Patients at
Risk of Bleeding From VEGF-Directed Risk of Bleeding From VEGF-Directed TherapiesTherapies
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
• 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
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesBackgroundBackground
1. Johnson et al. JCO. 20042. Sandler et al. NEJM. 2006
VEGF, vascular endothelial growth factor
36
• 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
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesBackground (cont.)Background (cont.)
1. Reck et al. JCO. 20092. Socinski et al. JCO. 2009
5. Rizvi et al. JCO. 20086. Reynolds et al J Thorac Oncol 2009
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
37
• 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
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesBackground (cont. 2)Background (cont. 2)
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor; ORR, overall response rate
38
• 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)
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesHypothesisHypothesis
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
39
• 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
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesStudy DesignStudy Design
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
40
• 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
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesSelect Patient Inclusion CriteriaSelect Patient Inclusion Criteria
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
41
• 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
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesSelect Patient Exclusion CriteriaSelect Patient Exclusion Criteria
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
42
• 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)
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesTrial EndpointsTrial Endpoints
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor; SPARC; secreted protein acidic and rich in cysteine
43
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Baseline characteristic (N = 35) n (%)
Mean age, years (range) 63.9 (36-82)
Caucasian, % 82.8
Tobacco use, mean pack years (min, max)
46.4 (4, 150)
Histology, nSquamousAdenocarcinomaAdenosquamousPoorly differentiatedLarge cell
237131
Eligibility criteria, nHemoptysisSquamous histologyThrombotic eventAnticoagulation
71921
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesStudy PopulationStudy Population
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
• Twenty-three patients (66%) had squamous histology, while 12 patients (34%) had non-squamous histology
44
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Adverse event (n = 35) Grade 3 (%) Grade 4 (%)
HematologicAnemiaNeutropeniaThrombocytopenia
036
3143
NeurologicSensory neuropathyMotor neuropathyConfusionSeizureMuscle weakness
313333
30000
InfectiousNeutropenic fever/infectionInfection without neutropenia
146
66
MetabolicAlkalosisHyperglycemiaHypokalemiaHyponatremiaHypophosphatemiaHypermagnesemia
303
1760
030003
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesSafety: Adverse Events (AEs)Safety: Adverse Events (AEs)
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
45
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Adverse event (n = 35) Grade 3 (%) Grade 4 (%)
PulmonaryHypoxiaRespiratory failureAirway obstructionDyspneaPulmonary hemorrhageBronchospasm/wheezing
300
1433
663600
CardiacHypertensionHypotension
33
03
GastrointestinalDehydrationDiarrheaNausea
1133
300
RenalRenal failure 3 3
OtherAnorexiaFatigue
320
00
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesSafety: Adverse Events (AEs)Safety: Adverse Events (AEs)
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
46
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.
Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291
Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapiesat Risk of Bleeding from VEGF-Directed TherapiesReferencesReferences
NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor
47
Results of a Randomized, Phase III Trial of Results of a Randomized, Phase III Trial of Albumin-bound Paclitaxel Plus Carboplatin Albumin-bound Paclitaxel Plus Carboplatin
Compared With Cremophor-based Paclitaxel Compared With Cremophor-based Paclitaxel Plus Carboplatin as First-line Therapy in Plus Carboplatin as First-line Therapy in Advanced Non-small Cell Lung CancerAdvanced 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.
48
• 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
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCBackgroundBackground
NSCLC, non-small cell lung cancer; MBC, metastatic breast cancer
1. Kelly 20012. Sandler 20063. Schiller 2002
4. Gradishar et al. JCO. 2005
49
• 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
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCRationaleRationale
1. Desai et al. 20082. Yoo et al. 2002
3. Chin et al. 20054. Koukorakis et al. 2003
NSCLC, non-small cell lung cancer; SPARC, secreted protein acidic and rich in cysteine
50
• A 7-arm trial investigated the safety and efficacy of albumin-bound 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
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCBackgroundBackground
NSCLC, non-small cell lung cancer; q3w, every-3-weeks; AUC, area under the curve; PFS, progression-free survival; OS, overall survival 1. Socinski et al. JTO. 2010
51
Stratification factors:•Stage (IIIb vs IV)•Age (< 70 vs > 70)•Sex•Histology (squamous vs nonsquamous)•Geographic region
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCStudy DesignStudy Design
NSCLC, non-small cell lung cancer; PS, Eastern Cooperative Oncology Group performance status; AUC, area under the curve
Chemo-naivePS 0-1
Stage IIIb/IV NSCLC
N = 1,050
Albumin-bound paclitaxel 100 mg/m2 d1, 8 15
Carboplatin AUC 6 d1No Premedication
n = 525
Paclitaxel 200 mg/m2 d1Carboplatin AUC 6 d1
With Premedication of Dexamethasone + Antihistamines
n = 525
1:1 Randomization
52
• 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)
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCStudy EndpointsStudy Endpoints
NSCLC, non-small cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors
53
• 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
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCSelected Patient Eligibility CriteriaSelected Patient Eligibility Criteria
NSCLC, non-small cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors; ECOG, Eastern Cooperative Oncology Group
54
• 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
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCStatistical ConsiderationsStatistical Considerations
NSCLC, non-small cell lung cancer; MBC, metastatic breast cancer; ECOG, Eastern Cooperative Oncology Group
55
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCPatient AccrualPatient Accrual
USUS12% (25 sites)12% (25 sites)
Russia Russia 45% (29 sites)45% (29 sites)
AustraliaAustralia1%1%
(5 sites)(5 sites)
JapanJapan14%14%
(21 sites)(21 sites)
CanadaCanada4% (6 sites)4% (6 sites) UkraineUkraine
24% (16 sites)24% (16 sites)
Planned enrollment: from Dec 14 2007 to Aug 1, 2009Actual 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.
56
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Baseline characteristic AB-P/C (n = 521) P/C (n = 531) All patients (N = 1052)Median age, years (range)< 70 years, n (%)≥ 70 years, n (%)
60 (28, 81)448 (86)73 (14)
60 (24, 84)449 (85)82 (15)
60 (24, 84)897 (85)155 (15)
Female sex, n (%) 129 (25) 134 (25) 263 (25)ECOG, n (%)01
133 (26)385 (74)
113 (21)416 (78)
246 (23)801 (76)
Histology of primary diagnosis, n (%)*AdenocarcinomaSquamous cell carcinomaLarge cell carcinomaOther
254 (49)228 (44)
9 (2)29 (6)
264 (50)221 (42)
13 (2)33 (6)
518 (49)449 (43)
22 (2)62 (6)
Stage at current diagnosis, n (%)*Stage IIIStage IV
99 (19)421 (81)
107 (20)424 (80)
206 (20)845 (80)
Prior chemotherapy, n (%) 12 (2) 8 (2) 20 (2)Smoking status, n (%)Never smokedSmoked and quitSmoked and still smokes
513138 (27)165 (32)210 (41)
521144 (28)146 (28)231 (44)
1034282 (27)311 (30)441 (43)
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCBaseline Patient CharacteristicsBaseline Patient Characteristics
* Data were missing for 1 patient at the time of this analysisAB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin; ECOG, Eastern Cooperative Oncology Group
NSCLC, non-small cell lung cancer
57
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCResults: Patient Responses, All HistologiesResults: Patient Responses, All Histologies
NSCLC, non-small cell lung cancer; AB-P/C; albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin
Response Ratio = 1.31(1.082 – 1.593)P = 0.005
Response Ratio = 1.26(1.060 – 1.496)P = 0.008
(n = 521)
(n = 531))
Pe
rce
nt
Re
sp
on
ses
58
Squamous Nonsquamous
* Not a pre-specified endpoint Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCResults: Patient Responses by Histologic StratificationResults: Patient Responses by Histologic Stratification
Pe
rce
nt
Re
sp
on
ses
P < 0.001 P = 0.060 P = 0.808 P = 0.069
n = 228 n = 221 n = 292 n = 310
NSCLC, non-small cell lung cancer; AB-P/C; albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin
59
• There was no limitation on the number of cycles• Patients in the albumin-bound P/C arm received a higher median dose
intensity
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Treatment characteristicAB-P/C
(n = 514)P/C
(n = 524)
Taxane dose intensity (mg/m2/wk)
Median (min, max) 83 (26.7, 102.9) 66 (32.9, 88.9)
Cycles administered
Median (min, max) 6 (1, 17) 6 (1, 22)
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCResults: Dose CharacteristicsResults: Dose Characteristics
NSCLC, non-small cell lung cancer
AB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin
60
*Favors albumin-bound P/C; ** Favors P/CAB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Adverse event, %
AB-P/C(n = 521)
P/C(n = 531)
P valueGrade 3 Grade 4 Grade 3 Grade 4
Hematologic NeutropeniaThrombocytopeniaAnemiaFebrile neutropenia
331322< 1
1245
< 1
33661
232
< 1< 1
0.009*< .001**< .001**
NSNonhematologic FatigueSensory neuropathyAnorexiaNauseaMyalgia
4321
< 1
< 10000
610< 1< 12
< 100
< 10
NS< .001*
NSNS
.011*
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCSafetySafety
NSCLC, non-small cell lung cancer
61
• 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
Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCConclusionsConclusions
NSCLC, non-small cell lung cancer
62
Albumin-Bound Paclitaxel Albumin-Bound Paclitaxel in Non-small Cell Lung Cancerin Non-small Cell Lung Cancer
Combination Therapy with Carboplatin and Bevacizumab
63
An Open-Label, Phase II Trial of Albumin-Bound An Open-Label, Phase II Trial of Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Paclitaxel, Carboplatin, and Bevacizumab in
First-Line Patients With Advanced Non-First-Line Patients With Advanced Non-Squamous Non-small Cell Lung CancerSquamous 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
64
• 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
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCStudy RationaleStudy Rationale
65
• 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
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCObjectivesObjectives
RECIST, response evaluation criteria in solid tumors
66
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCStudy DesignStudy Design
Cycle Study days CarboplatinAlbumin-bound
paclitaxel Bevacizumab
11 AUC = 6 300 mg/m2 15 mg/kg
2-21 Rest Rest Rest
21 AUC = 6 300 mg/m2 15 mg/kg
2-21 Rest Rest Rest
Open-label, single arm, phase II study
carboplatin albumin-bound paclitaxel bevacizumab
NSCLC, non-small cell lung cancer
AUC, area under the curve
67
• 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
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCPatient EligibilityPatient Eligibility
NSCLC, non-small cell lung cancer; RECIST, response evaluation criteria in solid tumors
68
• 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
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCPatient Eligibility (cont.)Patient Eligibility (cont.)
NSCLC, non-small cell lung cancer; NCI, National Cancer Institute
69
• 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 intra-abdominal 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
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCPatient Eligibility (cont.)Patient Eligibility (cont.)
NSCLC, non-small cell lung cancer; NCI, National Cancer Institute
70
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCSelect Patient DemographicsSelect Patient Demographics
Baseline characteristic (N = 50) n (%)
Median age, years 67 (32-83)
Female sex 28 (56)
HistologyAdenocarcinomaBronchioalveolarLarge cellNOS
43 (86)1 (2)4 (8)2 (4)
Prior surgery 19 (30)
Prior radiation therapy 4 (8)
Number of metastatic sites1234
19 (38)15 (30)9 (18)1 (2)
Baseline ECOG performance status
0
1
26 (52)
24 (48)
NSCLC, non-small cell lung cancer
NOS, not otherwise specified; ECOG, Eastern Cooperative Oncology Group
71
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 metastasisb 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
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCBest Response After TreatmentBest Response After Treatment
Treatment characteristic (na = 43) n (%)
PR 15 (35)
SD≥ 6 months< 6 months
26 (60)11 (26)15 (35)
PD 2 (4.7)
Not evaluated 5 (12)
Clinical benefit rate (CR + PR + SD ≥ 6 months) 26 (60)
Non-evaluable due to discontinuation 4 (9)
Non-evaluable due to lack of baseline tumor value 1 (2.3)
Reason for discontinuationNormal study completionAdverse eventInvestigator requestPDConsent withdrawal or treatment refusal
17 (40)16 (37)1 (2.3)11 (26)5 (12)
OS 20 (47)
NSCLC, non-small cell lung cancer
72
Median PFS: 9.8 (Range, <1-22.3 Months)
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCMedian Progression-Free SurvivalMedian Progression-Free Survival
NSCLC, non-small cell lung cancer; PFS, progression-free survival
1.0
0.9
0.8
0.7
Censored0.6
0.5
0.4
0.3
0.2
0.1
0.00 3 6 9 12 15 18 21
Es
tim
ate
dP
FS
Rat
e
Month
Median PFS: 9.8 (Range, <1-22.3 Months)
73
1.0
0.9
0.8
0.7
Censored0.6
0.5
0.4
0.3
0.2
0.1
0.00 3 6 9 12 15 18 21
Est
imate
dT
TP
Rate
Month
Median Survival Time: 16.8 (Range, <1-24.9 Months)
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCMedian Time to Tumor ProgressionMedian Time to Tumor Progression
NSCLC, non-small cell lung cancer
74
1.0
0.9
0.8
0.7
Censored
0.6
0.5
0.4
0.3
0.2
0.1
0.00 3 6 9 12 15 18 21 24
Esti
mat
ed
OS
Rate
Month
Median Survival Time: 16.8 (Range, <1-24.9 Months)
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCMedian Overall SurvivalMedian Overall Survival
NSCLC, non-small cell lung cancer
75
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCSafetySafety
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) 0a 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
76
• 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
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCConclusionsConclusions
NSCLC, non-small cell lung cancer; PFS, progression-free survival; OS, overall survival
77
• 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
Reynolds et al. J Thoracic Onc. 2009;4(12):1537-1543
First-Line Albumin-Bound Paclitaxel, Carboplatin, and First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLCBevacizumab in Advanced Non-Squamous NSCLCConclusions (cont.)Conclusions (cont.)
NSCLC, non-small cell lung cancer; q3w, every-3-week
78
The Effect of Adding Bevacizumab to The Effect of Adding Bevacizumab to Albumin-Bound Paclitaxel/Carboplatin Therapy Albumin-Bound Paclitaxel/Carboplatin Therapy
for Patients With Advanced for Patients With Advanced Non-small Cell Lung Cancer 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
• 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
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCBackgroundBackground
NSCLC, non-small cell lung cancer
80
• 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
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCStudy DesignStudy Design
NSCLC, non-small cell lung cancer; AUC, area under the curve; PFS, progression-free survival; RR, response rate; OS, overall survival
81
• 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
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCCorrelative Study EndpointsCorrelative Study Endpoints
CT, commuted tomography
82
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCStudy DesignStudy Design
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
Day Day After After At Time of-14 -2 Cycle 2 Cycle 4 Progression
BEV CAB CAB CAB CAB CABCAB BEV
At each time point: perfusion CT, FDG-PET (except Day -2), CECs, angiogenic cytokines
83
Bevacizumab alone significantly decreased
circulating CD34+ progenitor cells
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
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCResults: Correlative FindingsResults: Correlative Findings
RECIST, response evaluation criteria in solid tumors
1.0
CP
C a
t D
ay -
2 R
elat
ive
to D
ay -
14
0.9
0.8
0.7
0.6
0.5
0.4
Day -14 Day -2
P = 0.001
c-K
IT a
t D
ay -
2 R
elat
ive
to D
ay -
14
1.1
1.0
0.9
0.8
0.7
Day -14 Day -2
Blo
od
Flo
w a
fter
Bev
[m
L/m
in/1
00g
]
150
100
50
-10 0 10 20 30 40 50
RECIST Change (%)
Kendall's tp = 0.58, P = 0.009
P = 0.033
84
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCResults: Correlative FindingsResults: Correlative Findings
RECIST, response evaluation criteria in solid tumors; FDG-PET, fludeoxyglucose positron emission tomography; SUV, standardized uptake value
Contrast CT(RECIST)
Baseline
CT PerfusionBlood Flow
FDG PET
Post-Bevacizumab
SUV 7.62 SUV 4.01 SUV 2.1
Post-Treatment
Blood flow 23.33 mL/100g/min Blood flow 13.78 mL/100g/min Blood flow 7.59 mL/100g/min
85
• 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
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCResults: Correlative FindingsResults: Correlative Findings
RECIST, response evaluation criteria in solid tumors
86
• 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
Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612
Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCConclusionsConclusions
NSCLC, non-small cell lung cancer
87
Albumin-Bound Paclitaxel Albumin-Bound Paclitaxel in Non-small Lung Cancerin Non-small Lung Cancer
Combination Therapy with Carboplatin and Radiation
88
A Phase I Study of Albumin-Bound Paclitaxel A Phase I Study of Albumin-Bound Paclitaxel With Carboplatin and Thoracic Radiation (TRT) With Carboplatin and Thoracic Radiation (TRT)
in Patients With Locally Advanced NSCLCin 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
• 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
Albumin-BoundAlbumin-Bound Paclitaxel, Carboplatin, and Radiation Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCBackgroundBackground
90
• 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
Albumin-Bound Paclitaxel, Carboplatin, and Radiation Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCStudy DesignStudy Design
91
• Eight patients have been treated at 2 dose levels of albumin-bound 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
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
Albumin-Bound Paclitaxel, Carboplatin, and Radiation Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCPatient DispositionsPatient Dispositions
DLT, dose-limiting toxicity
92
• 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
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
Albumin-Bound Paclitaxel, Carboplatin, and Radiation Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCResults: SafetyResults: Safety
DLT, dose-limiting toxicity
93
• 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
Albumin-Bound Paclitaxel, Carboplatin, and Radiation Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCResults: EfficacyResults: Efficacy
94
• 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
Keedy et al. Abstract only, ASCO 2010; Abstract # e17504
Albumin-Bound Paclitaxel, Carboplatin, and Radiation Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCConclusionsConclusions
TRT, thoracic radiation therapy