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Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer

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Title: Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer


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 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 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 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 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
  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

NSCLC, non-small cell lung cancer
3
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 NSCLCStudy Rationale and
Objectives
  • 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
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
6
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCStudy 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
7
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCPatient 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 gt 12 weeks
  • Blood counts
  • Neutrophils gt 1500/mm3
  • Platelets gt 100,000/mm3
  • Clinical chemistry/liver function tests (normal
    limit defined by institution)
  • Key exclusion criteria
  • Grade 2 or greater peripheral neuropathy

Allerton JP et al. Presented at ASCO Annual
Meeting 2006 Abs 7127 Greco FA et al. Presented
at Chemotherapy Foundation Symposium 2006
NSCLC, non-small cell lung cancer
8
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCSelect Patient
Demographics
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
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

Allerton JP et al. Presented at ASCO Annual
Meeting 2006 Abs 7127 Greco FA et al. Presented
at Chemotherapy Foundation Symposium 2006
NSCLC, non-small cell lung cancer
9
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCResults
  • Six of 56 patients removed from study after lt 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 NSCLCResults
  • 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

Allerton JP et al. Presented at ASCO Annual
Meeting 2006 Abs 7127 Greco FA et al. Presented
at Chemotherapy Foundation Symposium 2006
TTP, time to tumor progression
11
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCResults TTP
  • Median TTP 28 weeks
  • Maximum follow-up 39 weeks

Allerton JP et al. Presented at ASCO Annual
Meeting 2006 Abs 7127 Greco FA et al. Presented
at Chemotherapy Foundation Symposium 2006
TTP, time to tumor progression
12
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCSafety 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 NSCLCProtocol 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

Allerton JP et al. Presented at ASCO Annual
Meeting 2006 Abs 7127 Greco FA et al. Presented
at Chemotherapy Foundation Symposium 2006
AUC, area under the curve
14
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCResults 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
15
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCSafety 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
16
First-Line Albumin-Bound Paclitaxel and
Carboplatin in Advanced NSCLCConclusions
  • 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 7127 Greco FA et al. Presented
at Chemotherapy Foundation Symposium 2006
NSCLC, non-small cell lung cancer
17
A Dose Finding Study of Weekly and Every-3-Week
Albumin-Bound Paclitaxel Followed by Carboplatin
as First-line Therapy in Patients with Advanced
Non-Small Cell Lung Cancer
  • M.A. Socinski, G.M. Manikhas, D.L. Stroyakovsky,
    A.N. Makhson, S.V. Cheporov, S.V. Orlov, P.K.
    Yablonsky, P.H. Bhar, and J. Iglesias

Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
18
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCStudy Rationale
  • Solvent-based paclitaxel 175225 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. 2008
Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
AUC, area under the curve
19
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCStudy 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-3-weeks
NSCLC, non-small cell lung cancer
Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
20
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCStudy 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
Q3W Q3W Q3W Q3W Weekly (Days 1, 8 every 21 days) Weekly (Days 1, 8, 15 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
AUC, area under the curve q3w, every-3-weeks
Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
21
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCObjectives
  • 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
Jun5(6)852-61.
22
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCPatient
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 gt 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
Jun5(6)852-61.
23
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCBaseline
Patient Characteristics
Baseline characteristic (N 175) Q3W Q3W Q3W Q3W Weekly (D1, 8) Weekly (D1, 8, 15) 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
Jun5(6)852-61.
24
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults
Efficacy
Clinical response(N 175) Q3W Q3W Q3W Q3W Weekly (D1, 8) Weekly (D1, 8, 15) 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)
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- gt20.1 15.0 10.0-gt18.4
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
Jun5(6)852-61.
25
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults PFS
  • 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, every-3-weeks
Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
26
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults OS
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

Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
OS, overall survival q3w, every-3-weeks
27
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults
Efficacy (Squamous Cell Carcinoma)
Albumin-Bound Paclitaxel Doses and Schedules
Clinical response(N 175) Q3W Q3W Q3W Q3W Weekly (D1, 8) Weekly (D1, 8, 15) 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-gt18.8 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
Jun5(6)852-61.
28
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults
Efficacy Stratified by Histologic Status
N/S
N/S
P 0.003
P 0.013
Non-squamous
P 0.014
N/S
N/S
N/S
Squamous
q3w, every-3-weeks NS, not statistically
significant
ORR, overall response rate PFS, progression-free
survival
Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
29
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults Select
Adverse Events
Grade 3/4 adverse event occurring in 5 of patients(N 175) Q3W Q3W Q3W Q3W Weekly (D1, 8) Weekly (D1, 8, 15) Weekly (D1, 8, 15)
Grade 3/4 adverse event occurring in 5 of patients(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)
Neutropenia Grade 3 Grade 4 8 (32) 8 (32) 9 (36) 6 (24) 9 (36) 3 (12) 7 (28) 5 (20) 8 (32) 11 (44) 9 (36) 7 (28) 7 (28) 8 (32)
Leukocytopenia Grade 3 Grade 4 8 (32) 1 (4) 6 (24) 0 (0) 7 (28) 0 (0) 9 (36) 1 (4) 12 (48) 0 (0) 6 (24) 0 (0) 5 (20) 1 (4)
Neuropathy Grade 3 Grade 4 3 (12) 0 (0) 4 (16) 0 (0) 6 (24) 0 (0) 12 (48) 0 (0) 2 (8) 0 (0) 2 (8) 0 (0) 4 (16) 0 (0)
Fatigue Grade 3 Grade 4 3(12) 0 (0) 1 (4) 0 (0) 4 (16) 0 (0) 3 (12) 0 (0) 1 (4) 0 (0) 0 (0) 0 (0) 4 (16) 0 (0)
Thrombocytopenia Grade 3 Grade 4 7 (28) 3 (12) 5 (20) 1 (4) 5 (20) 2 (8) 5 (20) 1 (4) 5 (20) 3 (12) 4 (16) 1 (4) 5 (20) 4 (16)
Anemia Grade 3 Grade 4 4 (16) 1 (4) 6 (24) 0 (0) 3 (12) 1 (4) 2 (8) 1 (4) 4 (16) 1 (4) 4 (16) 0 (0) 10 (40) 1 (4)
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
q3w, every-3-weeks
Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
30
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults
Peripheral Neuropathy Improvement
Improvement in treatment-related peripheral neuropathy(n 118) Q3W Q3W Q3W Q3W Weekly (D1, 8) Weekly (D1, 8, 15) Weekly (D1, 8, 15)
Improvement in treatment-related peripheral neuropathy(n 118) 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 gt48.0 23.0 8.0 15.5 gt24.0
95 CI 9.0 - gt21.0 6.0 - 34.0 6.0 - gt48.0 17.0 - gt66.0 --- 13.0 - 18.0 8.0 - gt24.0
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 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

Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
AE, adverse event
31
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCResults
Efficacy (Non-Squamous Cell Carcinoma)
Clinical response(N 175) Q3W Q3W Q3W Q3W Weekly (D1, 8) Weekly (D1, 8, 15) 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)
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-gt22.0 10.5 7.3-gt25.1 11.9 4.4-gt22.3 13.1 4.8-gt18.4 9.8 7.8-11.3 gt18.4 15.0-gt18.4
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
Socinski et al. J Thorac Oncol. 2010
Jun5(6)852-61.
NSCLC, non-small cell lung cancer
32
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCConclusions
  • 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
Jun5(6)852-61.
q3w, every-3-weeks
33
First-Line Sequential Albumin-Bound Paclitaxel
and Carboplatin in Advanced NSCLCConclusions
(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
Jun5(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
TherapiesBackground
  • 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

1. Johnson et al. JCO. 2004 2. Sandler et al.
NEJM. 2006
VEGF, vascular endothelial growth factor
Bertino et al. Presented at ASCO Annual Meeting,
2010 Abstract TPS291
36
Albumin-Bound Paclitaxel Carboplatin in NSCLC
Patients at Risk of Bleeding from VEGF-Directed
TherapiesBackground (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

1. Reck et al. JCO. 2009 2. Socinski et al. JCO.
2009 5. Rizvi et al. JCO. 2008 6. Reynolds et al
J Thorac Oncol 2009
NSCLC, non-small cell lung cancer VEGF, vascular
endothelial growth factor
Bertino et al. Presented at ASCO Annual Meeting,
2010 Abstract TPS291
37
Albumin-Bound Paclitaxel Carboplatin in NSCLC
Patients at Risk of Bleeding from VEGF-Directed
TherapiesBackground (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
TherapiesHypothesis
  • 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
TherapiesStudy 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
TherapiesSelect 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
TherapiesSelect 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
TherapiesTrial 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
TherapiesStudy Population
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
  • 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
TherapiesSafety Adverse Events (AEs)
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 3031760 030003
NSCLC, non-small cell lung cancer VEGF, vascular
endothelial growth factor
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
TherapiesSafety Adverse Events (AEs)
Adverse event (n 35) Grade 3 () Grade 4 ()
PulmonaryHypoxiaRespiratory failureAirway obstructionDyspneaPulmonary hemorrhageBronchospasm/wheezing 3001433 663600
CardiacHypertensionHypotension 33 03
GastrointestinalDehydrationDiarrheaNausea 1133 300
RenalRenal failure 3 3
OtherAnorexiaFatigue 320 00
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
TherapiesReferences
  • 1. Gradishar WJ, et al. J Clin Oncol
    2005237794-803.
  • 2. Nyman DW, et al. J Clin Oncol 2005237785-93.
  • 3. Green MR, et al. Ann Oncol 2006171263-8.
  • 4. Stinchcombe TE, et al. Cancer Chemother
    Pharmacol 200760759-66.
  • 5. Rizvi NA, et al. J Clin Oncol 200826639-43.
  • 6. Reynolds CD, et al. J Thorac Oncol
    200941537-43.

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.
48
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCBackground
  • 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

1. Kelly 2001 2. Sandler 2006 3. Schiller 2002 4.
Gradishar et al. JCO. 2005
NSCLC, non-small cell lung cancer MBC,
metastatic breast cancer
Socinski et al. Presented at ASCO 2010 Abstract
LBA7511.
49
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCRationale
  • 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

1. Desai et al. 2008 2. Yoo et al. 2002 3. Chin
et al. 2005 4. Koukorakis et al. 2003
NSCLC, non-small cell lung cancer SPARC,
secreted protein acidic and rich in cysteine
Socinski et al. Presented at ASCO 2010 Abstract
LBA7511.
50
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCBackground
  • 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

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
51
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCStudy Design
Albumin-bound paclitaxel 100 mg/m2 d1, 8
15 Carboplatin AUC 6 d1 No Premedication n 525
Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N 1,050
11 Randomization
Paclitaxel 200 mg/m2 d1 Carboplatin AUC 6 d1 With
Premedication of Dexamethasone
Antihistamines n 525
  • Stratification factors
  • Stage (IIIb vs IV)
  • Age (lt 70 vs gt 70)
  • Sex
  • Histology (squamous vs nonsquamous)
  • Geographic region

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.
52
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCStudy 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 Institutes
    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.
53
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCSelected 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 gt 1 year prior to
    study entry)
  • Active brain metastases (treated, controlled
    metastases allowed)
  • Baseline peripheral neuropathy gt 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.
54
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCStatistical 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.
55
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCPatient Accrual
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.
56
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCBaseline Patient Characteristics
Baseline characteristic AB-P/C (n 521) P/C (n 531) All patients (N 1052)
Median age, years (range) lt 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 () 0 1 133 (26) 385 (74) 113 (21) 416 (78) 246 (23) 801 (76)
Histology of primary diagnosis, n () Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Other 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 III Stage 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 smoked Smoked and quit Smoked and still smokes 513 138 (27) 165 (32) 210 (41) 521 144 (28) 146 (28) 231 (44) 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
Socinski et al. Presented at ASCO 2010 Abstract
LBA7511.
NSCLC, non-small cell lung cancer
57
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCResults 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
NSCLC, non-small cell lung cancer AB-P/C
albumin-bound paclitaxel plus carboplatin P/C,
paclitaxel plus carboplatin
Socinski et al. Presented at ASCO 2010 Abstract
LBA7511.
58
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCResults Patient Responses by Histologic
Stratification
Squamous
Nonsquamous
P lt 0.001
P 0.060
P 0.808
P 0.069
Percent Responses
NSCLC, non-small cell lung cancer AB-P/C
albumin-bound paclitaxel plus carboplatin P/C,
paclitaxel plus carboplatin
Not a pre-specified endpoint
Socinski et al. Presented at ASCO 2010 Abstract
LBA7511.
59
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCResults Dose Characteristics
Treatment characteristic AB-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)
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

Socinski et al. Presented at ASCO 2010 Abstract
LBA7511.
NSCLC, non-small cell lung cancer
60
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCSafety
Adverse event, AB-P/C (n 521) AB-P/C (n 521) P/C (n 531) P/C (n 531) P value
Adverse event, Grade 3 Grade 4 Grade 3 Grade 4 P value
Hematologic Neutropenia Thrombocytopenia Anemia Febrile neutropenia 33 13 22 lt 1 12 4 5 lt 1 33 6 6 1 23 2 lt 1 lt 1 0.009 lt .001 lt .001 NS
Nonhematologic Fatigue Sensory neuropathy Anorexia Nausea Myalgia 4 3 2 1 lt 1 lt 1 0 0 0 0 6 10 lt 1 lt 1 2 lt 1 0 0 lt 1 0 NS lt .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
Socinski et al. Presented at ASCO 2010 Abstract
LBA7511.
NSCLC, non-small cell lung cancer
61
Albumin-Bound Paclitaxel Carboplatin vs.
Cremophor-Paclitaxel Carboplatin in Advanced
NSCLCConclusions
  • 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 lt
    .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 lt .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.
NSCLC, non-small cell lung cancer
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 Non-Squamous
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.
20094(12)1537-1543
64
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCStudy 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.
20094(12)1537-1543
65
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCObjectives
  • 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.
20094(12)1537-1543
66
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCStudy Design
Open-label, single arm, phase II
study carboplatin ? albumin-bound paclitaxel ?
bevacizumab
Cycle Study days Carboplatin Albumin-bound paclitaxel Bevacizumab
1 1 AUC 6 300 mg/m2 15 mg/kg
1 2-21 Rest Rest Rest
2 1 AUC 6 300 mg/m2 15 mg/kg
2 2-21 Rest Rest Rest
AUC, area under the curve
Reynolds et al. J Thoracic Onc.
20094(12)1537-1543
NSCLC, non-small cell lung cancer
67
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCPatient 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.
20094(12)1537-1543
68
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCPatient Eligibility (cont.)
  • Key exclusion criteria
  • Another concurrent active malignancy
  • Pre-existing peripheral neuropathy of NCI grade
    gt1
  • Creatinine clearance lt30 mL/min or urine protein
    creatinine ratio (UPC) gt 1.0 at registration
  • Uncontrolled blood pressure gt 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.
20094(12)1537-1543
69
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCPatient 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 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

NSCLC, non-small cell lung cancer NCI, National
Cancer Institute
Reynolds et al. J Thoracic Onc.
20094(12)1537-1543
70
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCSelect Patient Demographics
Baseline characteristic (N 50) n ()
Median age, years 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.
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First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLC Best Response After Treatment
Treatment characteristic (na 43) n ()
PR 15 (35)
SD 6 months lt 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 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
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
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc.
20094(12)1537-1543
72
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCMedian Progression-Free Survival
Median PFS 9.8 (Range, lt1-22.3 Months)
Median PFS 9.8 (Range, lt1-22.3 Months)
NSCLC, non-small cell lung cancer PFS,
progression-free survival
Reynolds et al. J Thoracic Onc.
20094(12)1537-1543
73
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCMedian Time to Tumor Progression
Median Survival Time 16.8 (Range, lt1-24.9 Months)
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc.
20094(12)1537-1543
74
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCMedian Overall Survival
Median Survival Time 16.8 (Range, lt1-24.9 Months)
NSCLC, non-small cell lung cancer
Reynolds et al. J Thoracic Onc.
20094(12)1537-1543
75
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.
20094(12)1537-1543
76
First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCConclusions
  • 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.
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First-Line Albumin-Bound Paclitaxel, Carboplatin,
and Bevacizumab in Advanced Non-Squamous
NSCLCConclusions (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,
every-3-week
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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 NSCLCBackground
  • 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 NSCLCStudy 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 NSCLCCorrelative Study
Endpoints
  • To examine the effect of bevacizumab monotherapy
    on tumor perfusion, as assessed by CT scan before
    and after single dose o
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