1 Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer Combination Therapy...

1

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

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Albumin-Bound Paclitaxel Albumin-Bound Paclitaxel in Non-small Cell Lung Cancerin Non-small Cell Lung Cancer

Combination Therapy with Carboplatin

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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

Nicole Parker (AS)

During later factchecking: verify which reference is used on which slides for this section. Where unknown, both are listed.

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• 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


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• 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


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• 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

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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


ECOG, Eastern Cooperative Oncology Group


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


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• 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


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• 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


Albumin-bound paclitaxel (N = 43)

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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%)


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• 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


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• 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


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

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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

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• 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


First-Line Albumin-BoundFirst-Line Albumin-Bound Paclitaxel and Carboplatin in Paclitaxel and Carboplatin in Advanced NSCLCAdvanced NSCLCConclusionsConclusions


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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.

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• 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

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• To identify the optimal dose of albumin-bound paclitaxel plus carboplatin AUC = 6 q3w as first-line therapy in patients with advanced NSCLC


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

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• 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


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

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• 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


First-Line Sequential Albumin-BoundFirst-Line Sequential Albumin-Bound Paclitaxel and Paclitaxel and Carboplatin in Advanced NSCLCCarboplatin in Advanced NSCLCObjectivesObjectives

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• 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


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

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*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


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- >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


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)

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• 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


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

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Albumin-Bound Paclitaxel Doses and Schedules


*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



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)

John McGuire, PhD (MTM)

Percentage ORRs do not add up. Will verify or change during fact-check

28


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


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)

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


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 >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


*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



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)


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


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


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


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

Nicole Parker (AS)

Need references for all statements on this slide.

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


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


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


These reference numbers need to be revised. Numbers 7-10 don't match with anything on this deck subsection. Look up during fact-check

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)


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


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


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


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


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


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


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


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)


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



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


• Twenty-three patients (66%) had squamous histology, while 12 patients (34%) had non-squamous histology

44


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)


45


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)


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.


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



Will remove this slide after fact-check to rectify ref problems in background slides

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


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


Look up refs during fact check

Nicole Parker (AS)

Also need references for bullets 1 and 3 on this slide.

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


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


Not sure we can use this language.


Complete refs during fact-check

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


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


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)


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


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


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


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


57


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


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


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


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


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


Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLCPaclitaxel + Carboplatin in Advanced NSCLCConclusionsConclusions


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


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


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


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


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


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


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


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


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


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)


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


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)



It doesn't make sense to say that 20 patients had an overall survival. Verify this during fact-check

72

Median PFS: 9.8 (Range, <1-22.3 Months)


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)


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



Verify that this should not say: Median Time to Progression during fact check


During fact-check, look up actual TTP value

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)


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


75


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)


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


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


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


Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCBackgroundBackground


Nicole Parker (AS)

Need references for bullet 1 of this slide.

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


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


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


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


Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCResults: Correlative FindingsResults: Correlative Findings


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



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




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


Albumin-Bound Paclitaxel, Carboplatin, and Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Bevacizumab in Advanced NSCLCNSCLCConclusionsConclusions


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


Albumin-BoundAlbumin-Bound Paclitaxel, Carboplatin, and Radiation Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCBackgroundBackground


Need to look up refs during fact-check

Nicole Parker (AS)

Need references for bullets 1-3 on this slide.

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


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


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


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


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


Albumin-Bound Paclitaxel, Carboplatin, and Radiation Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced in Locally-Advanced NSCLCNSCLCConclusionsConclusions

TRT, thoracic radiation therapy

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