1 nab-paclitaxel in metastatic breast cancer combination studies

1

NAB-PaclitaxelNAB-Paclitaxelin Metastatic Breast Cancerin Metastatic Breast Cancer

Combination StudiesCombination Studies

2

Phase II Multicenter Trial of Nab–Paclitaxel Phase II Multicenter Trial of Nab–Paclitaxel and Capecitabine in First-Line Treatment of and Capecitabine in First-Line Treatment of Patients with with Metastatic Breast CancerPatients with with Metastatic Breast Cancer

Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication

3

First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCBackgroundBackground

• Cremophor® ELa paclitaxel1 and capecitabine1-3 have single agent activity in metastatic breast cancer

• Taxane and antimetabolite doublets may improve response rate and time to progression compared with single agent therapy4

• Weekly NAB- paclitaxel has demonstrated safety and efficacy for the first-line treatment of MBC5

MBC, metastatic breast cancer.MBC, metastatic breast cancer.

1. Talbot DC, et al. Br J Cancer. 2002;86:1367-1372.

2. O’Shaughnessy, et al. Ann Oncol. 2001. 3. Bajetta, et al. J Clin Oncol. 2005.

4. Miles, et al. Clin Breast Cancer. 2004. 5. Gradishar et al J Clin Onc. 2009;27:361-36919.

aaCremophor is a registered trademark of BASF.Cremophor is a registered trademark of BASF.


4

First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCObjectivesObjectives

• To evaluate the safety and efficacy of NAB- paclitaxel and capecitabine in a novel combination schedule in previously untreated MBC

• Endpoints

– Primary: • Response rate (ORR)

– Secondary: • Progression-free survival (PFS)

• Overall survival (OS)

• Safety

MBC, metastatic breast cancer.MBC, metastatic breast cancer. Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication

5

First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCKey Eligibility CriteriaKey Eligibility Criteria

• Inclusion criteria– Measurable MBC by RECIST criteria– Age > 18– ECOG PS ≤ 2– At least 6 months since adjuvant fluoropyrimidine or Cremophor®

EL paclitaxel– Adequate bone marrow, kidney, and liver function

• Exclusion criteria– Prior chemotherapy for metastatic disease– Prior capecitabine therapy

ECOG PS, Eastern Cooperative Oncology Group ECOG PS, Eastern Cooperative Oncology Group performance status; MBC, metastatic breast performance status; MBC, metastatic breast cancer; RECIST, response evaluation criteria in cancer; RECIST, response evaluation criteria in solid tumors.solid tumors. Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication

6

First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCStudy Design and TreatmentStudy Design and Treatment

bid, twice daily; IV, intravenous; MBC, bid, twice daily; IV, intravenous; MBC, metastatic breast cancer; q3w, every 3 metastatic breast cancer; q3w, every 3 weeks.weeks.

NAB- paclitaxel 125 mg/m2

IV over 30 minDays 1 and 8 q3w without

premedication

Capecitabine 825 mg/m2

Orally bidDays 1-14 q3w


Endpoints

• Primary: ORR

• Secondary: PFS, OS, safety

Purpose: A single arm, multi-center phase II trial to determine efficacy of NAB-paclitaxel + capecitabine as first line treatment of MBC patients (HER2-)

– N = 50– Patients with ECOG PS 0-2, HER2-, adequate organ function– Cycles of 21 days until disease progression or dose-limiting toxicity

7

First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCPatient CharacteristicsPatient Characteristics

8

Baseline characteristic (N = 50) Value

Age in years, median (range) 59.0 (23.7-83.8)

Prior chemotherapy, n (%)

Anthracycline

Taxane

Radiotherapy

25 (50)

20 (40)

17 (34)

17 (34)

Number of metastatic sites, n (%)

1

2

3

> 3

13 (26)

19 (38)

14 (28)

4 (8)

Most common metastatic site, n (%)

Bone

Liver

Other lymph node

Pulmonary

27 (54)

24 (48)

19 (38)

17 (34)


First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCSelect Patient CharacteristicsSelect Patient Characteristics


9

First-Line First-Line NAB-PaclitaxelNAB-Paclitaxel and Capecitabine in MBC and Capecitabine in MBCResults: Tumor ResponseResults: Tumor Response

Outcome (N = 46) n (%)

ORR

CR

PR

28 (61)

2 (4)

26 (57)

SD 10 (22)

PD 8 (17)

Note: 4 of the 50 patients not evaluable for response.

CR, complete response; MBC, metastatic breast MBC, metastatic breast cancer; cancer; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Schwartzberg et al., Clin Breast Cancer. 2011 on line ahead of publication

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The red line indicates product limit estimate of survival curve and circles indicate a censored observationThe red line indicates product limit estimate of survival curve and circles indicate a censored observation


First-Line First-Line NAB-PaclitaxelNAB-Paclitaxel and Capecitabine in MBC and Capecitabine in MBCResults: Progression Free SurvivalResults: Progression Free Survival

11

The red line indicates product limit estimate of survival curve and circles indicate a censored observationThe red line indicates product limit estimate of survival curve and circles indicate a censored observation

First-Line First-Line NAB-PaclitaxelNAB-Paclitaxel and Capecitabine in MBC and Capecitabine in MBCResults: Overall SurvivalResults: Overall Survival

12

Change in Target Lesions from Baseline to Best Response. The x-axis represents individual patients who remained on study through the first scheduled restaging (n 45). The y-axis represents the percentage change in tumor size from baseline.


First-Line First-Line NAB-PaclitaxelNAB-Paclitaxel and Capecitabine in MBC and Capecitabine in MBCResults: Change in target lesionsResults: Change in target lesions

13

First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCResults: Dose ModificationsResults: Dose Modifications


14

Frequency for all events 12 or any event grade 3. Patients may have had more than 1adverse event.Abbreviations: ALP alkaline phosphatase; AST aspartate aminotransferase.


First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCTreatment related adverse eventsTreatment related adverse events

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First-Line NAB-Paclitaxel and Capecitabine in MBCFirst-Line NAB-Paclitaxel and Capecitabine in MBCConclusionsConclusions

• NAB- paclitaxel plus capecitabine is a highly active combination regimen in first-line MBC with an ORR of 61%

• This combination therapy led to a favorable median PFS of 10.6 months

• This regimen is well tolerated and the schedule has a favorable safety profile with efficacy similar to known combinations

• This regimen could be considered for addition of biological therapy and/or in a phase III trial compared with other standard strategies for first-line treatment of MBC


16

Phase II Trial of Weekly NAB- Paclitaxel in Phase II Trial of Weekly NAB- Paclitaxel in Combination With Gemcitabine in Combination With Gemcitabine in

Patients With Metastatic Breast CancerPatients With Metastatic Breast Cancer

V. Roy, B. R. LaPlant, G. G. Gross,

C. L. Bane, F. M. Palmieri,

on behalf of the North Central Cancer Treatment Group

Roy V et al. Ann Oncol. 2009;20(3):449-453.

17


NAB- Paclitaxel Plus Gemcitabine in MBCNAB- Paclitaxel Plus Gemcitabine in MBCBackgroundBackground

• A randomized phase III trial showed superior efficacy of NAB- paclitaxel to Cremophor® EL paclitaxel¹

• In a phase III study, the addition of gemcitabine to Cremophor EL paclitaxel therapy increased tumor response in MBC patients previously treated with anthracyclines2

– Overall response rate of 41% vs. 26% for Cremophor EL paclitaxel alone

1. Gradishar WJ, et al, J Clin Oncol. 2005;23(31):7794-7803.

2. Albain KS, et al. J Clin Oncol. 2008;26(24):3950-3957.MBC, metastatic breast cancer.

18

NAB- Paclitaxel Plus Gemcitabine in MBCNAB- Paclitaxel Plus Gemcitabine in MBCObjectivesObjectives

• To evaluate the combination of NAB- paclitaxel and gemcitabine for the treatment of MBC

• Endpoints

– Primary:

• Confirmed response rate per RECIST criteria on 2 consecutive evaluations ≥ 6 weeks apart

MBC, metastatic breast cancer; RECIST, Response Evaluation Criteria in Solid Tumors. Roy V et al. Ann Oncol. 2009;20(3):449-453.

19


NAB- Paclitaxel Plus Gemcitabine in MBC NAB- Paclitaxel Plus Gemcitabine in MBC Key Eligibility CriteriaKey Eligibility Criteria

• Inclusion criteria

– Age ≥ 18 years

– Histologically and cytologically confirmed invasive breast cancer with clinical evidence of metastatic disease

– Eastern Cooperative Oncology Group performance status of 0 - 1

– Patients may have received prior hormonal therapy for MBC

– Taxane therapy allowed as adjuvant or neoadjuvant treatment if completed ≥ 6 months before study entry

• Exclusion criteria

– Active central nervous system metastasis

– Higher than grade 1 peripheral neuropathy

– Previous chemotherapy for metastatic disease

MBC, metastatic breast cancer.

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NAB- Paclitaxel Plus Gemcitabine in MBC NAB- Paclitaxel Plus Gemcitabine in MBC Study Design and TreatmentStudy Design and Treatment

• This was an open-label, multicenter phase II study conducted through the North Central Cancer Treatment Group

IV, intravenous; MBC, metastatic breast cancer.


Days 1 and 8 every 21 days

Gemcitabine 1000 mg/m2

Days 1 and 8 every 21 days


21


ECOG PS, Eastern Cooperative Oncology Group performance status;MBC, metastatic breast cancer.


Age in years, median (range) 56 (29 - 86)

ECOG PS, n (%)

0

1

23 (46)

27 (54)

Prior chemotherapy, n (%)a

Anthracycline

Taxane

25(50)

24 (48)

15 (30)


1

2

3+

5 (10)

15 (30)

30 (60)

a Patients may have had more than one type of prior therapy.

NAB- Paclitaxel Plus Gemcitabine in MBC NAB- Paclitaxel Plus Gemcitabine in MBC Baseline Patient CharacteristicsBaseline Patient Characteristics

22


a Overall confirmed response. CI, confidence interval; CR, complete response; MBC, metastatic breast cancer; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.

Outcome (N = 50) Value

Number of administered cycles, median (range) 7 (1-17)

ORRa (≥ PR), n (%; 95% CI) 25 (50; 36-64)

CR, n (%) 4 (8)

PR, n (%) 20 (42)

Duration of response in months, median (95% CI) 6.9 (5.7, NR)

PFS in months, median (95% CI) 7.9 (5.4-10)

OS in months, median (95% CI) NR

6-month PFS, % (95% CI) 60 (48-76)

6-month OS, % (95% CI) 92 (85-100)

NAB- Paclitaxel Plus Gemcitabine in MBCNAB- Paclitaxel Plus Gemcitabine in MBCResults: EfficacyResults: Efficacy

23

Adverse event, N = 50 Grade 3, n (%) Grade 4, n (%)

Neutropenia 21 (42) 6 (12)

Fatigue 14 (28) 0

Anemia 7 (14) 0

Dyspnea 7 (14) 0

Thrombocytopenia 5 (10) 1 (2)

Arthralgia 4 (8) 0

Vomiting 4 (8) 0

Neuropathy 4 (8) 0

Myalgia 3 (6) 0

Nausea 3 (6) 0

Pain, abdominal 3 (6) 0

AST elevation 3 (6) 0

• Neutropenia and thrombocytopenia were the only grade 4 AEs reportedNeutropenia and thrombocytopenia were the only grade 4 AEs reported• Fatigue was the most commonly reported nonhematologic grade 3/4 AEFatigue was the most commonly reported nonhematologic grade 3/4 AE

AE, adverse event; AST, aspartate aminotransferase; MBC, metastatic breast cancer. Roy V et al. Ann Oncol. 2009;20(3):449-453.

NAB- Paclitaxel Plus Gemcitabine in MBCNAB- Paclitaxel Plus Gemcitabine in MBCSafety: Grade 3/4 Adverse Events Occurring in > 5% of Safety: Grade 3/4 Adverse Events Occurring in > 5% of PatientsPatients

24

NAB- Paclitaxel Plus Gemcitabine in MBCNAB- Paclitaxel Plus Gemcitabine in MBCConclusionsConclusions

• Weekly NAB- paclitaxel in combination with gemcitabine demonstrated significant activity as first-line therapy in patients with MBC

• Toxicities were manageable; neutropenia was the most common AE

• No significant nonhematologic toxicities were encountered

• Grade 3 neuropathy occurred in 4 (8%) patients

AE, adverse event; MBC, metastatic breast cancer. Roy V et al. Ann Oncol. 2009;20(3):449-453.

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NAB-Paclitaxel and Bevacizumab Treatment NAB-Paclitaxel and Bevacizumab Treatment in Metastatic Breast Cancerin Metastatic Breast Cancer

J. S. Link, J. R. Waisman, B. Nguyen,

C. I. Jacobs

Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.

26

NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCBackgroundBackground

• It has been demonstrated that the combination of bevacizumab and Cremophor® EL paclitaxel has significant activity in MBC1

• Compared to Cremophor EL paclitaxel, NAB- paclitaxel has been shown to:

– Have increased paclitaxel delivery to tumor2

– Produce a higher response for MBC compared with Cremophor EL paclitaxel3


1. Miller K, et al. N Engl J Med. 2007;357:2666-2676.

2. Desai N, et al. Clin Cancer Res. 2006:12(4):1317-1324.

3. Gradishar WJ, et al. J Clin Oncol. 2005;23(31):7794-7803.MBC, metastatic breast cancer.MBC, metastatic breast cancer.

27


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCObjectivesObjectives

• To investigate the safety and efficacy of NAB- paclitaxel with bevacizumab in heavily pretreated women with MBC

• This retrospective chart analysis examined patients treated consecutively with NAB- paclitaxel and bevacizumab in the second-line setting

– Outcomes examined include:• ORR

– CR– PR

• SD

• TTP

• Safety: adverse events

CR, complete response; MBC, metastatic CR, complete response; MBC, metastatic breast cancer; ORR, overall response rate; breast cancer; ORR, overall response rate; PFS, progression-free survival; PR, partial PFS, progression-free survival; PR, partial response; SD, stable disease; TTP, time to response; SD, stable disease; TTP, time to tumor progression..tumor progression..

28

NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCStudy DesignStudy Design

• Retrospective chart review to identify all patients treated consecutively with a combination of NAB- paclitaxel and bevacizumab

MBC, metastatic breast cancer; q2w, MBC, metastatic breast cancer; q2w, every 2 weeks; qw 3/4, first 3 of 4 weeks.every 2 weeks; qw 3/4, first 3 of 4 weeks. Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.

NAB- paclitaxel Dose 1: 80-125 mg/m2

qw 3/4OROR

Dose 2: 170-200 mg/m2

q2w on 28-day cycle

Bevacizumab 10 mg/kg q2w

29


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCBaseline Patient CharacteristicsBaseline Patient Characteristics

• Forty women with heavily pretreated MBC received treatment

– Thirty-four patients (85%) received a minimum of 3 prior chemotherapy regimens for adjuvant or metastatic disease

– Prior taxanes: n = 35 (87%)

– Prior anthracyclines: n = 34 (85%)


30

• Median TTP among responding patients:

– q2w group (n = 14): 103 days

– Weekly group (n = 19): 148 days

Responses (n = 33)a n (%)

ORR (≥ PR)

CR

PR

16 (49)

3 (9)

13 (39)

SD 5 (15)

CR + PR + SD 21 (64)

PD 12 (36)a Evaluable patients.

CR, complete response; MBC, metastatic breast cancer; ORR, overall response rate; PR, partial response; PD, progressive disease; q2w, every 2 q2w, every 2 weeks; weeks; SD, stable disease; TTP, time to tumor TTP, time to tumor progression.progression. Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.

NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCResults: Tumor ResponseResults: Tumor Response

31


Adverse Events (N = 40)Grade 2

n (%)

Grade 3

n (%)

Fatigue 9 (23) 0

Pain (including bone pain) 5 (13) 3 (8)

Neuropathy 4 (10) 1 (3)

Hypertension 3 (8) 0

Anemia 2 (5) 2 (5)


• No grade 4 adverse events were observed during this analysis

NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCResults: Most Common Adverse EventsResults: Most Common Adverse Events

32

NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCConclusionsConclusions

• NAB- paclitaxel + bevacizumab is a relatively effective and safe treatment option for heavily pretreated MBC patients

• The safety profile of these patients was considered to be acceptable

• Additional studies may be warranted with this regimen

AE, adverse event; MBC, metastatic breast cancer. Link JS et al. Clin Breast Cancer. 2007;7(10):779-783.

33

Phase II Trial of Weekly Phase II Trial of Weekly NAB-Paclitaxel in Combination With NAB-Paclitaxel in Combination With

Bevacizumab as Bevacizumab as First-line Treatment in Metastatic First-line Treatment in Metastatic

Breast CancerBreast Cancer

M. Danso, J. Blum, N. Robert,

L. Krekow, R. Rotche, D. Smith,

P. Richards, T. Anderson, D. Richards,

J. O’Shaughnessy

Danso M et al. ASCO. 2008 [Abstract 1075].

34


First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCBackgroundBackground

• A clinical trial of Cremophor® EL paclitaxel ± bevacizumab in patients with locally recurrent MBC1

– N = 722

– Cremophor EL paclitaxel 90 mg/m² was administered weekly for 3 weeks followed by a week of rest

• With or without bevacizumab 10 mg/kg every 2 weeks

– Results

• The combination had a longer median progression-free survival (11.8 vs. 5.9 months; P < 0.001) and overall response rate (36.9% vs. 21.2%; P < 0.001)

1. Miller K et al. N Engl J Med.2007;357:2666-2676.MBC, metastatic breast cancer.MBC, metastatic breast cancer.

35

First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCObjectivesObjectives

• To evaluate safety, tolerability and efficacy of NAB- paclitaxel in combination with bevacizumab in MBC

• Endpoints

– Primary:• Incidence of treatment-emergent AEs, serious AEs

• Median PFS

– Secondary: • ORR: CR + PR determined according to RECIST guidelines

• Total Response: CR + PR + SD ≥ 16 weeks

• Duration of Response

• Overall survival


AE, adverse event; CR, complete response; AE, adverse event; CR, complete response; MBC, metastatic breast cancer; ORR, overall MBC, metastatic breast cancer; ORR, overall response rate; PFS, progression-free survival; response rate; PFS, progression-free survival; PR, partial response; RECIST, Response PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors.Evaluation Criteria In Solid Tumors.SD, stable disease. SD, stable disease.

36

First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCStudy Design and TreatmentStudy Design and Treatment

• This was a multicenter, open-label, phase II study

• Therapy with one or both study drugs could continue in the absence of disease progression or unacceptable toxicity

IV, intravenous; MBC, metastatic breast cancer; IV, intravenous; MBC, metastatic breast cancer; q2w, every 2 weeks; q3w, every 3 weeks. q2w, every 2 weeks; q3w, every 3 weeks. Danso M et al. ASCO. 2008 [Abstract 1075].


IV over 30 min q3w28-day cycle

Bevacizumab 10 mg/kg q2w

28-day cycle

37



Age in years, median (range) 58 (35 - 88)

ECOG PS, n (%)

0

1

2

24 (49)

23 (47)

2 (4)

Prior adjuvant therapiesa, n (%)

Chemotherapy

Docetaxel

Cremophor® EL paclitaxel

Doxorubicin

24 (48)

7 (14)

7 (14)

2 (4)a Patients may have had more than one type of prior therapy.

ECOG PS, Eastern Cooperative Oncology Group performance status; MBC, metastatic breast cancer.

First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCBaseline Patient CharacteristicsBaseline Patient Characteristics

38

Response (N = 45)a Value

ORR, n (%)

CR

PR

15 (33)

1 (2)

14 (31)

SD of any duration, n (%) 10 (22)

PFS in months, median (95% CI) 7.4 (5.4-9.2)A 45 of 50 patients were evaluable for response.


CI, confidence interval; CR, complete response; CI, confidence interval; CR, complete response; MBC, metastatic breast cancer; ORR, overall MBC, metastatic breast cancer; ORR, overall response rate; PFS, progression-free survival; response rate; PFS, progression-free survival; PR, partial response; SD, stable disease.PR, partial response; SD, stable disease.

First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCResults: EfficacyResults: Efficacy

39

Danso M et al. ASCO. 2008 [Abstract 1075].AE, adverse event; MBC, metastatic breast cancer; SD, standard deviation.

Adverse Event (N = 50)

Grade 3,

n (%)

Grade 4,

n (%)Mean nadir ± SD (×

109/L)

Neutropenia 15 (34) 7 (16) 1.35 ± 1.19

Leukopenia 12 (27) 3 (7) 2.73 ± 1.45

Anemia 3 (7) 2 (5) 105.0 ± 16.33

First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCSafety: Grade 3/4 Hematologic AEs in ≥ 5% of PatientsSafety: Grade 3/4 Hematologic AEs in ≥ 5% of Patients

40


• Sensory neuropathy and dehydration were the only grade 4 nonhematologic Sensory neuropathy and dehydration were the only grade 4 nonhematologic AEs reported in this studyAEs reported in this study

AE, adverse event; MBC, metastatic breast cancer.

First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCSafety: Nonhematologic AEs in ≥ 10% of patientsSafety: Nonhematologic AEs in ≥ 10% of patients

41


First-Line NAB- Paclitaxel and Bevacizumab for MBCFirst-Line NAB- Paclitaxel and Bevacizumab for MBCConclusionsConclusions

• In patients with MBC, weekly NAB- paclitaxel + bevacizumab demonstrated a 33% ORR and a median PFS of 7.4 months

• Overall, NAB- paclitaxel + bevacizumab as first-line therapy had manageable AEs

– < 50% of patients experienced grade 3/4 hematologic AEs

– Only 1 patient experienced grade 4 nonhematologic AEs (sensory neuropathy and dehydration)

AE, adverse event; MBC, metastatic breast cancer; ORR, overall response rate; PFS, progression-free survival.

42

Randomized Phase II Trial of NAB- Paclitaxel Randomized Phase II Trial of NAB- Paclitaxel in 3 Dosing Schedules With Bevacizumab as in 3 Dosing Schedules With Bevacizumab as

First-line Therapy for First-line Therapy for HER2- Metastatic Breast CancerHER2- Metastatic Breast Cancer

A.K. Conlin, C.A. Hudis, A. Bach,M.E. Moynahan, D. Lake, A. Forero-Torres,

G. Wright, M.H. Hackney, A. Clawson,

A.D. Seidman

Conlin AK et al. ASCO. 2009 [Abstract 1006].

43

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCBackgroundBackground

• Q3w 260 mg/m2 NAB- paclitaxel demonstrates higher response rates and time to tumor progression compared with q3w 175 mg/m2 Cremophor® EL paclitaxel1

• Weekly uninterrupted Cremophor EL paclitaxel is more effective than q3w Cremophor EL paclitaxel in MBC2

• Dose-dense every-2-week Cremophor EL paclitaxel confers a survival advantage over q3w as a component of adjuvant therapy3

• The addition of bevacizumab to weekly Cremophor EL paclitaxel for first-line therapy of MBC increases response rate (RR) and prolonged progression-free survival (PFS)4

• The combination of NAB- paclitaxel with bevacizumab has shown significant synergy in animal models5

1. Gradishar WJ, et al. J Clin Oncol. 2005;23(31):7794-7803.2. Seidman AD, et al. J Clin Oncol. 2008;26(10):1642-1649.

3. Citron ML, et al. J Clin Oncol. 2003;21(8):1431-1439.4. Miller K, et al. N Eng J Med. 2007;357:2666-2676.

5. Volk LD, et al. Neoplasia. 2008;10(6):613-623.

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; q3w, every 3 weeks. Conlin AK, et al. ASCO. 2009 [Abstract 1006].

44

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCObjectivesObjectives

• Endpoints

– Primary• Safety and tolerability

• ORR

– Secondary• TTP

• OS

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; TTP, time to tumor progression. Conlin AK et al. ASCO. 2009 [Abstract 1006].

45

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCKey Eligibility CriteriaKey Eligibility Criteria

• Inclusion– Stage IV adenocarcinoma of the breast– Not a candidate for trastuzumab– Measurable disease by RECIST criteria– Adequate renal, hepatic, and bone marrow function

• Exclusion– Adjuvant taxane < 12 months or any chemotherapy < 6 months

prior to study enrollment– Peripheral neuropathy > grade 1 at baseline– Central nervous system metastases– Uncontrolled hypertension, proteinuria, vascular disease or

coagulopathy– Prior chemotherapy in the metastatic setting

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; RECIST, Response Evaluation Criteria in Solid Tumors. Conlin AK et al. ASCO. 2009 [Abstract 1006].

46

ECOG PS, Eastern Cooperative Oncology Group performance status; G-CSF, granulocyte colony-stimulating factor; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks.

Arm C: NAB- paclitaxel 130 mg/m2 qw, bevacizumab 10 mg/kg q2w

Cycle: weekly infusions

Arm A: NAB- paclitaxel 260 mg/m2 q3w, bevacizumab 15 mg/kg q3w

Cycle: 1 infusion q3w

Arm B: NAB- paclitaxel 260 mg/m2 q2w + G-CSF support,

bevacizumab 10 mg/kg q2wCycle: 1 infusion q2w

Target N = 225

Stratification:Adjuvant TherapyECOG PS

Randomization

Conlin AK, et al. ASCO. 2009 [Abstract 1006].

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCStudy DesignStudy Design

47

Baseline characteristic (N = 205)

AB-paclitaxel Dose

260 mg/m2 q3w (n = 73)

260 mg/m2 q2w (n = 54)

130 mg/m2 qw (n = 78)

Median age, years (range)

< 65 years, n (%)

≥ 65 years, n (%)

59 (29-80)

52 (71)

21 (29)

56 (36-79)

41 (76)

13 (24)

56 (32-85)

62 (79)

16 (21)

ECOG performance status, n (%)

0

1

43 (59)

27 (37)

33 (61)

17 (31)

47 (60)

27 (35)

Visceral dominant disease, n (%)

Yes

No

Unknown

64 (88)

8 (11)

1 (1)

49 (92)

3 (6)

1 (2)

68 (87)

10 (13)

0

Premenopausal patients, n (%) 11 (15) 11 (20) 15 (19)

Prior chemotherapy, n (%)a

Cremophor® EL paclitaxel

Docetaxel

Doxorubicin

Epirubicin

46 (63)

18 (25)

9 (12)

35 (48)

2 (3)

33 (61)

14 (26)

7 (13)

23 (43)

4 (7)

47 (60)

18 (23)

13 (17)

37 (47)

3 (4)

aPrior neoadjuvant or adjuvant treatment.


AB, NAB-; ECOG; Eastern Cooperative Oncology Group; 2; HER2, human epidermal growth factor receptor ; MBC, metastatic breast cancer; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks.

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCBaseline Patient CharacteristicsBaseline Patient Characteristics

48

Dose level

AB-paclitaxel Dose

260 mg/m2 q3w 260 mg/m2 q2w 130 mg/m2 qw

0 260 260 130

-1 220 220 110

-2 180 180 90

• Doses were modified as shown if patients experienced excessive Doses were modified as shown if patients experienced excessive toxicities toxicities


AB, NAB-; AB, NAB-; HER2, human epidermal growth factor receptor 2; ; MBC, metastatic breast cancer; qw, qw, weekly; q2w, every 2 weeks; q3w, every 3 weekly; q2w, every 2 weeks; q3w, every 3 weeks.weeks.

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCPreplanned Dose ReductionsPreplanned Dose Reductions

49

Dose Parameter

AB-P

260 mg/m2

q3w(n = 73)

AB-P

260 mg/m2 q2w

(n = 54)

AB-P

130 mg/m2

qw(n = 78)

Patients with ≥ 1 dose reduction, n (%)

Due to grade 3/4 neurotoxicity, n/N (%)30 (41)

11/30 (37)

26 (48)

15/26 (58)

50 (64)

23/50 (46)

Patients with ≥ 1 dose delay, n (%)

Due to neurotoxicity, n/N, (%)

Due to other reasons, n/N (%)

36 (49)

19/36 (53)

20/36 (56)

22 (41)

11/22 (50)

17/22 (77)

67 (86)

38/67 (57)

49/67 (73)

Weeks of therapy, median 20 13 22

Dose intensity in mg/m2/week, mean (range)

79 (45.7-88.8)114 (68.6-

134.8)97 (61.7-130)

Relative dose intensity, % (Delivered/planned)

91 (79/86) 88 (114/130) 75 (97/130)


AB-P, NAB- paclitaxelAB-P, NAB- paclitaxel; MBC, metastatic breast cancer; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks; HER2, human epidermal growth factor receptor 2.

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCResults: Dose ParametersResults: Dose Parameters

50

Adverse Event, n (%)

AB-P 260 mg/m2 q3w

(n = 73)

AB-P 260 mg/m2

q2w (n = 54)

AB-P 130 mg/m2

qw(n = 78)

≥ 1 AE reportedGrade 3Grade 4Grade 5

42 (58)9 (12)1 (1)a

39 (72)5 (9)1 (2)a

52 (67)11 (14)

0

Sensory neuropathyGrade 2Grade 3Grade 4

20 (27)22 (30)

0

8 (15)25 (46)

1 (2)

18 (23)30 (38)

1 (1)

Febrile neutropeniaGrade 3/4b

2 (2) 1 (2) 0

a Not treatment related. b Only AEs of grade 3/4 reported. AEs based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0. Note: none of these overall comparisons were statistically significant.

AB-P, NAB- paclitaxelAB-P, NAB- paclitaxel; AE, adverse event; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks.


First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCResults: Adverse EventsResults: Adverse Events

51

Adverse event, n (%)

AB-P 260 mg/m2 q3w

(n = 73)

AB-P 260 mg/m2 q2w

(n = 54)

AB-P 130 mg/m2

qw (n = 78)P value

Fatigue, Grade 3/4 12 (16) 18 (33) 13 (17) Overall: .015

Nausea, Grade 3/4 3 (4) 4 (7) 1 (1) Overall: .111

Arthralgia Grade 2Grade 3

9 (12)4 (5)

9 (17)1 (2)

1 (1)0

Overall: < .001

Myalgia Grade 2Grade 3

6 (8)0

2 (4)3 (6)

00

Overall: NSB vs. C: .021

Bone pain Grade 2Grade 3

6 (8)2 (3)

8 (15)3 (6)

2 (3)1 (1)

Overall: .002

Hypertension, Grade 2/3 13 (18) 5 (9) 8 (10) Overall: NS

Diarrhea, Grade 3/4 0 3 (6) 5 (6)Overall: .048 A vs. C: .014

Nail changes Grade 2Grade 3

2 (3)0

2 (4)3 (6)

10 (13)7 (9)

Overall: .001A vs. C: < .001


AB-P, NAB- paclitaxel;AB-P, NAB- paclitaxel; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; qw, weekly: q2w, every 2 weeks; q3w, every 3 weeks.

Note: Adverse events graded on National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. P-values based on Cochran-Mantel-Haenszel test.

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCResults: Adverse Events (cont.)Results: Adverse Events (cont.)

52


AB-P, NAB- paclitaxel;AB-P, NAB- paclitaxel; AE, adverse event; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks.

• AE sensory neuropathy grade profiles were similar among the 3 groups (comparison P values not significant)

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCResults: Sensory NeuropathyResults: Sensory Neuropathy

53

ParameterAB-P

260 mg/m2 q3w(n = 73)

AB-P

260 mg/m2 q2w (n = 54)

AB-P

130 mg/m2 qw(n = 78)

Baseline grade 3/4 sensory neuropathy, n (%)

22 (30) 26 (48) 31 (40)

Improvement (≤ grade 2), n (%) 16 (73) 20 (77) 29 (94)

Time to improvement in days, median (95% CI)

37 (22-43) 22 (15-45) 15 (8-28)


AB-Pac, NAB- paclitaxel; CI, confidence interval; AB-Pac, NAB- paclitaxel; CI, confidence interval; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks.

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- Metastatic Breast CancerMetastatic Breast CancerResults: Improvement in Sensory NeuropathyResults: Improvement in Sensory Neuropathy

54

ResponseAB-P

260 mg/m2 q3w (n = 73)

AB-P

260 mg/m2 q2w

(n = 54)

AB-P

130 mg/m2

qw (n = 78)

ORRa (≥ confirmed PR), n (%)

95% CI

32 (44)

32.5-55.2

21 (39)

25.9-51.9

36 (46)

35.1-57.2

Confirmed CR, n (%) 1 (1) 1 (2) 1 (1)

Confirmed PR, n (%) 31 (42) 20 (37) 35 (45)

Patients with progressive disease, n (%)

38 (52) 28 (52) 32 (41)

TTP in months, median (95% CI) 7.7 (7.0-10.3) 6.3 (5.4-7.9) 9.0 (7.3-14.2)

• Data are immature; only 40% of patients have progressed• All analyses were performed on the treated population of patients

a Overall ORR P value = 0.575.


AB-P, NAB- paclitaxel;AB-P, NAB- paclitaxel; CI, confidence interval; CR, complete response; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; ORR, overall response rate; PR, partial response; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks; TTP, time to tumor progression.

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- Metastatic Breast CancerMetastatic Breast CancerResults: Confirmed Overall Response RateResults: Confirmed Overall Response Rate

55

• The median TTPs by investigator assessment for the q3w, q2w, and qw arms were 7.7, 6.3, and 9.0 months, respectively

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks; TTP, time to tumor progression. Conlin AK et al. ASCO. 2009 [Abstract 1006].

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- Metastatic Breast CancerMetastatic Breast CancerResults: Time to Tumor ProgressionResults: Time to Tumor Progression

56

First-Line NAB- Paclitaxel and Bevacizumab in HER2- First-Line NAB- Paclitaxel and Bevacizumab in HER2- MBCMBCConclusionsConclusions

• Sustained q2w NAB- paclitaxel at 260 mg/m2 with filgrastim for more than 4 cycles is not feasible in this population due to nonhematologic toxicity

• Neurotoxicity limited treatment in all 3 arms

• All 3 arms demonstrated similar efficacy

• Dose delay and reduction with weekly (uninterrupted) NAB- paclitaxel were common

• NAB- paclitaxel for the first 3 weeks of a 4-week schedule, adopted by prospective studies like CALGB 40502, might be preferable

CALGB, Cancer and Leukemia Group B; HER2, human epidermal growth actor receptor 2; MBC, metastatic breast cancer; q2w, every 2 weeks. Conlin AK et al. ASCO. 2009 [Abstract 1006].

57

Final Results of a Phase II Study of Final Results of a Phase II Study of NAB- Paclitaxel, Bevacizumab, and NAB- Paclitaxel, Bevacizumab, and

Gemcitabine as First-Line Therapy for Gemcitabine as First-Line Therapy for Patients With HER2- Metastatic Breast Patients With HER2- Metastatic Breast

CancerCancer

C. Lobo, G. Lopes, O. Baez, A. Castrellon, A. Ferrell, C. Higgins, E. Hurley, J. Hurley,

I. Reis, S. Richman, P. Seo, O. Silva, J. Slingerland, K. Tukia, C. Welsh, S. Gluck

Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

58

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast CancerGemcitabine in HER2- Metastatic Breast CancerBackgroundBackground

• NAB- paclitaxel was found to be more efficacious than Cremophor® EL paclitaxel in a phase III study of patients with MBC1

– Higher overall response rate (33% vs. 19%, P = .001)

– Significantly longer time to tumor progression (P = .006)

• The addition of gemcitabine² or bevacizumab³ to Cremophor EL paclitaxel has been shown to improve TTP and response rates

1. Gradishar WJ et al, J Clin Oncol 2005;23(31):7794-7803.

2. Albain KS et al. J Clin Oncol. 26(24):3950-3957.

3. Miller K et al. N Engl J Med. 2007;357:2666-2676.

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; TTP, time to tumor progression. Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

59

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast CancerGemcitabine in HER2- Metastatic Breast CancerObjectiveObjective

• Objective: to examine the efficacy and safety of NAB- paclitaxel plus bevacizumab plus gemcitabine as first-line treatment for patients with MBC

• Primary endpoint: progression-free survival

• Secondary endpoints – Overall survival– Overall response rate (ORR)

• Complete and partial response rates

– Clinical benefit (ORR + stable disease rate)– Safety/Tolerability

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer. Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

60

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast Cancer Gemcitabine in HER2- Metastatic Breast Cancer Key Eligibility CriteriaKey Eligibility Criteria

• HER2-, MBC treatment-naïve, or metastasis diagnosed ≥ 6 months after completion of primary or adjuvant systemic treatment

• No previous chemotherapy within 1 month of enrollment

• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Life expectancy > 3 months

• Adequate laboratory values

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer. Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

61

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast CancerGemcitabine in HER2- Metastatic Breast CancerStudy Design and TreatmentStudy Design and Treatment

• This was a phase II open-label single-center study

• All drugs were administered by IV infusion over 30 minutes on Days 1 and 15 of a 28-day cycle• All dose reductions followed the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 3.0) for hematologic and nonhematologic toxicity

HER2; human epidermal growth factor receptor 2; IV, intravenous.

11 1515 2828DayDay

Additional CyclesCycle 1

Evaluate responseafter 2 cycles

Treatment continued until:Disease progressionUnacceptable toxicity

Patient withdrawal

Gemcitabine 1500 mg/m2


Bevacizumab 10 mg/kg

CT scans every 2 cycles


62

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast Cancer Gemcitabine in HER2- Metastatic Breast Cancer Baseline Patient CharacteristicsBaseline Patient Characteristics

Baseline characteristics ( N = 29) Value

Age in years, median (range) 54 (34-69)

Female sex, n (%) 28 (96.6)

Race, n (%)

White

Black

Asian

20 (69)

8 (27.6)

1 (3.4)

Site of metastasis, n (%)

Bone

Liver

Lung

Lymph nodes

Chest wall

Brain

Gastrohepatic ligament

10 (34.5)

10 (34.5)

10 (34.5)

5 (17.2)

2 (6.9)

1 (3.4)

1 (3.4)

Baseline characteristics (N = 29) n (%)

Positive estrogen receptor status 16 (55.2)

Progesterone receptor status

Negative

Positive

Unknown

19 (65.5)

7 (24.1)

3 (10.3)

Number of treatment cycles

1.5

2-5

6-10

> 10

Median (range)

1 (3.4)

8 (27.6)

15 (51.7)

5 (17.2)

6.5 (1.5-23)

Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435. HER2, human epidermal growth factor receptor 2.

63

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast Cancer Gemcitabine in HER2- Metastatic Breast Cancer Results: EfficacyResults: Efficacy

Best patient responseAll evaluable

patients (N = 29)

n (%, 95% CI)

TNBC patientsa (n = 13)

n (%)

CR 8 (27.6, 13-47) 5 (38)

PR 14 (48.3, 29-68) 4 (31)

SD 5 (17.2, 6-36) 2 (15)

PD 2 (6.9, 0.8-23) 2 (15)

Clinical benefit (CR + PR + SD) 27 (93.1, 77-99) 11 (85)aNegative for the expression of estrogen receptor, progesterone receptor, and HER2.

• Twenty-two of 29 patients (76%) exhibited a confirmed response, including 8 Twenty-two of 29 patients (76%) exhibited a confirmed response, including 8 complete responsescomplete responses


CI, confidence interval; CI, confidence interval; CR, complete response; HER2, human epidermal growth factor receptor 2; PD, progressive disease; PR, partial response; SD, stable disease; TNBC, triple-negative breast cancer.

64

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2 Metastatic Breast CancerGemcitabine in HER2 Metastatic Breast CancerResults: Progression-Free SurvivalResults: Progression-Free Survival

Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435. CI, confidence interval; HER2, human epidermal growth factor receptor 2.

65

• Overall survival at 24 months was 61.7% (95% CI: 25.4 - 84.4)

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast Cancer Gemcitabine in HER2- Metastatic Breast Cancer Results: Overall SurvivalResults: Overall Survival

CI, confidence interval; HER2, human epidermal growth factor receptor 2. Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

66

• The 18 month TNBC PFS was 10.6% (95% CI: 0.6 - 36.8)• The 18 month ER+ PFS was 25.0% (95% CI: 7.8 - 47.2)

CI, confidence interval; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PFS, progression-free survival; TNBC, triple-negative breast cancer. Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast Cancer Gemcitabine in HER2- Metastatic Breast Cancer Results: Progression-Free Survival in Select SubgroupsResults: Progression-Free Survival in Select Subgroups

67

aGrade 3 event reported in 1 patient (3.4%).

Grade 2 adverse event (N = 29) n (%)

Alopecia 16 (55)

Nausea 8 (28)

Bone pain 7 (24)

Hand-foot syndrome 7 (24)

Skin rash/lesion 6 (21)

Fatigue 5 (17)

Headache 5 (17)

Peripheral neuropathya 5 (17)

Insomnia 4 (14)

Diarrhea 4 (14)

Neutropenia 3 (10)

Anxiety 3 (10)

Hypertension 3 (10)

AE, adverse event; HER2, human epidermal growth factor receptor 2. Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast Cancer Gemcitabine in HER2- Metastatic Breast Cancer Select Safety Results: Grade 2 AEs Reported in > 2 PatientsSelect Safety Results: Grade 2 AEs Reported in > 2 Patients

68

First-Line NAB- Paclitaxel, Bevacizumab, and First-Line NAB- Paclitaxel, Bevacizumab, and Gemcitabine in HER2- Metastatic Breast CancerGemcitabine in HER2- Metastatic Breast CancerConclusionsConclusions

• This novel combination demonstrated high efficacy– Median PFS = 10.4 months (95% CI: 5.6-15.2)– The ORR was 75.9%

• In the challenging-to-treat subgroup of patients with triple negative disease, the ORR was 69% and the clinical benefit rate (ORR+ SD) was 85%

• Treatment was well tolerated; there was a very low incidence of severe adverse events

• This novel combination of cytotoxic and biologic agents may represent an important new treatment option for the first-line treatment of patients with MBC

CI, confidence interval; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; ORR, overall response rate; SD, stable disease; PFS, progression-free survival. Lobo C et al. Breast Cancer Res Treat. 2010;123(2):427-435.

69

SPARC, EGFR, and VEGFR Expression SPARC, EGFR, and VEGFR Expression May Predict Response to NAB- May Predict Response to NAB-

Paclitaxel / Carboplatin / Bevacizumab Paclitaxel / Carboplatin / Bevacizumab Chemotherapy in Triple Negative Chemotherapy in Triple Negative

Metastatic Breast CancerMetastatic Breast Cancer

E. Hamilton, G. Kimmick, N. Desai, B. Peterson, S. Singh, J. Hopkins,

P. Marcom, V. Chadaram, R. Welch, V. Trieu, K. Blackwell

Hamilton E et al. ASCO. 2010 [Abstract 1109].

70

1. Liedtke C et al. J Clin Oncol. 2008;28(8):1275-1281.2. Bauer KR et al. Cancer. 2007;109(9):1721-1728.

3. Anders C and Carey LA. Oncology (Williston Park). 2008;22(11):1233-1243.

ER, estrogen receptor; HER2, human epidermal growth factor 2; PR, progesterone receptor; TNBC, triple-negative breast cancer; TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

• Triple-negative breast cancer (TNBC)

- Negative for expression of ER, PR, and HER2

- TNBC is associated with aggressive histology, early recurrences and shorter post-recurrence survival1-3

- Chemotherapy may represent the most effective treatment for these cancers because they offer no opportunity for targeted therapies against hormone receptors or HER2

- Instances of metastatic TNBC are referred to as triple-negative metastatic breast cancer

SPARC in NAB- Paclitaxel- / Carboplatin- / SPARC in NAB- Paclitaxel- / Carboplatin- / Bevacizumab-Treated TNMBC PatientsBevacizumab-Treated TNMBC PatientsBackgroundBackground

71

SPARC in NAB- Paclitaxel- / Carboplatin- / SPARC in NAB- Paclitaxel- / Carboplatin- / Bevacizumab-Treated TNMBC PatientsBevacizumab-Treated TNMBC PatientsBackground (cont.)Background (cont.)

• SPARC (secreted protein acidic and rich in cysteine) plays a role in extracellular matrix remodeling and invasion, which are elements of epithelial-mesenchymal transition1

• Albumin uptake is selectively enhanced in SPARC-expressing tumor cells2

– Albumin binds the gp60 receptor on the endothelial cell membrane

– This binding activates caveolin-1 to initiate an opening in the endothelial cell membrane, allowing entry of NAB- paclitaxel into tumor cells

1. Sarrio D et al. Cancer Res. 2008;68:989-997. 2. Hawkins MJ et al. Adv Drug Deliv Rev.

2008;60:876-885.TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

72

Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabBackground (cont.)Background (cont.)

• Multiplexed Collaborative Proximity ImmunoAssay (COPIA: Prometheus) platform used to determine expression/activation of the following pathways:

– EGFR (human epidermal growth factor receptor 1)

– HER2 (human epidermal growth factor receptor 2)

– HER3 (human epidermal growth factor receptor 3)

– IGF1-R (insulin-like growth factor 1 receptor)

– c-KIT (stem cell growth factor)

– PI3K (phosphoinositide-3 kinase)

– MAPK (mitogen-activated protein kinase)

– VEGFR (vascular endothelial growth factor receptor)

– AKT (protein kinase B)

TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

73

Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabObjectivesObjectives

• Expression profiles of TNMBC biopsies were measured to:

– Determine intratumoral SPARC expression

– Describe expression/activation of signaling pathways (EGFR, VEGFR, others) in TNMBC

– Correlate expression patterns with response (ORR, PFS)

• Endpoints

– Primary

• Safety and tolerability

– Secondary

• PFS, ORR, CBR

EGFR, epithelial growth factor receptor; ORR, overall response rate; PFS, progression-free survival; SPARC, secreted protein acidic and rich in cysteine; TNBC, triple-negative breast cancer; TNMBC, triple-negative metastatic breast cancer; VEGFR, vascular endothelial growth factor receptor. Hamilton E et al. ASCO. 2010 [Abstract 1109].

74

Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabKey Eligibility CriteriaKey Eligibility Criteria

• Measurable disease according to RECIST criteria

• Triple-negative (ER-, PR-, HER2-)

• ECOG performance status 0 or 1

• ≤ 1 prior chemotherapy regimen (excluding taxanes) in the metastatic setting

ECOG, Easter Cooperative Oncology Group; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; RECIST, Response Evaluation Criteria in Solid Tumors; TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

75

Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabStudy DesignStudy Design

• Open-label, phase II study

• Target enrollment: 35 first-line and 35 second-line TNMBC patients (for this analysis, 29 subjects with 18 biopsies)

• Primary and metastatic biopsies– First-line subjects only

AUC, area under the curve; IV, intravenous; q2w, every 2 weeks; qw 3/4, first 3 of 4 weeks; TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

NAB- paclitaxel 100 mg/m2 IV

qw 3/4 (28-day cycle)

Bevacizumab 10 mg/kg IV

q2w (28-day cycle)

Carboplatin AUC = 2 IV

qw 3/4 (28-day cycle)

76


Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabBaseline Patient CharacteristicsBaseline Patient Characteristics

Baseline characteristics (N = 29) Value

Age in years, median (range) 51.4 (29.9 – 75.7)

Race, n (%)

White

Black

Asian

Unknown

17 (58.6)

10 (35.6)

1 (3.4)

1 (3.4)


1

2

≥ 3

12 (41.4)

9 (31.0)

8 (27.6)

Line of therapy, n (%)

First

Second

25 (86)

4 (14)

• Nineteen patients (65.5%) had visceral metastases

TNMBC, triple-negative metastatic breast cancer.

77

Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabResults: Preliminary Response and SurvivalResults: Preliminary Response and Survival

• Median PFS: 160 days (= 23 weeks; 95% CI: 131-233 days)

CI, confidence interval; CR, complete response; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

Outcome (N = 27)a n (%)

ORR

CR

PR

24 (89)

4 (14)

20 (69)

SD 2 (7)

PD 1a 2 of 29 patients were not evaluable.

78

Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabResults: Metastatic BiopsiesResults: Metastatic Biopsies

• Metastatic biopsies available for 18 subjects

• Total EGFR

– Expressed in 11/18 (61%) biopsies

– Activated in 3/18 (17%) biopsies

• PI3K and AKT

– Overexpressed in 11/18 (61%) and 8/18 (44%) biopsies, respectively

– Co-expressed in 6/18 (33%) biopsies

AKT, protein kinase B; EGFR, epidermal growth factor receptor; PI3K, phospho-inositol 3 kinase; TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

79


Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabSafety: Most Common Adverse EventsSafety: Most Common Adverse Events

Adverse events (N = 29), n (%) Grade 2 Grade 3 Grade 4

Fatigue 11 (38) 0 0

Alopecia 7 (24) 0 0

Gastrointestinal disturbancesa 5 (17) 0 0

Neutropenia 5 (17) 10 (34) 0

Anemia 5 (17) 2 (7) 0

Neuropathy 4 (14) 2 (7) 0

Rash 4 (14) 0 0

Epistaxis 0 0 0

Thrombocytopenia 0 4 (14) 1 (3)

a Nausea, vomiting, mucositis, diarrhea, constipation.

TNMBC, triple-negative breast cancer.

80

Marker Prediction of TNMBC Patient Response to NAB- Marker Prediction of TNMBC Patient Response to NAB- Paclitaxel/Carboplatin/BevacizumabPaclitaxel/Carboplatin/BevacizumabConclusionsConclusions

• NAB- paclitaxel/carboplatin/bevacizumab offers a well-tolerated therapy with a high ORR in patients with TNMBC

• Overexpression of SPARC, specifically percent of tumor SPARC stain, appears to be predictive of response

ORR, overall response rate; SPARC, secreted protein acidic and rich in cysteine; TNMBC, triple-negative metastatic breast cancer. Hamilton E et al. ASCO. 2010 [Abstract 1109].

81

NAB-PaclitaxelNAB-Paclitaxelin Metastatic Breast Cancerin Metastatic Breast Cancer

Combination StudiesCombination Studies

HER2+ patients

82

NAB- Paclitaxel Combination Studies in MBCNAB- Paclitaxel Combination Studies in MBC

Trial Description Phase

HER2+ Patients

NAB- paclitaxel + carboplatin + trastuzumab in HER2+ MBC1 II

NAB- paclitaxel + lapatinib as first- or second-line treatment for HER2+ MBC2 II

1.1. Conlin AK et al. Conlin AK et al. Clin Breast CancerClin Breast Cancer. 2010;10(4):281-287. . 2010;10(4):281-287. 2.2. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

HER2, human epidermal growth factor receptor 2; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer.MBC, metastatic breast cancer.

83

NAB- Paclitaxel Combination Studies in MBCNAB- Paclitaxel Combination Studies in MBC

Trial Description Phase Main Idea

HER2+ Patients

NAB- paclitaxel + carboplatin + trastuzumab in HER2+ MBC1

II This therapy is active as first-line therapy for HER2+ MBC

NAB- paclitaxel + lapatinib as first- or second-line treatment for HER2+ MBC2

II Accrual to this trial is ongoing, with complete safety and efficacy data to be reported in the future

1.1. Conlin AK et al. Conlin AK et al. Clin Breast CancerClin Breast Cancer. 2010;10(4):281-287. . 2010;10(4):281-287. 2.2. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

HER2, human epidermal growth factor receptor 2; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer.MBC, metastatic breast cancer.

84

Phase II Trial of Weekly NAB- Paclitaxel With Phase II Trial of Weekly NAB- Paclitaxel With Carboplatin and Trastuzumab as First-Line Carboplatin and Trastuzumab as First-Line

Therapy for Women Therapy for Women With HER2-Overexpressing With HER2-Overexpressing

Metastatic Breast CancerMetastatic Breast Cancer

A. K. Conlin, A. D. Seidman, A. Bach, D. Lake,

B. M. Dickler, G. D’Andrea, T. Traina, M. Danso,

A. M. Brufsky, M. Saleh, A. Clawson, C. A. Hudis

Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.

85

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCBackgroundBackground

• Weekly Cremophor® EL paclitaxel + trastuzumab is active and tolerable as first-line treatment of HER2+ MBC1

• On a q3w schedule, adding carboplatin to Cremophor EL paclitaxel + trastuzumab improves response rate and progression-free survival as first-line therapy for HER2+ MBC2

• Weekly Cremophor EL paclitaxel + carboplatin + trastuzumab is also active and appears to be better tolerated than q3w administration3

• NAB- paclitaxel appears to be more active in first-line MBC patients when administered weekly vs. q3w4

1. Seidman AD et al. J Clin Oncol. 2008;26(10):1642-1649.

2. Robert N et al. J Clin Oncol. 2006;24(18):2786-2792.

3. Perez EA et al. Clin Breast Cancer. 2005;6(5):425-432.

4. Gradishar WJ et al. J Clin Oncol. 2009;25(22):3611-3619.

HER2, human epidermal growth factor receptor HER2, human epidermal growth factor receptor 2; 2; MBC, metastatic breast cancer; q3w, every 3 weeks. Conlin AK, et al. Clin Breast Cancer. 2010;10(4):281-287.

86

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCObjectivesObjectives

• Objective: to examine the safety and efficacy of weekly administration of NAB- paclitaxel, trastuzumab, and carboplatin in patients with previously untreated HER2+ MBC

• Primary endpoints: – Confirmed CR or PR based on RECIST – Safety/tolerability: toxicity, myelosuppression, dosing

modifications

• Secondary endpoints: – PFS– DoR – Overall survival

CR, complete response; DoR, duration of response; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; OS, overall survival; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.

87


First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCKey Eligibility CriteriaKey Eligibility Criteria

• Key inclusion criteria

– Measurable, pathologically confirmed adenocarcinoma of the breast (stage IV at enrollment)

– HER2-overexpressing

• Confirmed by either IHC (protein level) or FISH (genetic level)

– ≥ 4 weeks since radiotherapy or major surgery

– Adequate hematologic, hepatic, and renal function

– Normal LVEF

FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; MBC, metastatic breast cancer.

88


First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCKey Eligibility Criteria (cont.)Key Eligibility Criteria (cont.)

• Key exclusion criteria

– Prior chemotherapy for MBC

– < 9 months since taxane-based adjuvant chemotherapy

– Concurrent immunotherapy or hormone therapy

– Parenchymal brain metastases not documented to be clinically and radiographically stable for ≥ 6 months

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer.

89

AUC, area under the curve; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; wk, week. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCOriginal Phase II SchemaOriginal Phase II Schema

90

AUC, area under the curve; HER2, human epidermal growth factor receptor2; MBC, metastatic breast cancer; wk, week. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCRevised Phase II SchemaRevised Phase II Schema

91

ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.

Baseline characteristic ( N = 32) Value

Age in years, median (range) 52 (29 – 76)

ECOG PS, n (%)

0

1

2

19 (59)

12 (38)

1 (3)

Site of metastatic disease, n (%)

Lymph node

Skin/soft tissue/breast

Liver

Lung

Bone

24 (75)

21 (66)

15 (47)

19 (59)

22 (69)

Prior adjuvant or neoadjuvant chemotherapy, n (%)

Anthracycline

Taxane

14 (44)

11 (34)

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCBaseline Patient CharacteristicsBaseline Patient Characteristics

92


First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBC Trastuzumab in HER2+ MBC ResultsResults

• Median response duration: 17.8 months (95% CI, 15.9-37.0)• Median PFS: 16.6 months (95% CI, 7.5-26.5)• Thirty-two patients treated

– Seventeen treated solely on original regimen – Three switched from original to revised regimen– Twelve treated only on revised regimen

Confirmed responses (N = 32) Value

ORR (CR + PR), n (%; 95% CI) 20 (63; 45.7-79.3)

CR, n (%) 3 (9)

PR, n (%) 17 (53)

SD ≥ 16 weeks, n (%) 6 (19)

Clinical benefit (CR + PR + SD ≥ 16 weeks), n (%) 26 (81)

CI, confidence interval; CR, complete response; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; ORR, overall response rate; PR, partial response; SD, stable disease.

93

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.

Response by regimen n (%)

Original regimen only (n = 17) 11 (65)

Revised regimen only (n = 12) 8 (67)

Original + revised (n = 3) 1 (33)

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBC Trastuzumab in HER2+ MBC Results: Response by RegimenResults: Response by Regimen

94

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCResults: Drug ExposureResults: Drug Exposure

• Median dose intensity:

– NAB- paclitaxel: 56.9 mg/m2/week; 76% of the planned dose

– Carboplatin: 47.6 mg/week, 62% of the planned dose

• Median number of cycles: 8 (range 2-39 cycles)

• Eight patients who responded and had at least 6 cycles of NAB- paclitaxel and carboplatin continued to receive trastuzumab alone until progression of disease


95

aBased on laboratory data graded by National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.b1 episode of febrile neutropenia was observed.

Adverse Event, % Grade 1 Grade 2 Grade 3 Grade 4

Hematologica,b

Neutropenia

Leukopenia

Anemia

Thrombocytopenia

13

22

25

38

34

28

63

34

41

44

3

3

9

3

3

0

Non-hematologic

Sensory neuropathy

Nausea

Diarrhea

Rash/Desquamation

Arthralgia

Fatigue

Stomatitis

Elevated ALT

Elevated AST

47

56

19

22

16

38

28

9

9

13

16

25

9

3

31

13

6

0

3

0

0

0

0

16

0

3

0

0

0

0

0

0

0

0

0

0

ALT, alanine aminotransferase; AST, asparatate aminotransferase; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer. Conlin AK et al. Clin Breast Cancer. 2010;10(4):281-287.

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBC Trastuzumab in HER2+ MBC SafetySafety

96

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCSafety: Hypersensitivity ReactionsSafety: Hypersensitivity Reactions

• Steroid premedication

– Cycle 1 for all patients treated with monthly carboplatin(N = 15)

– Five patients continued premedication in subsequent cycles

– Two patients stopped premedication for subsequent cycles without any hypersensitivity reactions

• Total of 9 hypersensitivity reactions

– Carboplatin: 5 patients (none during monthly regimen)

– Trastuzumab: 4 patients

– NAB- paclitaxel: none


97

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCSafety: Dose ReductionsSafety: Dose Reductions

• Patients with ≥ 1 dose reduction– NAB- paclitaxel: 22 (69%)– Carboplatin: 19 (59%)– Majority of dose reductions (95%) were for hematologic toxicity

(each drug)

• Patients with ≥ 1 dose delay– Dose delays occurred in 22/32 (69%) patients– Of those,18/22 (82%) were for hematologic toxicities– None for peripheral neuropathy

• Patients with ≥ 1 dose interruption– NAB- paclitaxel: 2 (9%) – Carboplatin: 2 (9%)– Trastuzumab: 6 (19%)


98

First-Line NAB- Paclitaxel, Carboplatin, and First-Line NAB- Paclitaxel, Carboplatin, and Trastuzumab in HER2+ MBCTrastuzumab in HER2+ MBCConclusionsConclusions

• Weekly NAB- paclitaxel + trastuzumab + carboplatin (weekly or monthly) is active as first-line therapy for HER2+ MBC

• Hypersensitivity reactions to weekly carboplatin, generally occurring on infusions 6-8, make monthly carboplatin dosing preferable

• This combination may be the preferred regimen for patients with HER2+ MBC who need or want to avoid premedication


99

Safety Results of Lapatinib Plus NAB- Safety Results of Lapatinib Plus NAB- Paclitaxel in Women With First- or Paclitaxel in Women With First- or

Second-Line HER2-Overexpressing Second-Line HER2-Overexpressing Metastatic Breast CancerMetastatic Breast Cancer

D.A. Yardley, R. Wholf, L. D. Bosserman, M. Saleh, D. Waterhouse, S. Lahiri,

J. M. Mahoney, Y. Nagarwala, P. Richards

Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

100

Yardley DA, et al. ASCO Breast. 2009 [Abstract 245].

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBCTreatment for HER2+ MBCBackgroundBackground

• Lapatinib is an orally active, reversible, small-molecule tyrosine kinase inhibitor of both ErbB1 (EGFR) and ErbB2 (HER2) that is approved for combination with capecitabine in patients with HER2+ MBC1

• NAB- paclitaxel was found to be more efficacious than Cremophor® EL paclitaxel in a phase III study of patients with MBC2

EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer.

1. Lapatinib [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.

2. Gradishar WJ et al, J Clin Oncol 2005;23(31):7794-7803.

101

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBC Treatment for HER2+ MBC ObjectivesObjectives

• Primary endpoint

– Overall tumor response rate (CR + PR)

• Secondary endpoints

– Progression-free survival

– Overall survival

– Duration of response

– Time to response

– Time to tumor progression

– Toxicities

CR, complete response; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PR, partial response. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

102

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBC Treatment for HER2+ MBC Key Eligibility CriteriaKey Eligibility Criteria

• Key inclusion criteria

– RECIST-defined measurable disease

– HER2 overexpressing MBC (FISH+ or IHC 3+)

– ≤ 1 prior chemotherapeutic regimen in the metastatic setting

– Prior therapy with trastuzumab in the neoadjuvant, adjuvant, or metastatic setting was permitted

– Prior endocrine therapy was permitted in the neoadjuvant, adjuvant, or metastatic setting

FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; MBC, metastatic breast cancer; RECIST, Response Evaluation Criteria in Solid Tumors. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

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NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBCTreatment for HER2+ MBCStudy Design and TreatmentStudy Design and Treatment

• A planned safety analysis was to occur after the first 10 patients completed at least 1 cycle of treatment

• As of July 31, 2009, 26 of the expected 60 patients were enrolled

HER2, human epidermal growth factor receptor 2; IV, intravenous; MBC, metastatic breast cancer; po, by mouth; qw 3/4, first 3 of 4 weeks.

a Dose reduced to lapatinib 1000 mg daily + NAB- paclitaxel 100 mg/m2 IV weekly based on safety data from the first 5 patients treated.

b Patients will be treated with NAB- paclitaxel and lapatinib for a minimum of 6 cycles; if complete response (CR) is obtained prior to 6 cycles, patient is to receive 2 additional cycles beyond CR.

Continued until disease progression or withdrawal from the study due to unacceptable

toxicity or withdrawal of consent, or lost to follow-upb

N = 60Lapatinib 1250 mg po daily + NAB- paclitaxel 125 mg/m2

IV qw 3/4a

104

aAll patients were female

Baseline characteristic (N = 26)a Value

Age in years, median (range) 56.5 (37-80)

HER2 status, n (%)

IHC 3+

FISH+

IHC 3+ and FISH+

10 (38)

8 (31)

8 (31)

First-line metastatic treatment, n (%) 20 (77)

Second-line metastatic treatment, n (%) 6 (23)

FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; MBC, metastatic breast cancer. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBCTreatment for HER2+ MBCBaseline Patient CharacteristicsBaseline Patient Characteristics

105


a Patient was being treated in the 2nd-Line MBC setting. b 2 patients were being treated in 1st-Line MBC and 1 patient in 2nd-Line MBC.

Treatment response (N = 26) n (%)

ORR (CR + PR)

CRa

PRb

4 (15)1 (4)

3 (12)

SD 8 (31)

PD 2 (8)

Unknown 12 (46)

CR, complete response; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; ORR, overall response rate, PD, progressive disease; PR, partial response; SD, stable disease.

• Of the 12 unknown patients, 11 had not yet met a time point after baseline Of the 12 unknown patients, 11 had not yet met a time point after baseline for the measurement of a responsefor the measurement of a response

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBC Treatment for HER2+ MBC Preliminary Efficacy ResultsPreliminary Efficacy Results

106

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBCTreatment for HER2+ MBCSelect Safety ResultsSelect Safety Results

• Grade 3 toxicities were observed in the first 5 patients treated with NAB- paclitaxel 125 mg/m2 and lapatinib 1250 mg

– This prompted an early protocol-specified safety analysis

– Consequently, protocol amendment and dose modification occurred for all subsequent treatments

• NAB- paclitaxel reduced to 100 mg/m2

• Lapatinib reduced to 1000 mg

• Thirty-three percent of the subsequent 21 patients treated with reduced doses demonstrated at least one grade 3 event

– No grade 4 events occurred

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

107

aDose given for AB-Pac in mg/m2 the first 3 of 4 weeks; lapatinib dose given in mg daily. bn = 5.cn = 21; numbers and percentages reflect number of patients experiencing the event.

Maximum toxicity

Adverse Event

AB-Pac/Lapatinib

dosea

Grade 1 (%)

Grade 2 (%)

Grade 3 (%)

Neutropenia125/1250b 1 (20) 0 3 (60)

100/1000c 0 2 (10) 3 (14)

Diarrhea125/1250b 2 (40) 1 (20) 2 (40)

100/1000c 7 (33) 4 (19) 4 (19)

Rash125/1250b 0 3 (60) 1 (20)

100/1000c 5 (24) 3 (14) 2 (10)

AB-Pac, NAB- paclitaxel; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer.

• No grade 4 adverse events were reported


NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBCTreatment for HER2+ MBCSelect Safety Results (cont.)Select Safety Results (cont.)

108

Adverse event occurring in > 15% of patients, n (%)

All patients (N = 26)

Dose of AB-Pac/Lap

125/1250 (n = 5)

Dose of AB-Pac/Lap

100/1000 (n = 21)

Diarrhea 20 (77) 5 (100) 15 (71)

Fatigue 13 (50) 3 (60) 10 (48)

Nausea 12 (46) 5 (100) 7 (33)

Rash 12 (46) 3 (60) 9 (43)

Anemia 9 (35) 3 (60) 6 (29)

Neutropenia 8 (31) 3 (60) 5 (24)

Anorexia 6 (23) 1 (20) 5 (24)

Pyrexia 6 (23) 2 (40) 4 (19)

Vomiting 6 (23) 4 (80) 2 (10)

Alopecia 5 (19) 2 (40) 3 (14)

Constipation 5 (19) 3 (60) 2 (10)

Dehydration 5 (19) 3 (60) 2 (10)

Peripheral neuropathy 5 (19) 2 (40) 3 (14)

AB-Pac, NAB- paclitaxel; HER2, human epidermal growth factor receptor 2; lap, lapatinib; MBC, metastatic breast cancer. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBCTreatment for HER2+ MBCSelect Safety Results (cont.)Select Safety Results (cont.)

109

NAB- Paclitaxel Plus Lapatinib as First- or Second-Line NAB- Paclitaxel Plus Lapatinib as First- or Second-Line Treatment for HER2+ MBCTreatment for HER2+ MBCConclusionsConclusions

• Grade 3 toxicities were evident with the initial doses of 125 mg/m2 NAB- paclitaxel qw 3/4 and 1250 mg lapatinib daily

• This led to a 20% dose modification for both agents to 100 mg/m2 NAB- paclitaxel qw 3/4 and 1000 mg lapatinib daily

• With the dose modification, the incidence of grade 3 events decreased from 100% in the first 5 patients to 33% in the next 21 patients

• Accrual to this trial is ongoing, with complete safety and efficacy data to be reported

HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; qw 3/4, first 3 of 4 weeks. Yardley DA et al. ASCO Breast. 2009 [Abstract 245].

110

NAB-Paclitaxel combination studies

Update from San Antonio Breast Cancer Symposium 2011

111

Phase II Study Evaluating Lapatinib in Combination With nab®-Paclitaxel in

Women Who Have Received ≤1 Chemotherapy Regimen for HER2-

Overexpressing Metastatic Breast Cancer

Denise A. Yardley, Lowell Hart, Linda Bosserman, Mansoor N. Saleh, David M. Waterhouse, Maura K. Hagan, Paul

Richards, Michelle L. DeSilvio, Janine M. Mahoney, Yasir Nagarwala

Yardley DA et al. SABCS 2011 [Poster P1-12-10].

112

Author Phase N Regimen

Green et al. (2006) II 43 nab-paclitaxel 260 mg/m2 q3w

Rizvi et al. (2008) I/II 40 nab-paclitaxel 100 / 125 / 140 mg/m2 days 1,8,15 q4w

COMBINATION STUDIES

NAB- Paclitaxel and Lapatinib in MBC with NAB- Paclitaxel and Lapatinib in MBC with HER2+ Study Design and TreatmentStudy Design and Treatment


113

Patient Population• Women with HER2-overexpressing MBC who received ≤1 prior chemotherapeutic regimen in the

metastatic setting• Prior therapy with trastuzumab in the neoadjuvant, adjuvant, or metastatic setting was permitted• Prior endocrine therapy was permitted in the neoadjuvant, adjuvant, or metastatic setting

Primary Objective• Overall tumor response rate (CR and PR) of lapatinib in nab®-paclitaxel

Secondary Objectives• Progression-free survival (PFS)• Overall survival (OS)• Duration of response (DOR)• Time to response (TTR)• Time to progression (TTP)• To determine the qualitative and quantitative toxicities combination of oral lapatinib and IV nab®-

paclitaxel


NAB- Paclitaxel and Lapatinib in MBC with NAB- Paclitaxel and Lapatinib in MBC with HER2+ Study CharacteristicsStudy Characteristics

114


NAB- Paclitaxel and Lapatinib in MBC with NAB- Paclitaxel and Lapatinib in MBC with HER2+ Patient characteristicsPatient characteristics

115


NAB- Paclitaxel and Lapatinib in MBC with NAB- Paclitaxel and Lapatinib in MBC with HER2+ ResultsResults

116

Yardley DA et al. SABCS . 2011 [Poster P1-12-10].

NAB- Paclitaxel and Lapatinib in MBC with NAB- Paclitaxel and Lapatinib in MBC with HER2+ Serious adverse events and treatment discontinuationSerious adverse events and treatment discontinuation

117

• The ORR primary endpoint of 53% compares favorably with other HER2-based combinations in this setting and warrants further exploration

• Lapatinib 1000 mg with nab®-paclitaxel 100 mg/m2 IV is feasible with manageable and predictable toxicity

• Lapatinib dose interruption or reduction was primarily due to nonhematologic toxicities.

• nab®-paclitaxel dose delays/missed doses were primarily due to nonhematologic toxicities; dose delays were primarily due to hematologic toxicities

• At the time of this presentation, there are 5 patients still on single-agent lapatinib

Yardley DA et al. SABCS . 2011 [Poster P1-12-10].

NAB- Paclitaxel and Lapatinib in MBC with NAB- Paclitaxel and Lapatinib in MBC with HER2+ ConclusionsConclusions

118

Randomized Phase 2 Trial of Weekly vs Q 2-Weekly vs Q 3-Weekly NAB- Paclitaxel

With Bevacizumab as First-Line Therapy for Metastatic Breast Cancer

AD Seidman, AK Conlin, A Bach, A Forero-Torres, G Wright, MH Hackney, A Clawson, D Schofield, J

Iglesias, and CA Hudis

Seidman AD et al. SABCS 2011 [Poster P1-14-01].

119

Purpose: multicenter, open-label, randomized, phase 2 study to evaluate antitumor activity and safety of weekly NAB-paclitaxel vs q2w vs standard q3w infusion regimens, all in combination with bevacizumab, for first-line treatment of MBC


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCStudy Design Study Design

120

Inclusion criteria• Parenchymal brain metastases• Adjuvant taxane ≤ 12 months or any chemotherapy ≤ 6 months• Congestive heart failure (New York Heart Association grade ≥ 2)• Uncontrolled hypertension, proteinuria, vascular disease, or coagulopathy

Dose Modification• NAB-Paclitaxel could be delayed or reduced for neutropenia or for grade ≥ 3

nonhematologic toxicity• The dose of NAB-paclitaxel given q3w, q2w, or qw could be reduced up to 2 times by

40, 40, or 20 mg/m2 at each dose level, respectively. • Once reduced, doses could not be re-escalated


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCMethodsMethods

121


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCPatient CharacteristicsPatient Characteristics

122


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCResults: Tumor ResponseResults: Tumor Response

123


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCResults: Time To Progression by ScheduleResults: Time To Progression by Schedule

124


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCResults: Overall Survival by ScheduleResults: Overall Survival by Schedule

125


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCTreatment Related Adverse EventsTreatment Related Adverse Events

126

• NAB-paclitaxel + bevacizumab regimens studied demonstrated antitumor activity in women with MBC

• Neutropenia, sensory neuropathy, and fatigue were the most common grade ≥ 3 treatment-emergent adverse events observed. Sensory neuropathy was a common reason for treatment discontinuation

• Weekly NAB-paclitaxel + bevacizumab led to the longest, albeit non-significant, TTP and OS. Thus, this regimen appears to have the highest therapeutic index. However, sensory neuropathy was treatment-limiting, suggesting a 3 weeks-on and 1-week-off schedule may be preferred


NAB- Paclitaxel and Bevacizumab in MBCNAB- Paclitaxel and Bevacizumab in MBCConclusionsConclusions

1 nab-paclitaxel in metastatic breast cancer combination studies

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