NAB-Paclitaxel in Metastatic Breast Cancer Combination Studies

1
NAB-Paclitaxelin Metastatic Breast
CancerCombination Studies
2
Phase II Multicenter Trial of NabPaclitaxel and
Capecitabine in First-Line Treatment of Patients
with with Metastatic Breast Cancer
Schwartzberg et al., Clin Breast Cancer. 2011 on
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3
First-Line NAB-Paclitaxel and Capecitabine in
MBCBackground

• 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

1. Talbot DC, et al. Br J Cancer.
2002861367-1372. 2. OShaughnessy, 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. 200927361-36919.
aCremophor is a registered trademark of BASF.
MBC, metastatic breast cancer.
Schwartzberg et al., Clin Breast Cancer. 2011 on
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4
First-Line NAB-Paclitaxel and Capecitabine in
MBCObjectives

• 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.
Schwartzberg et al., Clin Breast Cancer. 2011 on
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5
First-Line NAB-Paclitaxel and Capecitabine in
MBCKey Eligibility Criteria

• Inclusion criteria
• Measurable MBC by RECIST criteria
• Age gt 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
performance status MBC, metastatic breast
cancer RECIST, response evaluation criteria in
solid tumors.
Schwartzberg et al., Clin Breast Cancer. 2011 on
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6
First-Line NAB-Paclitaxel and Capecitabine in
MBCStudy Design and Treatment
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

• Endpoints
• Primary ORR
• Secondary PFS, OS, safety

bid, twice daily IV, intravenous MBC,
metastatic breast cancer q3w, every 3 weeks.
Schwartzberg et al., Clin Breast Cancer. 2011 on
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First-Line NAB-Paclitaxel and Capecitabine in
MBCPatient Characteristics
8
First-Line NAB-Paclitaxel and Capecitabine in
MBCSelect Patient Characteristics
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 gt 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)
MBC, metastatic breast cancer.
Schwartzberg et al., Clin Breast Cancer. 2011 on
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9
First-Line NAB-Paclitaxel and Capecitabine in
MBCResults 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. Note 4 of the 50 patients not evaluable for response.
CR, complete response MBC, metastatic breast
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
10
First-Line NAB-Paclitaxel and Capecitabine in
MBCResults Progression Free Survival
The red line indicates product limit estimate of
survival curve and circles indicate a censored
observation
Schwartzberg et al., Clin Breast Cancer. 2011 on
line ahead of publication
11
First-Line NAB-Paclitaxel and Capecitabine in
MBCResults Overall Survival
The red line indicates product limit estimate of
survival curve and circles indicate a censored
observation
12
First-Line NAB-Paclitaxel and Capecitabine in
MBCResults Change in target lesions
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.
Schwartzberg et al., Clin Breast Cancer. 2011 on
line ahead of publication
13
First-Line NAB-Paclitaxel and Capecitabine in
MBCResults Dose Modifications
Schwartzberg et al., Clin Breast Cancer. 2011 on
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First-Line NAB-Paclitaxel and Capecitabine in
MBCTreatment related adverse events
Frequency for all events 12 or any event grade
3. Patients may have had more than 1 adverse
event. Abbreviations ALP alkaline phosphatase
AST aspartate aminotransferase.
Schwartzberg et al., Clin Breast Cancer. 2011 on
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First-Line NAB-Paclitaxel and Capecitabine in
MBCConclusions

• 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

Schwartzberg et al., Clin Breast Cancer. 2011 on
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16
Phase II Trial of Weekly NAB- Paclitaxel in
Combination With Gemcitabine in Patients 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. 200920(3)449-453.
17
NAB- Paclitaxel Plus Gemcitabine in MBCBackground

• 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.
200523(31)7794-7803. 2. Albain KS, et al. J
Clin Oncol. 200826(24)3950-3957.
MBC, metastatic breast cancer.
Roy V et al. Ann Oncol. 200920(3)449-453.
18
NAB- Paclitaxel Plus Gemcitabine in MBCObjectives

• 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. 200920(3)449-453.
19
NAB- Paclitaxel Plus Gemcitabine in MBC Key
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.
Roy V et al. Ann Oncol. 200920(3)449-453.
20
NAB- Paclitaxel Plus Gemcitabine in MBC Study
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.
Roy V et al. Ann Oncol. 200920(3)449-453.
21
NAB- Paclitaxel Plus Gemcitabine in MBC Baseline
Patient Characteristics
Baseline characteristic (N 50) Value
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)
Number of metastatic sites, n () 1 2 3 5 (10) 15 (30) 30 (60)
a Patients may have had more than one type of prior therapy. a Patients may have had more than one type of prior therapy.
ECOG PS, Eastern Cooperative Oncology Group
performance status MBC, metastatic breast cancer.
Roy V et al. Ann Oncol. 200920(3)449-453.
22
NAB- Paclitaxel Plus Gemcitabine in MBCResults
Efficacy
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)
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.
Roy V et al. Ann Oncol. 200920(3)449-453.
23
NAB- Paclitaxel Plus Gemcitabine in MBCSafety
Grade 3/4 Adverse Events Occurring in gt 5 of
Patients
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 reported
• Fatigue 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. 200920(3)449-453.
24
NAB- Paclitaxel Plus Gemcitabine in
MBCConclusions

• 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. 200920(3)449-453.
25
NAB-Paclitaxel and Bevacizumab Treatment in
Metastatic Breast Cancer

• J. S. Link, J. R. Waisman, B. Nguyen,
• C. I. Jacobs

Link JS et al. Clin Breast Cancer.
20077(10)779-783.
26
NAB- Paclitaxel and Bevacizumab in MBCBackground

• 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. 20073572666-2676.
   
2. Desai N, et al. Clin Cancer Res.
   200612(4)1317-1324.
3. Gradishar WJ, et al. J Clin Oncol.
   200523(31)7794-7803.

MBC, metastatic breast cancer.
Link JS et al. Clin Breast Cancer.
20077(10)779-783.
27
NAB- Paclitaxel and Bevacizumab in MBCObjectives

• 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 breast
cancer ORR, overall response rate PFS,
progression-free survival PR, partial response
SD, stable disease TTP, time to tumor
progression..
Link JS et al. Clin Breast Cancer.
20077(10)779-783.
28
NAB- Paclitaxel and Bevacizumab in MBCStudy
Design

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

MBC, metastatic breast cancer q2w, every 2
weeks qw 3/4, first 3 of 4 weeks.
Link JS et al. Clin Breast Cancer.
20077(10)779-783.
29
NAB- Paclitaxel and Bevacizumab in MBCBaseline
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)

Link JS et al. Clin Breast Cancer.
20077(10)779-783.
MBC, metastatic breast cancer.
30
NAB- Paclitaxel and Bevacizumab in MBCResults
Tumor Response
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.

• Median TTP among responding patients
• q2w group (n 14) 103 days
• Weekly group (n 19) 148 days

CR, complete response MBC, metastatic breast
cancer ORR, overall response rate PR, partial
response PD, progressive disease q2w, every 2
weeks SD, stable disease TTP, time to tumor
progression.
Link JS et al. Clin Breast Cancer.
20077(10)779-783.
31
NAB- Paclitaxel and Bevacizumab in MBCResults
Most Common Adverse Events
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

MBC, metastatic breast cancer.
Link JS et al. Clin Breast Cancer.
20077(10)779-783.
32
NAB- Paclitaxel and Bevacizumab in MBCConclusions

• 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.
20077(10)779-783.
33
Phase II Trial of Weekly NAB-Paclitaxel in
Combination With Bevacizumab as First-line
Treatment in Metastatic Breast Cancer

• M. Danso, J. Blum, N. Robert,
• L. Krekow, R. Rotche, D. Smith,
• P. Richards, T. Anderson, D. Richards,
• J. OShaughnessy

Danso M et al. ASCO. 2008 Abstract 1075.
34
First-Line NAB- Paclitaxel and Bevacizumab for
MBCBackground

• 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
  lt 0.001) and overall response rate (36.9 vs.
  21.2 P lt 0.001)

1. Miller K et al. N Engl J Med.20073572666-2676
.
MBC, metastatic breast cancer.
Danso M et al. ASCO. 2008 Abstract 1075.
35
First-Line NAB- Paclitaxel and Bevacizumab for
MBCObjectives

• 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 MBC,
metastatic breast cancer ORR, overall response
rate PFS, progression-free survival PR, partial
response RECIST, Response Evaluation Criteria In
Solid Tumors. SD, stable disease.
Danso M et al. ASCO. 2008 Abstract 1075.
36
First-Line NAB- Paclitaxel and Bevacizumab for
MBCStudy 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
q2w, every 2 weeks q3w, every 3 weeks.
Danso M et al. ASCO. 2008 Abstract 1075.
37
First-Line NAB- Paclitaxel and Bevacizumab for
MBCBaseline Patient Characteristics
Baseline characteristic (N 50) Value
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. a Patients may have had more than one type of prior therapy.
ECOG PS, Eastern Cooperative Oncology Group
performance status MBC, metastatic breast cancer.
Danso M et al. ASCO. 2008 Abstract 1075.
38
First-Line NAB- Paclitaxel and Bevacizumab for
MBCResults Efficacy
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. A 45 of 50 patients were evaluable for response.
CI, confidence interval CR, complete response
MBC, metastatic breast cancer ORR, overall
response rate PFS, progression-free survival
PR, partial response SD, stable disease.
Danso M et al. ASCO. 2008 Abstract 1075.
39
First-Line NAB- Paclitaxel and Bevacizumab for
MBCSafety Grade 3/4 Hematologic AEs in 5 of
Patients
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

AE, adverse event MBC, metastatic breast cancer
SD, standard deviation.
Danso M et al. ASCO. 2008 Abstract 1075.
40
First-Line NAB- Paclitaxel and Bevacizumab for
MBCSafety Nonhematologic AEs in 10 of
patients

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

AE, adverse event MBC, metastatic breast cancer.
Danso M et al. ASCO. 2008 Abstract 1075.
41
First-Line NAB- Paclitaxel and Bevacizumab for
MBCConclusions

• 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
• lt 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.
Danso M et al. ASCO. 2008 Abstract 1075.
42
Randomized Phase II Trial of NAB- Paclitaxel in 3
Dosing Schedules With Bevacizumab as First-line
Therapy for HER2- 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- MBCBackground

• 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

• Gradishar WJ, et al. J Clin Oncol.
  200523(31)7794-7803.2. Seidman AD, et al. J
  Clin Oncol. 200826(10)1642-1649.3. Citron ML,
  et al. J Clin Oncol. 200321(8)1431-1439.4.
  Miller K, et al. N Eng J Med. 20073572666-2676.
  5. Volk LD, et al. Neoplasia.
• 200810(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- MBCObjectives

• 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- MBCKey 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 lt 12 months or any chemotherapy lt
  6 months prior to study enrollment
• Peripheral neuropathy gt 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
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCStudy Design
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.
Conlin AK, et al. ASCO. 2009 Abstract 1006.
47
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCBaseline Patient Characteristics
Baseline characteristic (N 205) AB-paclitaxel Dose AB-paclitaxel Dose AB-paclitaxel Dose
Baseline characteristic (N 205) 260 mg/m2 q3w (n 73) 260 mg/m2 q2w (n 54) 130 mg/m2 qw (n 78)
Median age, years (range) lt 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.
Conlin AK et al. ASCO. 2009 Abstract 1006.
48
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCPreplanned Dose Reductions
Dose level AB-paclitaxel Dose AB-paclitaxel Dose AB-paclitaxel Dose
Dose level 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 toxicities

AB, NAB- HER2, human epidermal growth factor
receptor 2 MBC, metastatic breast cancer qw,
weekly q2w, every 2 weeks q3w, every 3 weeks.
Conlin AK et al. ASCO. 2009 Abstract 1006.
49
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCResults Dose Parameters
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- paclitaxel MBC, metastatic breast
cancer qw, weekly q2w, every 2 weeks q3w,
every 3 weeks HER2, human epidermal growth
factor receptor 2.
Conlin AK et al. ASCO. 2009 Abstract 1006.
50
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCResults Adverse Events
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 reported Grade 3 Grade 4 Grade 5 42 (58) 9 (12) 1 (1)a 39 (72) 5 (9) 1 (2)a 52 (67) 11 (14) 0
Sensory neuropathy Grade 2 Grade 3 Grade 4 20 (27) 22 (30) 0 8 (15) 25 (46) 1 (2) 18 (23) 30 (38) 1 (1)
Febrile neutropenia Grade 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. 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. 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. 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- 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.
Conlin AK et al. ASCO. 2009 Abstract 1006.
51
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCResults Adverse Events (cont.)
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 2 Grade 3 9 (12) 4 (5) 9 (17) 1 (2) 1 (1) 0 Overall lt .001
Myalgia Grade 2 Grade 3 6 (8) 0 2 (4) 3 (6) 0 0 Overall NS B vs. C .021
Bone pain Grade 2 Grade 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 2 Grade 3 2 (3) 0 2 (4) 3 (6) 10 (13) 7 (9) Overall .001 A vs. C lt .001
Note Adverse events graded on National Cancer
Institute Common Toxicity Criteria (NCI-CTC)
version 3.0. P-values based on Cochran-Mantel-Haen
szel test.
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.
Conlin AK et al. ASCO. 2009 Abstract 1006.
52
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCResults Sensory Neuropathy

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

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.
Conlin AK et al. ASCO. 2009 Abstract 1006.
53
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- Metastatic Breast CancerResults
Improvement in Sensory Neuropathy
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)
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
HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer qw, weekly q2w,
every 2 weeks q3w, every 3 weeks.
Conlin AK et al. ASCO. 2009 Abstract 1006.
54
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- Metastatic Breast CancerResults Confirmed
Overall Response Rate
Response AB-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)
a Overall ORR P value 0.575.

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

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.
Conlin AK et al. ASCO. 2009 Abstract 1006.
55
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- Metastatic Breast CancerResults Time to
Tumor Progression

• 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.
56
First-Line NAB- Paclitaxel and Bevacizumab in
HER2- MBCConclusions

• 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 NAB-
Paclitaxel, Bevacizumab, and Gemcitabine as
First-Line Therapy for Patients With HER2-
Metastatic Breast Cancer

• 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.
2010123(2)427-435.
58
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast
CancerBackground

• 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
200523(31)7794-7803. 2. Albain KS et al. J
Clin Oncol. 26(24)3950-3957. 3. Miller K et al.
N Engl J Med. 20073572666-2676.
HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer TTP, time to tumor
progression.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
59
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast
CancerObjective

• 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.
2010123(2)427-435.
60
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Key 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 gt 3 months
• Adequate laboratory values

HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
61
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast
CancerStudy 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.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
62
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Baseline 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 gt 10 Median (range) 1 (3.4) 8 (27.6) 15 (51.7) 5 (17.2) 6.5 (1.5-23)
HER2, human epidermal growth factor receptor 2.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
63
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Results Efficacy
Best patient response All 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. aNegative for the expression of estrogen receptor, progesterone receptor, and HER2. aNegative for the expression of estrogen receptor, progesterone receptor, and HER2.

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

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.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
64
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2 Metastatic Breast
CancerResults Progression-Free Survival
CI, confidence interval HER2, human epidermal
growth factor receptor 2.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
65
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Results Overall Survival

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

CI, confidence interval HER2, human epidermal
growth factor receptor 2.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
66
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Results Progression-Free Survival in Select
Subgroups

• 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.
2010123(2)427-435.
67
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast Cancer
Select Safety Results Grade 2 AEs Reported in gt
2 Patients
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)
aGrade 3 event reported in 1 patient (3.4).
AE, adverse event HER2, human epidermal growth
factor receptor 2.
Lobo C et al. Breast Cancer Res Treat.
2010123(2)427-435.
68
First-Line NAB- Paclitaxel, Bevacizumab, and
Gemcitabine in HER2- Metastatic Breast
CancerConclusions

• 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.
2010123(2)427-435.
69
SPARC, EGFR, and VEGFR Expression May Predict
Response to NAB- Paclitaxel / Carboplatin /
Bevacizumab Chemotherapy in Triple Negative
Metastatic 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
SPARC in NAB- Paclitaxel- / Carboplatin- /
Bevacizumab-Treated TNMBC PatientsBackground

• 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

ER, estrogen receptor HER2, human epidermal
growth factor 2 PR, progesterone receptor TNBC,
triple-negative breast cancer TNMBC,
triple-negative metastatic breast cancer.
1. Liedtke C et al. J Clin Oncol.
200828(8)1275-1281. 2. Bauer KR et al. Cancer.
2007109(9)1721-1728. 3. Anders C and Carey LA.
Oncology (Williston Park). 200822(11)1233-1243.
Hamilton E et al. ASCO. 2010 Abstract 1109.
71
SPARC in NAB- Paclitaxel- / Carboplatin- /
Bevacizumab-Treated TNMBC PatientsBackground
(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. 200868989-997.
2. Hawkins MJ et al. Adv Drug Deliv Rev.
200860876-885.
TNMBC, triple-negative metastatic breast cancer.
Hamilton E et al. ASCO. 2010 Abstract 1109.
72
Marker Prediction of TNMBC Patient Response to
NAB- Paclitaxel/Carboplatin/BevacizumabBackground
(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- Paclitaxel/Carboplatin/BevacizumabObjectives

• 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- Paclitaxel/Carboplatin/BevacizumabKey
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- Paclitaxel/Carboplatin/BevacizumabStudy
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.
76
Marker Prediction of TNMBC Patient Response to
NAB- Paclitaxel/Carboplatin/BevacizumabBaseline
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)
Number of metastatic sites, n () 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.
Hamilton E et al. ASCO. 2010 Abstract 1109.
77
Marker Prediction of TNMBC Patient Response to
NAB- Paclitaxel/Carboplatin/BevacizumabResults
Preliminary Response and Survival
Outcome (N 27)a n ()
ORR CR PR 24 (89) 4 (14) 20 (69)
SD 2 (7)
PD 1
a 2 of 29 patients were not evaluable. a 2 of 29 patients were not evaluable.

• 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.
78
Marker Prediction of TNMBC Patient Response to
NAB- Paclitaxel/Carboplatin/BevacizumabResults
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- Paclitaxel/Carboplatin/BevacizumabSafety
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. a Nausea, vomiting, mucositis, diarrhea, constipation. a Nausea, vomiting, mucositis, diarrhea, constipation. a Nausea, vomiting, mucositis, diarrhea, constipation.
TNMBC, triple-negative breast cancer.
Hamilton E et al. ASCO. 2010 Abstract 1109.
80
Marker Prediction of TNMBC Patient Response to
NAB- Paclitaxel/Carboplatin/BevacizumabConclusion
s

• 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-Paclitaxelin Metastatic Breast
CancerCombination Studies

• HER2 patients

82
NAB- Paclitaxel Combination Studies in MBC
Trial Description Phase
HER2 Patients HER2 Patients
NAB- paclitaxel carboplatin trastuzumab in HER2 MBC1 II
NAB- paclitaxel lapatinib as first- or second-line treatment for HER2 MBC2 II

1. Conlin AK et al. Clin Breast Cancer.
   201010(4)281-287.
2. Yardley DA et al. ASCO Breast. 2009 Abstract
   245.

HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer.
83
NAB- Paclitaxel Combination Studies in MBC
Trial Description Phase Main Idea
HER2 Patients 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. Conlin AK et al. Clin Breast Cancer.
   201010(4)281-287.
2. Yardley DA et al. ASCO Breast. 2009 Abstract
   245.

HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer.
84
Phase II Trial of Weekly NAB- Paclitaxel With
Carboplatin and Trastuzumab as First-Line Therapy
for Women With HER2-Overexpressing Metastatic
Breast Cancer

• K. Conlin, A. D. Seidman, A. Bach, D. Lake,
• M. Dickler, G. DAndrea, T. Traina, M. Danso,
• A. M. Brufsky, M. Saleh, A. Clawson, C. A. Hudis

Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
85
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCBackground

• 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.
200826(10)1642-1649. 2. Robert N et al. J Clin
Oncol. 200624(18)2786-2792. 3. Perez EA et al.
Clin Breast Cancer. 20056(5)425-432. 4.
Gradishar WJ et al. J Clin Oncol.
200925(22)3611-3619.
HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer q3w, every 3 weeks.
Conlin AK, et al. Clin Breast Cancer.
201010(4)281-287.
86
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCObjectives

• 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.
201010(4)281-287.
87
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCKey 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.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
88
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCKey Eligibility Criteria
(cont.)

• Key exclusion criteria
• Prior chemotherapy for MBC
• lt 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.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
89
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCOriginal Phase II Schema
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.
201010(4)281-287.
90
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCRevised Phase II Schema
AUC, area under the curve HER2, human epidermal
growth factor receptor2 MBC, metastatic breast
cancer wk, week.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
91
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCBaseline Patient
Characteristics
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)

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.
201010(4)281-287.
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First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBC Results
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)

• 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

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.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
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First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBC Results Response by
Regimen
Response by regimen n ()
Original regimen only (n 17) 11 (65)
Revised regimen only (n 12) 8 (67)
Original revised (n 3) 1 (33)
HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
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First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCResults 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

HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
95
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBC Safety
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
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.
ALT, alanine aminotransferase AST, asparatate
aminotransferase HER2, human epidermal growth
factor receptor 2 MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
96
First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCSafety 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

HER2, human epidermal growth factor receptor 2
MBC, metastatic breast cancer.
Conlin AK et al. Clin Breast Cancer.
201010(4)281-287.
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First-Line NAB- Paclitaxel, Carboplatin, and
Trastuzumab in HER2 MBCSafety Dose Reductions

• Patients with 1 dose reduction
• NAB- paclitaxel 22 (69)
• Car