Transcript ASCO 2012: Breast Cancer Updates

ASCO 2012:
Breast Cancer Updates
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
UCSF Helen Diller Family Comprehensive Cancer Center
Outline
• What’s new in the treatment of HER2 positive
metastatic breast cancer?
– Emilia - TDM1 compared to lapatinib/capecitabine
• Blackwell et al, #LBA1
– MA.31 - Is lapatinib as good or better than trastuzumab?
• Gelmon et al, #LBA671
– NSABP B-41 – lapatinib as neoadjuvant therapy
• Robidoux et al, #LBA506
• Do bisphosphonates improve breast cancer outcome?
– MA.27 – Impact of osteoporosis and osteoporosis therapy
• Sheperd et al, #501
– AZURE – impact in postmenopausal women
• Marshal, Coleman et al, #502
Outline (2)
• DCIS
– RTOG 9804 - does everyone with DCIS need radiation?
• McCormick et al, #1004
• Evaluating chemotherapy combinations, doses
– NSABP B-38 – adding gemcitabine, sequential versus
combination chemotherapy in early stage disease?
• Swain et al, #LBA1000
– CALGB 40502 – comparing microtubule toxins in the
metastatic setting
• Rugo et al, #CRA1002
– What is the role of maintenance chemotherapy for
patients with metastatic disease?
• Im et al, #1003
– Can we target the androgen receptor in TNBC?
• Gucalp et al, #1006
HER2 Positive MBC
• The problem
– Despite high response rates, almost all patients
eventually develop progressive disease
• How can we overcome resistance that we don’t
understand?
• Data before pertuzumab and T-DM1:
– Start with trastuzumab + chemotherapy/hormone rx
– Continue HER2 directed therapy through progression
• Capecitabine/lapatinib > capecitabine (Geyer et al)
• Capecitabine/trastuzumab > capecitabine (von Minckwitz et al)
• Lapatinib/trastuzumab > lapatinib (Blackwell et al)
T-DM1: Dual Mechanisms of Action
Combined Targeted Therapy
Trastuzumab
Biologic Activity
• Blocks downstream HER2
signaling to inhibit
proliferation of tumor cells
• Flags HER2-positive tumor
cells for destruction via
antibody-dependent cellmediated cytotoxicity
• Inhibits HER2 shedding
aDM1
is 25–500 fold more potent than taxane in cytotoxic assays.
Targeted Intracellular
Delivery of DM1a
• T-DM1 binds to the HER2
receptor and is internalized
• DM1 is released inside the
cell, resulting in mitotic arrest
and apoptosis
• Systemic toxicity is limited
due to low HER2 expression
in normal tissues
T-DM1 selectively delivers DM1 to
HER2-positive tumor cells
• Targeted intracellular delivery of a potent antimicrotubule
agent, DM1
T-DM1 binds to the HER2 protein
• Spares normal tissue from toxicity of free
DM1
on cancer cells
HER2 to HER2
• Trastuzumab-like activity by binding
Receptor-T-DM1 complex is
internalized into HER2-positive
cancer cell
Potent antimicrotubule
agent is released once inside
the HER2-positive
tumor cell
Phase II Randomized International
Open Label Studyb
Trastuzumab
HER2-positive,
recurrent locally
advanced breast
cancer or MBC
(N=137)
First line setting
8 mg/kg loading dose;
6 mg/kg q3w IV
1:1
PDa
+ Docetaxel
75 or 100 mg/m2 q3w
Crossover to
T-DM1
(optional)
(n=70)
T-DM1
3.6 mg/kg q3w IV
PDa
(n=67)
•
Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval
•
Primary end points: PFS by investigator assessment, and safety
•
Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover
•
Key secondary end points: OS, ORR, DOR, CBR, and QOL
•
Demographics imbalanced: 29 vs 34 % stage IV at diagnosis, 27 vs 18% exposed to prior
trastuzumab, 40 vs 33% exposed to prior taxanes
aPatients
were treated until PD or unacceptable toxicity.
was a hypothesis generating study; the final PFS analysis was to take place after
72 events had occurred.
bThis
Hurvitz et al, ESMO 2011
PFS by Investigator
Proportion progression-free
1.0
Median
PFS, mos
N=137
Trastuzumab
+ docetaxel (n=70) 9.2
T-DM1
(n=67) 14.2
0.8
Hazard
ratio 95% CI
0.594
0.364–
0.968
Log-rank
P value
0.0353
0.6
0.4
Crossover allowed to TDM1
Significantly less toxicity
with TDM1, better patient
reported outcomes
0.2
0.0
0
2
4
Number of patients at risk
T+D 70
66
63
T-DM1 67
60
51
6
8
10
Time (months)
12
14
16
18
20
53
46
43
42
12
22
4
15
2
6
2
3
0
0
Hazard ratio and log-rank P value were from stratified analysis.
27
35
Hurvitz SA, et al. Abstract 5.001. ESMO 2011.
Clinical Rationale for EMILIA
• T-DM1
– Two single-arm phase 2 trials in patients who received ≥1
HER2-directed therapies for MBC
– ORR: 25.9% (N=112)1 and 34.5% (N=110)2
• Capecitabine + lapatinib
– Randomized phase 3 trial in patients who received prior
trastuzumab
– Median TTP longer with capecitabine + lapatinib (n=163)
vs. capecitabine (n=161), no difference in OS
– 8.4 vs. 4.4 months (HR=0.49; P<0.001)4
1Burris
HA, et al. J Clin Oncol 2011; 2Krop I, et al. J Clin Oncol 2012;
3Hurvitz S, et al. ESMO 2011; 4Geyer CE, et al. N Engl J Med 2006.
EMILIA Study Design
HER2+ (central)
LABC or MBC
(N=980)
•Prior taxane and
trastuzumab
T-DM1
3.6 mg/kg q3w IV
PD
1:1
•Progression on
metastatic tx or
within 6 mos of
adjuvant tx
Capecitabine
1000 mg/m2 orally bid, days 1–14, q3w
+
Lapatinib
PD
1250 mg/day orally qd
• Stratification factors: World region, number of prior chemo regimens for
MBC or unresectable LABC, presence of visceral disease
• Primary end points: PFS by independent review, OS, and safety
• Key secondary end points: PFS by investigator, ORR, duration of
response, time to symptom progression
Blackwell et al, ASCO 2011
EMILIA - Demographics
• 496 vs 495 randomized
• Median age 53, 27% from U.S.
• Prior therapy
– All treated with prior taxane
– 16% received prior trastuzumab for early stage
disease
– 57% received at least one year of prior
trastuzumab, 88% prior treatment for MBC
– 79% measurable disease, 53-57% HR+
Progression-Free Survival
by Independent Review
Median (mos)
No. events
Cap + Lap
6.4
304
T-DM1
9.6
265
Stratified HR=0.650 (95% CI, 0.55, 0.77)
P<0.0001
Subroup analysis:
TDM1 superior regardless of line of
therapy (1-3) and HR status
No. at risk by independent review:
Cap + Lap 496
404
310
176
129
73
53
35
25
14
9
8
5
1
0
0
T-DM1
183
130
101
72
54
44
30
18
9
3
1
0
495
419
341
236
Unstratified HR=0.66 (P<0.0001).
Overall Survival: Interim Analysis
Unstratified HR=0.63 (P=0.0005).
NR=not reached.
Objective Response Rate (ORR) and Duration of
Response (DOR) in Patients with Measurable Disease
ORR
DOR
Overview of Adverse Events
Cap + Lap
(n=488)
T-DM1
(n=490)
All-grade AE, n (%)
477 (97.7)
470 (95.9)
Grade ≥3 AE, n (%)
278 (57.0)
200 (40.8)
52 (10.7)
29 (5.9)
5 (1.0)
1 (0.2)
7 (1.6)
8 (1.7)
AEs leading to treatment discontinuation
(for any study drug), n (%)
AEs leading to death on treatment, n (%)
a
LVEF <50% and ≥15-point decrease from
b
baseline, %
aCap
+ Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS;
aT-DM1: metabolic encephalopathy.
bEvaluable pts: 445 (Cap + Lap); 481 (T-DM1).
• Cap and Lap: More grade 3 diarrhea (21 vs 1.6%), hand foot syndrome (16 vs 0%)
• TDM1: More transaminiitis (4 vs 1%), grade 3/4 thrombocytopenia (13 vs 0%)
Summary and Ongoing Trials
• T-DM1 superior to cap/lap
– PFS, interim OS, response, safety
– Will clearly be a new standard in this setting
– Approval expected towards the end of 2012
• Marianne (n=1092, untreated HER2+ MBC)
– Three arms
• Trastuzumab + taxane
• TDM1 + pertuzumab
• TDM1 plus placebo
• Th3RESA (n=795)
– Prior trastuzumab/lapatinib/anthra/taxane/cape
– 2:1 randomization to TDM1 v TPC
Early Stage Trials
• Post-neoadjuvant cooperative group
• Neoadjuvant company sponsored
• Adjuvant small tumors: ATTEMPT Trial
Stage I BC
HER2+
N=500
Randomize
3:1
– Tolaney PI (DFCI)
3
1
Trastuzumab emtansine q 3 weeks x 17
N=375
Paclitaxel + Trastuzumab weekly x 12
Trastuzumab every 3 weeks x 13
N=125
Two Questions
• Can lapatinib overcome trastuzumab
resistance?
– Doesn’t require externalized receptor
– Can this agent overcome resistance mediated
by alterations of the PI3K pathway?
• Can dual targeting of the HER2 Receptor
overcome resistance more effectively?
– Maintains benefits of trastuzumab while
targeting the pathway through an alternate
mechansim
Trastuzumab
T
1
1
2
2
1
2
L
L
L
L
L
L
Downstream signaling pathways
Cell proliferation
Cell survival
Lapatinib
MA.31/ EGF108919: Metastatic Disease
Randomize
EXPERIMENTAL ARM
24 Weeks:
Lapatinib
plus
Taxane
Until PD:
Lapatinib
STANDARD ARM
24 Weeks:
Until PD:
Trastuzumab
plus
Trastuzumab
Taxane
Primary Outcome: PFS
Sample Size: ~ 600 (536 centrally confirmed HER2+ patients)
Gelmon et al, LBA671, ASCO 2012
Progression Free Survival
Centrally-confirmed HER2+ Analysis
Median PFS TTAX/T= 13.7 months
Median PFS LTAX/L = 9.0 months
HR = 1.48 (95% CI = 1.15 – 1.92), P = 0.003
TTAX/T
LTAX/L
TTAX/T
LTAX/L
Serious Adverse Events
LTAX/L
(Total SAE reports = 136)
EVENT
TTAX/T
(Total SAE reports = 78)
Total
Number*
Number post
amendment **
EVENT
Total
Number*
Number post
amendment **
Diarrhea
32
25
Diarrhea
5
3
Febrile
Neutropenia
17
7
Febrile
Neutropenia
7
6
** Protocol Amendment after first 189 patients were randomized mandated
*primary
IncludedGCSF
as oneprophylaxis
of the adverse
terms
a single
report
for event
patients
onwithin
docetaxel
andSAE
lapatinib
• Discontinuation rates significantly higher for lapatinib arm
Gelmon et al, LBA671, ASCO 2012
Neo-Altto
GeparQuinto
(N=455)
(N=615)
Baselga J et al. Lancet 2012
Untch M et al. Lancet Oncology 2012
Pertuzumab + trastuzumab: improved pCR
(NeoSphere, Tryphaena)
NSABP B-41
Schema (n=529)
Tissue for
Biomarkers
Tissue for
Biomarkers
Operable
Breast
Cancer
HER-2 neu
Positive
T > 2 cm
AC→ WP + T
R
AC→ WP +
L1250
AC→ WP + T
+ L 750
WP=Weekly Paclitaxel
S
U
R Trastuzumab
for a total of
G
1 year
E
R
Y
Endpoints: pCR, cardiac events, DFS, OS
WP: d 1, 8, 15 q 28 d x 4
Robidoux et al, #LBA506
Results
• pCR breast
– 53% (T) vs 53% (L)vs 62% (TL) (P 0.095 for TL vs T)
• pCR breast and nodes
– 49% (T) vs 47% (L) vs 60% (TL) (p=0.056 TL vs T)
• pCR based on HER2 (IHC 3+, n=421, 81%)
– 55% (T) vs 53% (L) vs 71% (TL) (p=0.006 TL vs T)
• Completion of protocol defined neoadjuvant Rx
– 78% (T) vs 68% (L) vs 63% (TL) (p=0.01)
• Toxicity similar except diarrhea and overall
– Grade 3: 2% (T) vs 20% (L) vs 27% (TL) (p<0.001)
ALTTO
Paclitaxel weekly or TCH
Surgery
Lapatinib
Closed due to futility
+/Anthracycline
containing
CT
Trastuzumab
Lapatinib
Lapatinib
Trastuzumab
Trastuzumab
1 year
Clinical Context
• What does this data mean to our clinical practice?
– TDM-1 is a new and effective treatment for HER2+ metastatic
disease progressing on trastuzumab
– Toxicities are unique but generally well tolerated
– Likely to be FDA approved by the end of the year
• Pertuzumab approved in the first-line setting in
combination with trastuzumab/docetaxel (PFS 18.5 mo.)
• Lapatinib is associated with more toxicity and less efficacy
than trastuzumab in the first-line metastatic setting
• Lapatinib/capecitabine is still an option for later line therapy
or in special settings (low EF (?), brain metastases)
Pertuzumab/
Trastuzumab/
Taxane
Pertuzumab/
Trastuzumab
TDM-1
Lapatinib/
Capecitabine
Multiple drugs in clinical trials: inhibitors of mTOR, HSP90, TKs, vaccines
?
Osteoporosis
• Osteoporosis is characterized
by decreased bone mineral
density.
• The increased bone resorption
associated with osteoporosis
may provide fertile “soil” for
cancer growth.
• Will osteoporosis or therapy
for osteoporosis affect
outcome in patients with early
stage breast cancer?
Observational Studies of Bisphosphonate Use
and Breast Cancer Incidence
Author
Study
Design
Patient Cases
Control Subjects
(% bisphosphonate)
(% bisphosphonate)
Breast
Cancer
Association
Rennert
Casecontrol
1822 (10.5%)
2207 (14.8%)
OR 0.72
(0.57-0.90)
Newcomb
Casecontrol
2336 (4.4%)
2975 (6.2%)
OR 0.67
(0.51-0.89)
Chlebowski Cohort
154, 768 women, 2816 (1.8%)
bisphosphonate users, 5,092 breast
cancer cases
Rennert G, Pinchev M, Rennert HS JCO, 2010 June 12 Epub ahead of print
Newcomb PA, Trentham-Dietz A, Hampton JM Bristish J of Cancer 2010;102:799-802
Chlebowski RT, Chen Z, Cauley JA, et al JCO 2010 June 12 Epub ahead of print
HR 0.68
(0.52-0.88)
• Osteoporosis: 17% (1294)
• Osteoporosis therapy: 36% (2711)
– 116 (0.2%) took raloxifene prior to study
– 39 started after randomization
• Of those with osteoporosis
– 85% (1101) took osteoporosis therapy
• Of those taking osteoporosis therapy
– 25.6% (1610) did not report osteoporosis
Shepherd LE et al, ASCO 2012, #501
EFS by Osteoporosis Therapy
HR (Yes/No) = 0.70
p<.00001
Shepherd LE et al, ASCO 2012, #501
Conclusions
• Patients with self-reported osteoporosis and
osteoporosis therapy had a lower incidence
of breast cancer relapse
• Patients receiving osteoporosis therapy,
regardless of report of osteoporosis, had a
lower incidence of relapse
• Limitations
– Self reporting
– Variations in osteoporosis therapy and duration
– Event rate (9.2%) and distant relapse rate low
(4.1%)
The seed and soil hypothesis
'While many researchers have been studying
‘the seed’, the properties of ‘the soil’ may
reveal valuable insights into the ‘metastatic
peculiarities’ in cancer cases.'
The Distribution of Secondary
Growths in Cancer of the Breast.
The Lancet. 1889
Stephen Paget
1855–1926
AZURE: Study Design
Accrual September 2003 - February 2006
Standard therapy
3,360
Breast Cancer
Patients
R
Stage II/III
Standard therapy +
Zoledronic acid 4 mg
No difference in
disease free or
invasive disease free
survival (IDFS)
6 doses
Q3-4 weeks
Months
6
8 doses
Q 3 months
5 doses
Q 6 months
30
Zoledronic acid treatment duration 5 years
Coleman et al. N Engl J Med 2011; 365:1396-1405
60
AZURE: Invasive DFS and OS by
Menopausal Status
IDFS: Pre, Peri, and Unknown Menopause
IDFS: > 5 Yrs Postmenopausal
1.0
Proportion Alive and
invasive Disease Free
Proportion Alive and
invasive Disease Free
1.0
0.8
Adjusted HR: 1.15
0.6
(95% CI: 0.97-1.36; P = .11)
288 vs 256 events
0.4
Pts at Risk, n
ZOL:
0.2 1162 1088 996
919
829
393
57
0
No ZOL:
1156 1092
920
853
388
47
0
0
0
995
0.8
0.6
0.4
0.2
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Adjusted HR: 0.75
(95% CI: 0.59-0.96; P = .02)
116 vs 147 events
Pts at Risk, n
ZOL:
519
490
No ZOL:
522
482
0
Time From Randomization (Mos)
0.8
Proportion Alive
Proportion Alive
0.8
Adjusted HR: 0.97
(95% CI: 0.78-1.21; P = .81)
161 vs 165 events
0.4
Pts at Risk, n
ZOL:
0
1076
1032
25
0
431
396
368
156
21
0
OS: > 5 Yrs Postmenopausal
1.0
0
177
N=1041
1.0
No ZOL:
1156 1123
393
Time From Randomization (Mos)
OS: Pre, Peri, and Unknown Menopause
0.2 1162 1131 1078 1020
418
6 12 18 24 30 36 42 48 54 60 66 72 78 84
N=2318
0.6
447
955
466
71
0
963
446
60
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Time From Randomization (Mos)
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.
0.6
0.4
0.2
0
Adjusted HR: 0.74
(95% CI: 0.55-0.98; P = .04)
82 vs 111 events
Pts at Risk, n
ZOL:
519
502
No ZOL:
522
509
0
482
448
422
190
29
0
475
441
401
177
26
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Time From Randomization (Mos)
Treatment Effects on First IDFS Recurrence
Outside Bone by Menopausal Status
Menopausal Group
Odds Ratio
Pre, Peri and unknown
menopause
HR: 1.32 (95% CI: 1.09-1.59)
> 5 yrs postmenopause
HR: 0.70 (95% CI: 0.54-0.92)
TOTAL: 6% +/- 8
Z = .79, P = .43
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
21 (heterogeneity) = 14.00; P = < .001
for imbalances
in ER, lymphin
node
status,
and T stage. by menopausal status or age
NoAdjusted
significant
differences
bone
recurrence
SABCS 2011
Conclusions
• In this population of patients, primarily treated with
adjuvant chemotherapy
– No effect of zoledronate on breast cancer outcome in the
unselected overall population
– Suggestion of improved outcome in pts with >5 years of
menopause, due to recurrence outside bone
• Unplanned subset analysis of interest but not sufficient to
influence patient care
– Variable results in 7 published trials
– Bisphosphonates should be used to prevent or treat bone loss in
patients with breast cancer
– Bisphosphonates should not be used only for the purpose of
preventing breast cancer recurrence
• Ongoing studies are evaluating the impact of denosumab
on breast cancer outcome in women with early stage
disease
– D-Care, ABCSG-18
– UCSF phase II trial in pts with DTCs
RTOG 9804: Does Good Risk DCIS
Always Need Radiation?
• Common disease, low long-term risk
• Primary goal of treatment is to prevent
invasive IBTR
• Clearly variable risk exist based on biology,
age, extent of disease
• We have transitioned from mastectomy to
lumpectomy and radiation with essentially
equivalent outcomes
– Does everyone need radiation?
McCormick et al, #1004
RTOG 9804: Eligibility and Schema
No palpable mass, low or intermediate grade, < 2.5 cm, margins > 3 mm
Age
1. < 50
2 ≥ 50
Final Path Margins
1. Negative (re-excision)
2. 3-9 mm
3.  10 mm
Mammographic/Pathologic
Size of Primary
1. ≤ 1 cm
2. > 1 cm to ≤ 2.5 cm
Nuclei Grade
1. Low
2. Intermediate
Tamoxifen Use
1. No
2. Yes
N=585
Arm 1
Observation ±
tamoxifen, 20 mg per
day for 5 years
Arm 2
Radiation therapy to
McCormick et al, #1004
the whole breast, ±
tamoxifen, 20 mg per
day for 5 years
Results at 5 years
• Local failure in
ipsilateral breast
• 3.2 vs 0.4%
• HR 0.14, p=0.0022
• 15 vs 2 events
• DFS
• Identical
• HR 0.84, p=0.48
Summary
• In patients with good risk DCIS, the addition
of radiation
– Added little to local control
– Added nothing to survival
• Use of genomic tests, such as the GH DCIS
score, may help refine treatment decisions
• Longer follow-up of this trial will be
interesting.
NSABP B-38 Schema
(n=4894, med FU 5.3 yrs)
Stratification: # nodes, HR status + or neg, Surgery and RT
TAC q 3 wk
All arms
pegfilgrastim or
filgrastim
AC q 2 wk
P q 2 wk
AC q 2 wk
PG q2 wk
N+
Swain et al, LBA#1000
ER positive:
hormonal
therapy for 5 yrs
after chemo
80% ER+
65% 1-3+ nodes
P = paclitaxel 175 mg/m2
G = gemcitabine 1000 mg/m2
0.8
0.2
0.6
0.4
Treat
TAC
1610 327
ACP 1618 294
ACPG 1613 320
N
Events
P-value* (vs ACPG)
0.410
0.388
0.0
Disease-Free Survival
1.0
NSABP B-38
Disease-Free Survival
0
1
1532
1554
1533
3
4
Years since Randomization
# at risk
1610
1618
1613
2
1424
1452
1453
1331
1348
1350
* Stratified log-rank test adjusting for randomization factors
1217
1240
1244
719
754
730
5
Survival, Toxicity and Conclusions
• Overall survival no different between arms
• More deaths on treatment in the TAC arm than
AC/P or AC/PG (13/5/7, p=0.2)
• Addition of gemcitabine did not improve outcome
• DD AC/P similar to TAC
– More FN, anemia, diarrhea, less neuropathy with TAC
• This trial started in 2004 and completed accrual in
2007
– About 10 years from initial planning to negative results
– We can no longer do large trials testing therapy based
solely on extent of disease
CALGB 40502 - NCCTG N063H - CTSU 40502
An Open Label Phase III Trial of Firstline Therapy
for Locally Recurrent
or Metastatic
Breast Cancer
Exp 1
N = 900
(planned)
Strata:
Adj taxanes
ER/PR status
1
nab-paclitaxel 150 mg/m2 weekly +
bevacizumab 10 mg/kg q 2 wks2
mg/m2
weekly +
Control paclitaxel 90
bevacizumab 10 mg/kg q 2 wks1
Exp 2
ixabepilone 16 mg/m2 weekly +
bevacizumab 10 mg/kg q 2 wks3
Restage q 2
cycles until
disease
progression
• All chemotherapy was given on a 3 week on, one week off schedule
• Patients could discontinue chemotherapy
and continue
bevacizumab alone after 6 cycles if stable or responding disease
1. Miller et al, N Engl J Med, 2007 2. Gradishar et al, J Clin Oncol, 2009
3. Dickson et al, Proc ASCO 2006.
0.8
HR
P-value
95% CI
nab vs. pac
1.19
0.12
Pac
0.96-1.49
ixa vs. pac
1.53
< 0.0001
1.24-1.90
Ixa
Nab
0.4
0.6
Comparison
0.2
paclitaxel
nab-paclitaxel
ixabepilone
0.0
Proportion Progression-Free
1
CALGB 40502
Progression-Free Survival By Treatment Arm
0
10
20
30
Months From Study Entry
Agent
N
Median PFS
paclitaxel
283
10.6
nab-Paclitaxel
271
9.2
ixabepilone
245
7.6
1
CALGB 40502
Overall Survival
0.6
0.4
0.2
Comparison
HR
P-value
95% CI
nab vs. pac
1.02
0.92
0.75-1.38
ixa vs. pac
1.28
0.10
0.95-1.72
0.0
Proportion Alive
0.8
paclitaxelPac
nab-paclitaxel
Nab
ixabepilone
Ixa
0
10
20
30
Months From Study Entry
Agent
N
Median OS
paclitaxel
283
26
nab-paclitaxel
271
27
ixabepilone
245
21
Dose
Reductions
by Cycle 3
duction
All Cause Cumulative
Discontinuation by Cycle
45%
60
50
paclitaxel
nab-paclitaxel
ixabepilone
Percent
40
15%
15%
30
20
10
0
nab Pac
pac ixa
nab
Ixa
Cycle 33
Cycle
1
2
3
Cycle number
4
5
Other AEs –
Grade 3+
Sensory
Neuropathy
Arm
nab
(N = 258)
Grade 3+ Leukopenia
25%
Neutropenia
(N = 262)
ixa
(N = 237)
pac
ixa
(N = 258)
(N = 262)
(N = 237)
17%
p = 0.0004
47%
p = 0.0001
7%
18%
3%
p = 0.042
7%
p = 0.0002
p=0.012
Hypertension
pac
nab
16%
25%
p=0.022
Fatigue
Pain
Motor
neuropathy
7%
16%
p = 0.010
10%
p = 0.010
10%
p = 0.0003
8%
9%
4%
2%
11%
15%
p = 0.036
4%
6%
p = 0.021
Summary and interpretation
• Neither weekly nab-paclitaxel or ixabepilone
are superior to weekly paclitaxel
• Weekly paclitaxel appears to offer better
progression-free survival than ixabepilone
• Hematologic toxicity was greater with nabpaclitaxel; sensory neuropathy was greater in
both experimental arms compared to paclitaxel
• Paclitaxel is a reasonable choice in a similar
setting
• 100 mg/m2 is the most appropriate dose for
weekly nab-paclitaxel
Study Design: Role of Maintenance Therapy
Prospective, phase III, multi-center, randomized study
Enroll period: 2007.05 – 2010.09
Off the study
PD
324 MBC
patients with
no prior
chemotherapy
 till PD
6 cycles of PG
PG regimen
Paclitaxel
175 mg/m2 Day 1
Gemcitabine 1,250 mg/m2 Day 1 & 8
every 3 weeks
CR/PR/SD
N=231
R
N=115
Observation till PD
Stratification
1. Visceral diseases
2. Prior adjuvant taxane
3. Response(CR/PR vs. SD)
4. HR(+) vs. HR(-)
N=116
Primary Endpoint; PFS from Randomization
Secondary Endpoints; OS, Toxicities, QoL, and Response Duration
Im et al, #1003
75% HR positive, ~20% received hormone
therapy in the metastatic setting
• Subgroup analysis
– Primary benefit in HR
negative (n=59), and in
premenopausal women
• Toxicity
– More toxicity in the
maintenance arm > cycle 6
– QOL similar between the
two arms
• Interpretation complicated
by lack of use of hormone
therapy in the control arm
– This should not change our
general management of
patients in this setting
– For hormone receptor
negative disease, better to
continue at least a low dose
of chemotherapy
Other Interesting Data
• Targeting the androgen receptor in ER/PR
negative disease (Gucalp et al, #1006, TBCRC)
– 12% of screened patients were AR+
– Treated with bicalutamide 150 mg/day
• 26 patients
– Median age 66
– 15% visceral metastases
– Median 1 prior chemotherapy regimen for MBC
• 24% clinical benefit rate (5/24)
– Disease in LN, breast and bone, one GI
• A larger trial is planned
Summary
• New HER2 directed therapy provides increased efficacy
without significant toxicity
– Adjuvant and neoadjuvant trials are ongoing or planned
• Zoledronate may improve outcome in subsets of women
with early stage breast cancer and high bone turnover
– This is not practice changing
– The current recommendation is to use potent bisphosphonates to
treat osteoporosis, or osteopenia in high risk women
• Radiation appears to add little benefit to patients with low
risk DCIS treated with BCT
Summary (2)
• Early stage disease
– Gemcitabine does not add to DD AC/P but increases
toxicity
– Approach to clinical trials needs to change
• Its all about biology and understanding the drivers of disease
• Metastatic disease
– Paclitaxel is the preferred microtubule targeting agent in
1st line MBC
– Maintenance chemotherapy may provide benefit, but
this is likely to be in HR negative or resistant disease
– More studies targeting the androgen receptor are
warranted
Phase 1b Study: all BC
PLX3397 oral daily dosing
Eribulin: 1.4 mg/m2 iv, day 1 and 8
Each cycle of treatment lasts 21 days
First Cohort = 600 mg/day
3-6 patients
KOMEN Promise Grant:
Can inhibition of macrophages
Second Cohort = 800 mg/day
reverse chemotherapy
3-6 patients
resistance?
Phase II Primary Endpoint:
PFS at 12 weeks
Third Cohort = 1000 mg/day
3-6 patients
Phase II Study: Metastatic TNBC
Lead in period of 5-7d with PLX3397 at MTD
oral daily dosing (day -7/5 to day 0)
Biopsy for immune
profiling
Starting Day 1
Add Eribulin 1.4 mg/m2 iv day 1 and 8
Each cycle of treatment lasts 21 days
PI: Hope S. Rugo, UCSF, Lisa Coussens, OHSU, Shelley Hwang, Duke.