Transcript Challenges in the Treatment of Breast Cancer: Overcoming

Expert Review of Breast Cancer Treatment
Clinical Application of Evolving Treatment
Paradigms in Advanced Breast Cancer
Clifford A. Hudis, MD
Chief, Breast Cancer Medicine Service
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, NY
Case 1
• 47 year-old woman, BRCA1 (+) with h/o stage IIa
breast cancer (3-years ago) at age 44
─ ER weakly positive
─ PR negative
─ HER2 negative
─ Treatment: dose-dense AC→T and on tamoxifen for 2+ years
• Presents now with RUQ pain, 4kg weight loss, and
fatigue
─ LFTs normal
─ CT with multiple hepatic metastases confirmed by biopsy c/w
original tumor
Case 1
Which treatment option would you recommend:
 Hormone therapy
 Chemotherapy
 Bevacizumab
Case 1
Which treatment option would you recommend:
 Hormone therapy
 Chemotherapy
 Bevacizumab
Recommended Approach:

Clinical considerations for selection of appropriate treatment
will be discussed
Management of Metastatic Breast Cancer
Diagnosis of Metastatic Breast Cancer
Determination of sites and extent of disease. Assessment of HER2,
hormonal receptor status, disease-free interval, age, and menopausal status
No life-threatening disease
Hormone-responsive
Hormone-unresponsive, or
Life-threatening disease
1st-line hormonal therapy
1st-line chemotherapy
Response
Progression
2nd-line hormonal therapy
Progression
No
Response
No
Response
Response
Progression
3rd-line hormonal therapy
2nd-line chemotherapy
Progression
3rd-line chemotherapy
No
Response
Supportive care
Many Chemotherapy Options
• Spindle toxins
– paclitaxel (Pac)
• Platinums
• Antifolates
– docetaxel (Doc)
– methotrexate (MTX)
– vinorelbine (Vin)
– pemetrexed (PTX)
– nab-Pac* (ABI-007)
– Ixabepilone (Ixa)
• Nucleoside analogues
– gemcitabine (Gem)
– capecitabine (Cap)
– 5-fluorouracil (5-FU_
• Topoisomerase inhibitors
– CPT-11 (Topo)
– doxorubicin (Dox)
• Unique delivery
– liposomal doxorubicin (LD)
• Targeted therapy
– HER2: trastuzumab (Trastuzumab)
and lapatinib (Lap)
– VEGF: BVM and small-molecule TKIs
(investigational)
– farnesyltransferase inhibitors
– EGFR inhibitors (investigational)
*Albumin-bound paclitaxel.
CPT = camptothecin; VEGF = vascular endothelial growth factor; BVM = bevacizumab;
mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor.
Approval is Different from Common Usage
Adjuvant
Anthracyclines (A)
Metastatic1
1st Line
2nd Line
Taxanes (after A)
Taxanes (after A)
Cap (after A+T)
Cap (after A + T)
Cap (after A + T)
Ixa (after A+T+Cap)
Ixa (after A + T +Cap)
Cap (after A + T)
Taxanes (T)
3rd Line
Combination
Cap+taxane
(after A)
Gem + taxane
(after A)
Cap + Ixa
(after A + T)
• Despite treatment, most advanced tumors become resistant and progress2
• Chemoresistance is the major cause of treatment failure3
1. Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer
V.2.2007. http://www.nccn.org. Accessed April 30, 2007;
2. Bernard-Marty C et al. Oncologist. 2004;9(6):617-632;
3. Longley DB, Johnson PG. J Pathol. 2005;205(2):275-292.
Rationale for Combination Therapy
in the Treatment of MBC
Principles of Treatment With Multiple Agents
• MBC-inherent drug resistance = barrier to response (cure)
– There are many subpopulations of cancer cells with
different types of resistance
– Combination CT should reduce the different sensitive subpopulations of
cancer cells, leading to an improved
disease response
• Improved disease response will translate into an improvement in
outcome
– Meta-analysis (2005): standard CT vs intensified CT
(10 trials, 2126 patients)
– Intensified CT associated with OR=0.60 for response
– Tumor response was predictive of survival (P<0.001)
• Median OS: CR=29 mon; PR=21 mon; NR=15 mon
OR = odds ratio; OS = overall survival; CR = complete response;
PR = partial response; NR = no response.
Bruzzi P et al. J Clin Oncol. 2005;23(22):5117-5125.
Single-agent vs Combination
Front-line CT in MBC
• Response rate  favors combination
• TTP  favors combination
• Survival  ?
• Toxicity  favors single agent
• Quality of life  ?
Very few combination trials using investigational drugs truly tested
the hypothesis of combination vs sequential single-agent therapy
TTP = time to progression.
Single-agent vs Combination Trials
Clinical Trial*
Median TTP
(mon)
Overall
Survival
(mon)
Grade IV
Neutropenia
(%)
2.9
15.8
7
5.2
18.5
17
4.2
6.1
11.5
14.5
11
12
Albain et al (N=529)
Pac
Pac + Gem
O’Shaughnessy et al (N=511)
Docetaxel (Doc)
Doc + Cap
Albain KS et al. J Clin Oncol. 2004;22(14) Abstract 810.
O'Shaughnessy J et al. J Clin Oncol. 2002;20(12):2812-2823.
E1193 Phase III Trial
Dox vs Pac vs Dox + Pac Combination in MBC
Results: Efficacy and Tolerability
Outcome
Dox
Pac
Dox + Pac
P Value
36
34
47
0.007*
0.004†
Median survival (mon)
18.9
22.2
22.0
NS
TTP (mo)
6.0
6.3
8.2
0.0022*
0.0567†
Gr III/IV leukopenia (%)
47
60
55
—
Gr III/IV infection (%)
4.1
8.3
12.7
—
Gr III/IV neurologic
complications (%)
1.6
3.7
10.7
—
Response rate (%)
*Dox vs Dox + Pac; †Pac vs Dox + Pac.
*Sledge GW et al. J Clin Oncol. 2003;21(4):588-592.
CALGB 9840: Design
1998–2000 (N=171)
2000–2003 (N=406)
(HER2 status unknown)
(HER2 status known)
Pac q 3 wks








Pac q wk


Pac q 3 wks + Trastuzumab
Pac 80
q wk –or–
2
175 mg/m q 3 wks
mg/m2
Tras 4-mg/kg load,
then 2 mg/kg/wk





Pac q wk + Trastuzumab


Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
CALGB 9840
Results (All Patients)
Tumor Response
Time to Progression
50
10
HR=1.61; P=0.017
40
30
8
Time (mon)
Response Rate (%)
40
28
20
10
0
6
9
Adjusted HR=1.45;
P=0.0008
5
4
2
Pac q 3 Wks
(N=373)
Pac Weekly
(N=344)
0
Pac q 3 Wks
(N=373)
Events/patients:
Pac Weekly
(N=344)
221/350
324/385
Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
CALGB 9840
Conclusions
• Pac once weekly is superior to Pac q 3 wks for the
treatment of MBC (with respect to response rate and TTP)
• Pac once weekly is associated with slightly less frequent
myelosuppression but more frequent neurotoxicity than
Pac q 3 wks
• Trastuzumab does not improve outcome when added to
Pac in HER2-neutral MBC
Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
TAX-31: Docetaxel vs Paclitaxel
s/p anthracycline / 0-1 prior chemo for MBC
Docetaxel 100q3w
(N=225)
*P ≤ 0.05
ORR (ITT)
Paclitaxel 175q3w
(N=224)
32%
25%
TTP
5.7*
3.6
OS
15.4*
12.7
(3 deaths)
(0 deaths)
Neutropenia*
93%
55%
Feb Neutropenia*
15%
2%
Infection
10%
2%
Anemia*
10%
7%
Neurosensory
7%
4%
Neuromotor
5%
2%
Asthenia*
21%
5%
Peripheral oedema*
7%
1%
Stomatitis
11%
0%
Diarrhea*
5%
1%
Severe AE (>5%)
Jones et al. JCO 2005.
New Formulations
Nab-Pac Transport & Tumor Targeting
Tapping Into Biology of Albumin and Rapid Cell Growth
Tumor
interstitium
Leaky junction
(A) Albumin,
the body’s natural
transporter
of water-insoluble
nutrients
Lumen of
tumor
microvessel
Tumor cell
(C) High tumor uptake
(SPARC binding of
albumin complexes)
Albumin-receptor (gp60, albondin)
Caveolae (vesicles)
Tumor
cell
(B) Receptor-mediated
transcytosis of albumin complexes
(gp60/caveolin-1 pathway)
SPARC = secreted protein and rich in cysteine.
Phase III Trial
Albumin-Bound (Nab) Pac vs Pac in MBC
Albumin-bound Pac: 260 mg/m2 q3w; Pac: 175 mg/m2 q3w
Albumin-Bound
(Nab) Pac
Pac
(N=229)
(N=225)
ORR (%)
33
19
0.001
TTP (wk)
23.0
16.9
0.006
9
22
<0.001
10*
2
<0.001
Gr IV neutropenia (%)
Gr III sensory neuropathy (%)
P Value
*Median time to improvement: 22 days.
Gradishar WJ et al. J Clin Oncol. 2005;23(31):7794-7803.
Phase II Study of Weekly or q3wk Nab-Pac
vs q3wk Doc as First-line Therapy in MBC
Eligibility criteria:
• Stage IV
adenocarcinoma
• No prior CT for
metastatic disease
R
A
N
D
O
M
I
Z
E
Arm A:
nab-Pac 300 mg/m2 q3wk
Arm B:
nab-Pac 100 mg/m2
weekly, 3 out of 4
Arm C:
nab-Pac 150 mg/m2
weekly, 3 out of 4
Arm D:
Doc 100 mg/m2 q3wk
Primary endpoint Antitumor response (q 8 wks) and toxicity
nab-Pac vs Doc (A, B, C vs D) weekly vs q3wk nab-Pac (B, C vs A)
Comparisons low- vs high-dose weekly nab-Pac (B vs C)
Gradishar W et al. SABCS 2006. Abstract 46.
Where Exactly Are We?
Hudis JCO 2005.
Novel Microtubule Inhibitors
Need for change in
Novel microtubule inhibitors
Toxicity profile
Albumin-bound Pac (nab-Pac)
Therapeutic Efficacy
Halicrobdrin analogue (E7389)
– Improve effect at target site
Epothilones (Ixa, patupilone)
– Overcome resistance
Polyglutamic acid conjugated Pac (CT 2103)
– Cross blood-brain barrier
Vinflunine (novel vinca alkaloid)
Lee JJ, Swain SM. Semin Oncol. 2005;23(2 suppl 7):S22-26.
Cortes J, Baselga J. Oncologist. 2007;12(3):271-280.
Epothilones in Clinical Development
for Breast Cancer
Agent
(Manufacturer)
Epothilone Analog
Phase in
Development
Clinical Toxicities
EPO-906/patupilone
Epothilone B
(natural product)
III
Diarrhea
ZK-EPO
Epothilone B
(fully synthetic)
II
Neuropathy, nausea, ataxia
KOS-1584
Epothilone D
(desoxyepothilone B)
II
Myelosuppression, neuropathy
BMS-310705
Epothilone B
(semi-synthetic)
I / II
Hypersensitivity reactions,
pancytopenia, neuropathy,
arthralgia/myalgia
Goodin S et al. J Clin Oncol. 2004;22(10):2015-2025.
Kolman A. Curr Opin Investig Drugs. 2005;6(6):616-622.
Schmid P et al. J Clin Oncol. 2005;23(16 suppl): Abstract 2051.
Ixabepilone (Ixa)
First in the New Class of Epothilones
• Naturally occurring epothilone B
chemically modified to improve
metabolic activity, protein
binding, and antitumor activity1
O
S
OH
N
HN
O
OH
O
Ixabepilone
Semi-synthetic analog
of epothilone B
• Tubulin-binding mode distinct
from other microtubulestabilizing agents1
• Active against multiple tumor
xeno grafts, including drugresistant types that overexpress
P-gP, MRP-1, and b-III tubulin
isoforms1
• Active in taxane-resistant
disease2,3
1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
2. Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.
3. Thomas E et al. J Clin Oncol. 2007;25(23):3399 3406.
Ixa: Mechanism of Action
Extracellular
Ixa
MRP-1
P-gP
Intracellular
Ixa
Tubulin
ß-tubulin
ßIII-tubulin
• Poor substrate for efflux pumps, eg,
P-gP and MRP-11
– P-gP and MRP-1 are involved in drug
resistance2
• Binds multiple ß-tubulin isoforms,
including ßIII-tubulin to inhibit
microtubule dynamics1
– Overexpression of ßIII is associated
with in vivo and clinical resistance to
taxanes3,4
1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
2. Lee JJ, Swain SM. Semin Oncol. 2005;32(6 suppl 7):S22-S26.
3. Kamath K et al. J Biol Chem. 2005;280(13):12902-12907.
4. Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.
Phase II Trial Ixa in Anthracycline-, Taxane-,
and Capecitabine-Resistant MBC
Efficacy
Efficacy (N=113 Evaluable Patients)
ORR
11.5%
SD
50.0%
Median PFS
3.1 mo
Grade III/IV Toxicities
%
Neutropenia
54
Peripheral neuropathy
14
Fatigue
10
Myalgia
7
Stomatitis
7
Single-agent Ixa 40 mg/m2 IV over 3 hrs q3w until disease progression
Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.
Ixa Study 046
Design
Ixa in Combination With Cap in Patients Resistant to an Anthracycline and a Taxane
MBC
Demonstrated
resistance to
anthracycline
and taxane
N=752
Combination therapy:
Ixa 40 mg/m2 IV over 3 h q 21 days +
Cap 2000 mg/m2/d PO Days 1–14
Monotherapy:
Primary
Endpoint
PFS (IRR)
Cap 2500 mg/m2/d PO Days 1–14
Strict resistance criteria prospectively defined as
• Disease progression = 3 mon of the last anthracycline dose in the metastatic
setting –OR– recurrence = 6 mon in the adjuvant or neoadjuvant setting
–AND–
• Disease progression = 4 mon of the last taxane dose in the metastatic setting –OR–
recurrence = 12 mon in the adjuvant or neoadjuvant setting
*Pts who received a minimum cumulative dose of 240 mg/m2 of Dox or 360 mg/m2 of epirubicin were also eligible.
RR = independent radiologic review.
Imprexa (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
Thomas ES et al. J Clin Oncol. 2007; 25(33):5210-5217.
Ixabepilone Study 046
Significant Improvement in Median PFS*
1.0
Proportion not Progressed
0.9
0.8
Ixa + Cap
0.7
Cap
Median PFS
5.8 mos
vs
4.2 mos
(95% CI, 3.8–4.5)
0.6
0.5
P=0.0003†
0.4
HR = 0.75
(95% CI, 0.64–0.88)
0.3
0.2
0.1
0.0
0
4
8
12
16
20
24
28
32
36
40
Months
*Based on IRR of ITT population; †Stratified by visceral metastasis in liver/lung, prior CT in metastatic
setting, and anthracycline resistance..
Thomas ES et al. J Clin Oncol. 2007; Early online release; 0: JCO.2007.12.6557v1.
Grade 3/4 Non-hematologic Toxicities
80
Ixabepilone + Capecitabine (N=369)
% of Patients
Capecitabine (N=368)
60
40
23
18 17
20
9
0
0
8
3
6
0.3
9
4
2
3
2
3
2
3
0
What About Anti-angiogenics?
E2100
Study Design
Stratify:
• DFI ≤24 mon
vs >24 mon
• <3 vs ≥3
metastatic sites
• Adjuvant CT:
yes vs no
• ER(+) vs ER(–)
vs ER unknown
R
A
N
D
O
M
I
Z
E
Pac + Bev
Pac
28-day cycle
Pac 90 mg/m2
D1, 8, and 15
BVM 10 mg/kg
D1 and 15
DFI = disease-free interval.
Miller KD et a. SABCS 2005. Abstract 3.
First-line Therapy of Metastatic Breast Cancer with
Bevacizumab Added to Paclitaxel Improved PFS
Pac. + Bev. 11.4 mos
1.0
Paclitaxel
6.11 mos
PFS Probability
0.8
HR = 0.51 (0.43-0.62)
0.6
Log Rank Test P < 0.0001
0.4
0.2
0.0
0
6
12
18
24
30
Months
484 events reported
Miller K, NEJM 2007.
AVADO
Double-blind, Placebo-controlled Trial
1st line locally recurrent or
mBC (N=705)
Stratification factors:
• region
• prior taxoid/time to
relapse since adjuvant
chemo
• measurable disease
• hormone receptor
status
Docetaxel* 100mg/m2
+ placebo q3w
Docetaxel* + bevacizumab
7.5mg/kg q3w
Treat with
placebo/
bevacizumab
to disease
progression
All patients
given option
to receive
bevacizumab
with
nd
2 line
chemotherapy
Docetaxel* + bevacizumab
15mg/kg q3w
*Docetaxel was administered for a maximum of 9 cycles, but earlier discontinuation was permitted
• Primary endpoint:
Progression-free survival
• Secondary endpoints:
Overall response rate, duration of response, time to
treatment failure, overall survival, safety, quality of life
Progression-free Survival
(ITT population)
Placebo +
docetaxel (n=241)
Bev 7.5† +
docetaxel (n=248)
HR + 95% CI (unstratified)
8.0
1.0
1.0
0.8
0.8
0.6
0.4
0.2
0.61 (0.48–0.78)
P < 0.0001
8.0
Median
8.7
Bev 15† +
docetaxel (n=247)
0.72 (0.57–0.90)
P = 0.0036
HR + 95% CI (stratified*)
0.69 (0.54–0.89)
P = 0.0035
PFS estimate
PFS estimate
HR + 95% CI (unstratified)
0.79 (0.63–0.98)
P = 0.0318
HR + 95% CI (stratified*)
Median
Placebo +
docetaxel (n=241)
8.8
0.6
0.4
0.2
0.0 0
†mg/kg
6
q3w
Months
12
18
0.0 0
6
Months
12
18
*Data censored for non-protocol therapy prior to PD
Sorafenib Targets Both Tumor-cell
Proliferation and Angiogenesis
Tumour cell
Endothelial cell or pericyte
VEGF
Autocrine loop
PDGF-b
Paracrine stimulation
EGF/IGF
PDGFR-b
VEGFR-2
Apoptosis
RAS
RAS
RAF
Mcl-1
RAF
Angiogenesis:
Mitochondria
MEK
HIF-2
ERK
EGF/TGF-a
PDGF
Nucleus
Mitochondria
MEK
Apoptosis
ERK
Differentiation
Proliferation
Migration
Tubule formation
VEGF
Nucleus
Proliferation
Survival
PDGF =
EGF =
VEGF =
TGF-a =
Mcl-1 =
platelet-derived growth factor
epidermal growth factor
vascular endothelial growth factor
transforming growth factor-alpha
myeloid cell leukemia-1
Sorafenib
Wilhelm SM, et al. Cancer Res 2004;64:7099–109.
Sorafenib in Breast Cancer
Six Randomized, Double-blind, Placebo-controlled Phase 2b Trials
Paclitaxel
Capecitabine*
Dr. GRADISHAR Dr. BASELGA
(Northwestern,
(SOLTI)
ACORN)
Started Aug 07
Started Jun 07
2
Triplet
Dr. SLEDGE
(HOG)
Planned
TRIALS
INVESTIGATING
THE EFFECTS
OF SORAFENIB
IN BREAST
CANCER
Aromatase
Inhibitors*1
Dr. PEREZ
(MCCRC)
Planned
1. Letrozole, anastrozole, or exemestane
2. Paclitaxel/bevacizumab +/- sorafenib
3. Bevacizumab-progressors
Gemcitabine*3
Drs. HUDIS &
SCHWARTZBERG
(MSKCC/
ACORN)
Started Jun 07
Docetaxel or
Letrozole
Dr. GIANNI
(Michelangelo)
Planned
*includes 2nd line patients
Conclusions
• Newly approved and other novel agents for the treatment of
patients with MBC continue to improve outcomes
– The addition of biologics may make a substantial impact
• There is a clear and immediate need for larger, better
designed clinical trials to assess the role of these
new agents
– As monotherapy
– As combination therapy
– As additions to therapies employing a growing number
of biologics