Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer
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Transcript of Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer
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
Expert Review of Breast Cancer Treatment
• 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
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 CancerDiagnosis of Metastatic Breast Cancer
No Response
Determination of sites and extent of disease. Assessment of HER2, hormonal receptor status, disease-free interval, age, and menopausal status
No life-threatening diseaseHormone-responsive
Hormone-unresponsive, orLife-threatening disease
1st-line hormonal therapy 1st-line chemotherapy
ResponseNo
Response
2nd-line hormonal therapy
2nd-line chemotherapy
Progression
Progression
Progression
Progression
3rd-line hormonal therapy
Response
No Response
3rd-line chemotherapy
Supportive care
Many Chemotherapy Options
• Spindle toxins
– paclitaxel (Pac)
– docetaxel (Doc)
– vinorelbine (Vin)
– nab-Pac* (ABI-007)
– Ixabepilone (Ixa)
• Nucleoside analogues
– gemcitabine (Gem)
– capecitabine (Cap)
– 5-fluorouracil (5-FU_
• Topoisomerase inhibitors
– CPT-11 (Topo)
– doxorubicin (Dox)
• Platinums
• Antifolates
– methotrexate (MTX)
– pemetrexed (PTX)
• 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
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)
CombinationCap+taxane
(after A)Gem + taxane
(after A)Cap + Ixa
(after A + T)
Metastatic1
3rd Line2nd Line1st Line
Adjuvant
Anthracyclines (A)
Taxanes (T)
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.
• Despite treatment, most advanced tumors become resistant and progress2
• Chemoresistance is the major cause of treatment failure3
Rationale for Combination Therapy
in the Treatment of MBC
Principles of Treatment With Multiple AgentsPrinciples 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 ?
TTP = time to progression.
Very few combination trials using investigational drugs truly tested the hypothesis of combination vs sequential single-agent therapy
Single-agent vs Combination Trials
Clinical Trial*Median TTP
(mon)
Overall Survival (mon)
Grade IV Neutropenia
(%)
Albain et al (N=529)
PacPac + Gem
2.9
5.2
15.8
18.5
7
17
O’Shaughnessy et al (N=511)Docetaxel (Doc) Doc + Cap
4.26.1
11.514.5
1112
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
Outcome Dox Pac Dox + Pac P Value
Response rate (%) 36 34 470.007*
0.004†
Median survival (mon) 18.9 22.2 22.0 NS
TTP (mo) 6.0 6.3 8.20.0022*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 —
*Sledge GW et al. J Clin Oncol. 2003;21(4):588-592.
Results: Efficacy and Tolerability
*Dox vs Dox + Pac; †Pac vs Dox + Pac.
CALGB 9840: Design
Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
Pac q wk + Trastuzumab
Pac q 3 wks + Trastuzumab
Pac q wk
Pac q 3 wks
2000–2003 (N=406)(HER2 status known)
1998–2000 (N=171)(HER2 status unknown)
Pac 80 mg/m2 q wk –or– 175 mg/m2 q 3 wks
Tras 4-mg/kg load, then 2 mg/kg/wk
CALGB 9840Results (All Patients)
Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
28
40
0
10
20
30
40
50
Pac Weekly(N=344)
Pac q 3 Wks(N=373)
Res
pons
e R
ate
(%)
Tumor Response
HR=1.61; P=0.017
Time to Progression
5
9
0
2
4
6
8
10
Tim
e (
mon
)
Pac Weekly(N=344)
Pac q 3 Wks(N=373)
Adjusted HR=1.45; P=0.0008
Events/patients: 221/350 324/385
• 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
CALGB 9840Conclusions
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)
Paclitaxel 175q3w
(N=224)
ORR (ITT)
TTP
OS
32%
5.7*
15.4*
25%
3.6
12.7
Severe AE (>5%)
Neutropenia*
Feb Neutropenia*
Infection
Anemia*
Neurosensory
Neuromotor
Asthenia*
Peripheral oedema*
Stomatitis
Diarrhea*
(3 deaths)
93%
15%
10%
10%
7%
5%
21%
7%
11%
5%
(0 deaths)
55%
2%
2%
7%
4%
2%
5%
1%
0%
1%
*P ≤ 0.05
Jones et al. JCO 2005.
New Formulations
Nab-Pac Transport & Tumor TargetingTapping Into Biology of Albumin and Rapid Cell Growth
Tumor cell
Lumen of tumor
microvessel
Caveolae (vesicles)
Leaky junctionTumor interstitium
Albumin-receptor (gp60, albondin)
SPARC
Tumor cell
SPARC
(A) Albumin,the body’s natural
transporter of water-insoluble
nutrients
(B) Receptor-mediated transcytosis of albumin complexes
(gp60/caveolin-1 pathway)
(C) High tumor uptake (SPARC binding of albumin complexes)
SPARC = secreted protein and rich in cysteine.
Phase III TrialAlbumin-Bound (Nab) Pac vs Pac in MBC
Albumin-Bound (Nab) Pac
(N=229)
Pac
(N=225)
P Value
ORR (%) 33 19 0.001
TTP (wk) 23.0 16.9 0.006
Gr IV neutropenia (%) 9 22 <0.001
Gr III sensory neuropathy (%) 10* 2 <0.001
Albumin-bound Pac: 260 mg/m2 q3w; Pac: 175 mg/m2 q3w
Gradishar WJ et al. J Clin Oncol. 2005;23(31):7794-7803.
*Median time to improvement: 22 days.
Phase II Study of Weekly or q3wk Nab-Pac Phase II Study of Weekly or q3wk Nab-Pac vs q3wk Doc as First-line Therapy in MBCvs q3wk Doc as First-line Therapy in MBC
Eligibility criteria:
• Stage IV adenocarcinoma
• No prior CT for metastatic disease
Gradishar W et al. SABCS 2006. Abstract 46.
RANDOMIZE
RANDOMIZE
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
Comparisonsnab-Pac vs Doc (A, B, C vs D) weekly vs q3wk nab-Pac (B, C vs A) low- vs high-dose weekly nab-Pac (B vs C)
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.
Agent (Manufacturer)
Epothilone AnalogPhase in
DevelopmentClinical Toxicities
EPO-906/patupiloneEpothilone B
(natural product)III Diarrhea
ZK-EPOEpothilone B
(fully synthetic)II Neuropathy, nausea, ataxia
KOS-1584Epothilone D
(desoxyepothilone B)II Myelosuppression, neuropathy
BMS-310705Epothilone B
(semi-synthetic)I / II
Hypersensitivity reactions, pancytopenia, neuropathy,
arthralgia/myalgia
Epothilones in Clinical Developmentfor Breast Cancer
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
S
N
HN
O OOH
O
OH
IxabepiloneSemi-synthetic analog
of epothilone B
• Naturally occurring epothilone Bchemically modified to improvemetabolic activity, proteinbinding, and antitumor activity1
• Tubulin-binding mode distinctfrom other microtubule-stabilizing agents1
• Active against multiple tumor xeno grafts, including drug-resistant types that overexpressP-gP, MRP-1, and III tubulinisoforms1
• 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
Ixa
ß-tubulin
Ixa
MRP-1
P-gP
Tubulin
ßIII-tubulin
Extracellular
Intracellular
• 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
Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.
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
Ixa Study 046Design
MBC
Demonstratedresistance toanthracyclineand 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:
Cap 2500 mg/m2/d PO Days 1–14
Primary Endpoint
PFS (IRR)
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
Imprexa (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
Thomas ES et al. J Clin Oncol. 2007; 25(33):5210-5217.
Ixa in Combination With Cap in Patients Resistant to an Anthracycline and a Taxane
*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.
Ixabepilone Study 046Significant Improvement in Median PFS*
*Based on IRR of ITT population; †Stratified by visceral metastasis in liver/lung, prior CT in metastatic setting, and anthracycline resistance..
Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 4 8 12 16 20 24 28 32 36 40
Ixa + Cap
Cap
P=0.0003†
Pro
port
ion
not P
rogr
esse
d
Median PFS
5.8 mosvs
4.2 mos(95% CI, 3.8–4.5)
HR = 0.75(95% CI, 0.64–0.88)
Thomas ES et al. J Clin Oncol. 2007; Early online release; 0: JCO.2007.12.6557v1.
Grade 3/4 Non-hematologic ToxicitiesP
erip
hera
l
neur
opat
hy
23
0
Mya
lgia
8
0.3
Han
d-fo
ot
synd
rom
e
18 17
Dia
rrhe
a
69
Muc
ositi
s
3 2
Vom
iting
4 2
Fatig
ue
9
3
Nau
sea
3 2
Art
hral
gia
30
0
% o
f P
atie
nts
Ixabepilone + Capecitabine (N=369)
Capecitabine (N=368)
20
40
60
80
What About Anti-angiogenics?
E2100 Study Design
Miller KD et a. SABCS 2005. Abstract 3.
RANDOMIZE
Pac28-day cycle
Pac 90 mg/m2
D1, 8, and 15BVM 10 mg/kg
D1 and 15
Stratify:• DFI ≤24 mon
vs >24 mon• <3 vs ≥3
metastatic sites• Adjuvant CT:
yes vs no• ER(+) vs ER(–)
vs ER unknown
Pac + Bev
DFI = disease-free interval.
First-line Therapy of Metastatic Breast Cancer with Bevacizumab Added to Paclitaxel Improved PFS
0.0
0.2
0.4
0.6
0.8
1.0
Months
PFS
Pro
babili
ty
0 6 12 18 24 30
HR = 0.51 (0.43-0.62)
Log Rank Test P < 0.0001
Pac. + Bev. 11.4 mos
Paclitaxel 6.11 mos
484 events reportedMiller K, NEJM 2007.
*Docetaxel was administered for a maximum of 9 cycles, but earlier discontinuation was permitted
AVADODouble-blind, Placebo-controlled Trial
• Primary endpoint: Progression-free survival
• Secondary endpoints: Overall response rate, duration of response, time to treatment failure, overall survival, safety, quality
of life
Docetaxel* 100mg/m2 + placebo q3w
Docetaxel* + bevacizumab 7.5mg/kg q3w
Docetaxel* + bevacizumab 15mg/kg q3w
All patientsgiven optionto receive
bevacizumabwith
2nd linechemotherapy
1st line locally recurrent or mBC (N=705)
Stratification factors:• region• prior taxoid/time to
relapse since adjuvant chemo
• measurable disease• hormone receptor
status
Treat withplacebo/
bevacizumabto disease
progression
Progression-free Survival (ITT population)
Months
PF
S e
stim
ate
*Data censored for non-protocol therapy prior to PD†mg/kg q3w
HR + 95% CI (unstratified)
Bev 7.5† +docetaxel (n=248)
1.0
0.8
0.6
0.4
0.2
0.0 0 6 12 18Months
PF
S e
stim
ate
1.0
0.8
0.6
0.4
0.2
0.0 0 6 12 18
HR + 95% CI (stratified*) 0.69 (0.54–0.89)P = 0.0035
0.79 (0.63–0.98)P = 0.0318
Placebo +docetaxel (n=241)
Median 8.78.0
HR + 95% CI (stratified*) 0.61 (0.48–0.78)P < 0.0001
Median 8.88.0
0.72 (0.57–0.90)P = 0.0036
HR + 95% CI (unstratified)
Bev 15† +docetaxel (n=247)
Placebo +docetaxel (n=241)
Sorafenib Targets Both Tumor-cell Proliferation and Angiogenesis
Wilhelm SM, et al. Cancer Res 2004;64:7099–109.
PDGF = platelet-derived growth factor
EGF = epidermal growth factorVEGF = vascular endothelial growth factor
TGF-a = transforming growth factor-alpha
Mcl-1 = myeloid cell leukemia-1
RAS
Endothelial cell or pericyte
Proliferation
Angiogenesis:
PDGF-VEGF
VEGFR-2PDGFR-
Paracrine stimulation
DifferentiationMitochondria
Apoptosis
Tumour cell
PDGF
VEGF
EGF/TGF-
Proliferation
Survival
Mitochondria
EGF/IGF
HIF-2
Nucleus
Autocrine loop
Apoptosis
ERK
RAS
MEK
RAF
Nucleus
ERK
MEK
RAF
Sorafenib
MigrationTubule formation
Mcl-1
Sorafenib in Breast CancerSix Randomized, Double-blind, Placebo-controlled Phase 2b Trials
1. Letrozole, anastrozole, or exemestane2. Paclitaxel/bevacizumab +/- sorafenib3. Bevacizumab-progressors
PaclitaxelDr. GRADISHAR(Northwestern,
ACORN)Started Jun 07
Capecitabine*Dr. BASELGA
(SOLTI)Started Aug 07
AromataseInhibitors*1
Dr. PEREZ(MCCRC)Planned
Docetaxel orLetrozole
Dr. GIANNI(Michelangelo)
Planned
Gemcitabine*3
Drs. HUDIS & SCHWARTZBERG
(MSKCC/ACORN)
Started Jun 07
Triplet2
Dr. SLEDGE(HOG)
Planned
TRIALS INVESTIGATING THE EFFECTS
OF SORAFENIB IN BREAST
CANCER
*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