chemotherapy options and decision-making for advanced...
TRANSCRIPT
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Chemotherapy Options and Decision-Making for
Advanced Breast Cancer
Debu Tripathy, M.D.
Professor of Medicine
University of Southern California
31st Annual Miami Breast
Cancer Conference
March 6-9, 2014
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Decision Points: Chemotherapy for Advanced Breast Cancer
• When to use chemotherapy for ER/PR+ or HER2+
disease
• Initial agents
• Combination vs. Single Agents
• Use of maintenance or holidays
• Options for refractory disease
• Triple negative subsets, basal/BRCA-related –
should they be treated differently?
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Sequence of Therapy for Advanced Triple Negative or Hormonally
Refractory Breast Cancer
• Prior response/stability to
therapy
• Low disease burden, minimal
visceral involvement
• Low level of symptoms
• Monotherapy
• Significant visceral
involvement
• Significant symptoms
• Likely clinical sequelae
with small degree of
progression
• Combination therapy e.g.:
• Paclitaxel + gemcitabine
• Docetaxel + capecitabine
Maintenance
Therapy
“Induction”
• Drug Holiday
?Max Response
• e.g. Eribulin
Progression
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Cell Cycle-Specific Activity of Cytotoxics
•Vinca Alkaloids Vinorelbine
Vinblastine
•Taxoids Paclitaxel
Docetaxel
Epothilones
•Antimetabolites 5-FU, fluoropyrimidines
Gemcitabine
Methotrexate
Cell Cycle Non-
Specific Agents
• Alkylating Agents
Platinum
Cyclophos-
phamide
Thiotepa
Nitrosoureas
• Antibiotics
Anthracyclines
o Doxorubicin
o Epirubicin
o Mitoxantrone
•Podopyllotoxins Etoposide
•Camptothecins Irinotecan
•Dynamic Microtubule Inhibitors Eribulin
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Single vs Combination Chemotherapy: Recent Positive Trials in MBC - Overall Survival
O'Shaughnessy J et al JCO 2002
Albain K et al JCO 2009
Vahdat L et al. JCO 2007
11.5 14.5
Hazard ratio = 0.775
Log-rank
p=0.0126
Capecitabine/docetaxel
Docetaxel
15.8 18.5
0 10 20
Survival
Gemcitabine +
Paclitaxel (n=267)
Paclitaxel
(n=262)
12 mo 70.7% 60.9%
18 mo 50.7% 41.9%
Log rank P=0.018
HR 0.78 (0.63-0.96)
0 12 24
Months
Months
100%
100%
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Combination vs. Single-Agent Therapy for MBC: Meta-Analysis of Randomized Trials
0 0.5 1.0 1.5 2.0
Combination better Single agent better
Efficacy: c2
17.5 (p=0.00002)
0.87 (0.78–0.97)
0.70 (0.59–0.84)
0.82 (0.75–0.90)
Hazard ratio of death
(combination:single agent)
Regimens
Single agent Combination
Subtotal (deaths/patients)
Subtotal (deaths/patients)
Total (deaths/patients)
AV A + DBD A + MMC VAC CF + P ± V A + ETO AV + MMC E + VDS FEC 75
CMF + VBL CMF CMFV + P CF + P ± V CF + P ± V
FEC 50
619/738
206/252
825/990
A A A A A A A E E
C PAM F CCNU I
E
649/747
225/249
874/996
Fossati R et al. J Clin Oncol 1998
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Doxorubicin
+ Paclitaxel
36% 34% 47%
QOL
Median TTF
Response
Paclitaxel Doxorubicin
6 mos. 6 mos. 8 mos.
= = =
19 mos. 22 mos. 22 mos. Median Survival
Single vs. Combination vs. Sequential Chemotherapy
Crossover Responses: } A
T A
T = 22%
= 20%
NS
Sledge G et al. J Clin Oncol 2003
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Study Treatment Schedules N
Med TTP
(mo)
p
Med OS
(mo)
p
Coates A et al
NEJM 1987
AC/CMF until PD
305
6
0.02
10.7
0.19 AC x 3 cycles 4 9.4
Harris AL et al
Lancet 1990
Mitoxantrone until PD 43
5.5 NS
11 NS
Mitoxantrone x 4 6.5 12
Muss H et al
NEJM 1991
FAC x 6 → CMF x 12
145
9.4
<0.001
21.1
0.67 FAC x 6 3.2 19.6
Ejlertsen B
Eur J Ca 1993
FEC + TAM x 18
254
14
< .003
23
0.03 FEC + TAM x 6 10 18
Gregory R et al
Eur J Ca 1997
VAC/VEC x 6 → MMM x 6
100
10
0.01
13.0
0.3 VAC/VEC/MMM x 6 7 10.5
Falkson G et al
JCO 1998
A x 6 → CMFPTH x 8
195
18.7
<0.0001
32.2
0.74 A x 6 7.8 28.7
Nooij M et al
Eur J Ca 2003
CMF until PD
196
5.2
0.01
14.0
0.77 CMF x 6 3.5 14.4
Trials Examining Continuous vs. Interrupted/Fixed Therapy
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Study Treatment Schedules N
Med
TTP
(mo)
p
Med
OS
(mo)
p
Gennari A
et al
JCO 2006
E/A + P x 6-8 → P x 8
215
8.0*
0.817
26.0
0.547 E/A + P x 6-8 9.0* 29.0
Alba E
et al
BCRT 2010
A →T x 6 → PLD
155
13.2
8.4* 0.006*
0.002
24.8
0.44
A →T x 6 10.2
5.1* 22.0
Trials Examining Continuous vs. Interrupted/Fixed Therapy - Contemporary Regimens
* From time of randomization to maintenance arm
E = epirubicin; A = doxorubicin; P = paclitaxel; T = docetaxel; PLD
= pegylated liposomal doxorubicin
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PLD Maintenance Treatment: Toxicity
PLD (n = 78) Observation (n = 77)
Toxicity Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
Neutropenia 32% 12% 9% 0
Anemia 35% 0 12% 0
Nausea/Vomiting 21% 0 4% 0
Fatigue 32% 3% 8% 0
Alopecia 29% 0 4% 0
Mucositis 32% 5% 0 0
PPE 29% 4%* 0 0
PLD (n = 78) Observation (n = 77)
Decreased LVEF ≥10% 5 (6%) 1 (1%)
Congestive Heart Failure 0 0
* Grade 3 only Alba E, et al. Breast Cancer Res Treat 2010
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Korean Cancer Study Group (KCSG-BR07-02) Phase III Maintenance Trial
• Metastatic/Recurrent Breast Cancer
• Stability or response after 6 cycles
• Paclitaxel 175 mg/m2 q 21 d
• Gemcitabine 1250 mg/m2 d 1, 8 q 21 d
Maintenance Therapy
With Same regimen
until PD or toxicity
Observation
Randomize
Stratification
• PR/CR vs. SD
• Visceral
• ER status
• Adjuvant taxane
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Korean Cancer Study Group (KCSG-BR07-02) Phase III Maintenance Trial
Park JY, et al. J Clin Oncol 2013
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Korean Cancer Study Group (KCSG-BR07-02) Phase III Maintenance Trial
Park JY, et al. J Clin Oncol 2013
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KCSG-BR07-02: Grade 3/4 Toxicities
Park JY, et al. J Clin Oncol 2013
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Meta-Analysis of Chemotherapy Duration Survival Impact
Gennari A, et al. J Clin Oncol 2011
≈1-2 months
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Intermittent vs. Continuous Chemotherapy
Coates AS, et al. NEJM 1987
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Intermittent vs. Continuous Chemotherapy Survival and Quality of Life
Coates AS, et al. NEJM 1987
QoL index
Uniscale Score
Physical Wellbeing
Pain
Mood
Appetite Nausea/
vomiting
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What Constitutes “Best First Line” Single Agent Therapy?
• Numerous agents are active
• Effects on survival may be difficult to discern
because of heterogeneity of subsequent therapy
• Prior therapy with adjuvant anthracycline/taxane
or taxane-based therapy is common
• Initial therapy is typically taxane or capecitabine
• Taxanes are schedule dependent
• Optimal capecitabine dose undefined
• No established best initial therapy
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Paclitaxel vs Docetaxel Every 3 weeks
Jones SE, et al. J Clin Oncol 2005
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Randomized nab-Paclitaxel: CA012 Trial Progression-Free Survival
Albumin-bound paclitaxel 260
mg/m2
iv over 30 min q3w
No standard premedication
Paclitaxel 175 mg/m2
iv over 3 hrs q3w
Standard premedication with
dexamethasone and
antihistamines
Randomisation (1:1)
n = 460
Gradishar et al. J Clin Oncol 2005
Nab-Paclitaxel
Paclitaxel
p=0.006
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Paclitaxel: Dose/Schedule Comparison
CALGB 9840
Seidman A, et al. J Clin Oncol 2008
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Nab-Paclitaxel: Different Dose/Schedules vs. Docetaxel
Gradishar W et al. JCO 2009
100
mg/m2
q3w
n = 74
300
mg/m2
q3w
n = 76
100
mg/m2
qw 3/4
n = 76
150
mg/m2
qw 3/4
n = 74
Docetaxel Nab-Paclitaxel
Response Rates
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Months From Study Entry
Pro
port
ion P
rog
ressio
n-F
ree
0 10 20 30
0.0
0.2
0.4
0.6
0.8
1
PacNabIxa
Comparison HR P-value 95% CI
nab vs. pac 1.19 0.12 0.96-1.49
ixa vs. pac 1.53 < 0.0001 1.24-1.90
CALGB 40502 Progression-Free Survival By Treatment Arm
paclitaxel nab-paclitaxel ixabepilone
Agent N Median PFS
paclitaxel 283 10.6
nab-Paclitaxel 271 9.2
ixabepilone 245 7.6
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First Line Weekly Paclitaxel vs. Capecitabine w/ Bevacizumab
TURANDOT
Study
Lang I, et al. Lancet Oncol 2013
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Overall survival (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 28 26 24 22 20 18 16 14 12 10 8 6 4 2
Surv
ival pro
babili
ty
Overall Survival
Eribulin Median 13.12 months
TPC Median 10.65 months
HR* 0.81 (95% CI 0.66, 0.99) p-value†=0.041
2.47 months
TPC (n=254)
Eribulin (n=508) 53.9%
1 year survival
43.7%
ITT population; *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata †p value from stratified log-rank test (pre-defined primary analysis); HR, hazard ratio; CI, confidence intervals
Cortes et al 2010 Lancet 2011; 6736: 60070-6
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Heterogeneity of Triple Negative Breast Cancer
Otto Metzger-Filho O et al., 2012
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TNBC Responses to Platinum Agents
Baselga J et al. ESMO 2010; O’Shaughnessy J et al. SABCS 2007; Carey L, et al ASCO 2008; Isakoff J, et al. ASCO 2011; Byrski
T et al. JCO 2010; Gronwald, J, et al. ASCO 2009; Silver DP, et al. JCO 2010, Alba E, et al. ASCO 2011
Neo Adjuvant Population N pCR Rate Ref
CMF
BRCA 1
Mutation (retrospective)
14 7%
Byrski
AC 23 22%
FAC 28 21%
AT 25 8%
Cisplatin 12 83%
Cisplatin BRCA1 Mut 25 72% Gronwald
Cisplatin TNBC 28 21% Silver
EC D TNBC Basal
46 30% Alba
EC DP 47 30%
Stage IV Population ORR Ref
Control arm BALI-1 (CDDP) TNBC 10% Baselga
Control arm Phase III iniparib (Gem/carbo) TNBC 30% O’Shaughnessy
TBCRC 001 (Cetuximab/Carbo) TNBC 17% Carey
TBCRC 009 (Carboplatin or Cisplatin) TNBC 30% Isakoff
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Eribulin vs. Capecitabine OS HR by Subsets
Kaufman P, et al. SABCS 2012, Abstr S6-6
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Replication Lesions
• Base excision repair
PARP1
Mechanisms of DNA Repair
Single Strand Breaks
• Nucleotide excision repair
• Base excision repair
PARP1
Double Strand Breaks
• Non-homologous end-joining
• Homologous recombination
BRCA1/BRCA2
• Fanconi anemia pathway
• Endonuclease-mediated repair
DNA DAMAGE
Cell Death
Environmental factors
(UV, radiation, chemicals)
Normal physiology
(DNA replication, ROS)
MAJOR DNA REPAIR
PATHWAYS
Chemotherapy
(alkylating agents, antimetabolites)
Radiotherapy
Helleday et al. Nature Reviews. 2008
DNA Adducts/Base Damage
• Alkyltransferases
• Nucleotide excision repair
• Base excision repair
PARP1
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Response to Olaparib in BRCA Mutation-Associated MBC
Tutt A et al. Lancet 2010
400 mg bid 100 mg bid
400 mg bid; N=27 100 mg bid; N=27
ORR 11 (41%) 6 (22%)
CR 1 (4%) 0 (0)
PR 10 (37%) 6 (22%)
PFS (mo) 5.7 (4.6 – 7.4) 3.8 (1.9-5.5)