Secuencia óptima de tratamiento de
quimioterapia en el cáncer de mama
metastásico
Javier Cortes,
Ramon y Cajal University Hospital, Madrid, Spain
Vall d´Hebron Institute of Oncology (VHIO),
Medica Scientia Innovation Research (MedSIR)
Barcelona, Spain
Systemic Treatment Approach for HER2-Negative, Metastatic Breast Cancer
Metastatic Breast Cancer
• Asymptomatic disease
•Limited metastases (bone & soft tissue)
• Positive hormone receptors
• Hormone responsive
• Disease-free interval 2 years
• Symptomatic disease
•Extensive metastases or visceral crisis
• Negative hormone receptors
• No response to hormones
Hormonal Therapy Chemotherapy
Response No response No progression Progression of disease
If disease progresses, second-line hormonal therapy Second-line chemotherapy
Efficacy with different cytotoxic agents
G. Hortobagyi, ASCO 2003 Educational Session
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
VRL DCT PCT DOX EPI 5-FU CAP
• Anthracyclines and taxanes: the standard of care
– Increasing use in the adjuvant setting
– 15-40% relapse rate after anthracycline-taxane therapy
– No treatment has resulted in an improvement in OS after anthracyclines/taxanes
• Few proven options for patients failing anthracyclines/taxanes
– Capecitabine is the “preferred” agent for anthracycline and/or taxane failures
– Response Rates of 10-20% in phase II/III studies
– Limited efficacy of other agents (e.g. gemcitabine, liposomal doxorubicin, vinorelbine, …)
MBC: Systemic Treatment Approach
USO INTERNO
ORR Independent of Line of Therapy and Across Various Subgroups
All First-Line ≥ Second-Line Anthracycline Visceral
Patients Therapy Therapy Exposed Disease
P = .001
0
10
20
30
40
50
60
33.2%
27.0%
42.3%
18.7%
P = .029
26.5%
13.2%
P = .006
34.1%
18.3%
33.5%
P = .002 P = .002
18.7%
OR
R (±
95
% C
I)
nab-Paclitaxel: 229 97 132 176 176
Solvent-based
paclitaxel: 225 89 136 175 182
Gradishar WJ, et al. J Clin Oncol. 2005;23(31):7794-7803.
Gradishar WJ, et al. J Clin Oncol. 2011;29(Suppl 27): Abstract 275.
Months
1.00
0.75
0.50
0.25
0.00
10 20 30 40 50
Pro
bab
ilit
y o
f S
urv
ival
0
Investigator-Assessed Survival
nab-Paclitaxel 300 mg/m2 q3w (n = 76) – 27.7 months
nab-Paclitaxel 100 mg/m2 q3w (n = 76) – 22.2 months
nab-Paclitaxel 150 mg/m2 q3w (n = 74) – 33.8 months
Docetaxel 100 mg/m2 q3w (n = 74) – 26.6 months
nab-Paclitaxel vs Docetaxel: Results
CALGB 40502: Trial Design
Treatment-naïve patients
with locally recurrent or
metastatic breast cancer
(N = 799)
Paclitaxel 90 mg/m2/wk +
Bevacizumab* 10 mg/kg q2w
(n = 283)
nab-paclitaxel 150 mg/m2/wk +
Bevacizumab* 10 mg/kg q2w
(n = 271)
Ixabepilone 16 mg/m2/wk +
Bevacizumab* 10 mg/kg q2w
(n = 245)
Disease progression† Stratified by receipt of adjuvant
taxanes and HR status
Note: All chemotherapy given for 3 wks on, 1 wk off.
*Protocol amended in March 2011 (n = 669) to allow optional use of bevacizumab following ODAC recommendation that
approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab. †Patients with SD or responding disease after 6 cycles could discontinue chemotherapy and continue bevacizumab alone.
Rugo HS, et al. J Clin Oncol. 2012;30(Suppl): Abstract CRA1002.
CALGB 40502 PFS by Treatment Arm
Comparison HR P Value 95% CI
Nab vs Pac 1.19 .12 0.96-1.49
Ixa vs Pac 1.53 <.0001 1.24-1.90
Pro
po
rtio
n P
rog
ress
ion
Fre
e
1
0.8
0.6
0.4
0.2
0
0 10 20 30 Months
Paclitaxel
nab-Paclitaxel
Ixabepilone
Agent N Median PFS, Months from Study Entry
Paclitaxel 283 10.6
nab-Paclitaxel 271 9.2
Ixabepilone 245 7.6
Rugo HS, et al. J Clin Oncol. 2012;30(Suppl): Abstract CRA1002.
CALGB 40502 PFS by Treatment Arm
Rugo HS, et al. J Clin Oncol. 2012;30(Suppl): Abstract CRA1002.
11
Capecitabine in Anthracycline-Taxane-pretreated
Metastatic Breast Cancer
1. Blum JL, et al. J Clin Oncol. 1999;17:485-493.
2. Blum JL et al. Eur J Cancer 001;37:S190 (Abstract 693)
3. Blum JL et al. Cancer 2001;92:1759-1768.
4. Reichardt P et al. Ann Oncol. 2003;14:1227-1233.
5. Fumoleau P et al. Eur J Cancer. 2004;40:536-542.
Study N CR +
PR, %
Disease
Control
(CR +
PR +
SD), %
Median
Response
Duration
, mos
Median
TTP,
mos
Median
Surviva
l, mos
Blum et al.1-2 162 20 63 7.9 3.0 11.6
Blum et al.3 74 26 57 8.3 3.2 12.2
Reichardt et al.4 136 15 62 7.4 3.5 10.1
Fumoleau et al.5 126 25 54 5.0 4.6 15.2
Nab-paclitaxel in taxane-refractory patients
1. Blum JL et al., Proc Am Soc Clin Oncol. 2004. Abstract 543.
• Albumin-bound paclitaxel, nanoparticle formulation
• Phase II trial, taxane-refractory MBC (N = 106)
– 100 mg/m2 weekly, Days 1, 8, and 15 every 28 days
– Objective PR in 16 pts (15%); PR+SD ≥ 16 wks, 32 (30%)
– Probability of surviving to 12 months, 38%
– Well tolerated without steroids or G-CSF prophylaxis
• Grade 4 neutropenia, 1%; grade 3, 14%
• Grade 3 sensory neuropathy, 4%
Ixabepilone
New Compounds
Eribulin mesylate
Etirinotecan Pegol
OO
MeO
OO
O
O
O
OO
Me
HH
H
H
H3N
HO
Eribulin Mesylate
1
MsO
Vinflunine
Locally recurrent or metastatic breast cancer (n=852)
• Prior treatment with anthracycline, a taxane, and capecitabine
• ECOG PS 0-1
• 2-5 prior chemotherapies for advanced disease
• Stable brain mets allowed
BEACON Phase 3 Study Design
Single-Agent Etirinotecan Pegol
145 mg/m2 every 3 weeks
(n=429)
Single-Agent Treatment of Physician’s Choice (TPC)
Docetaxel, eribulin, gemcitabine, ixabepilone, nab-paclitaxel,
paclitaxel or vinorelbine
(n=423)
R
Stratification:
• Geographic region
• Prior eribulin use
• Receptor status
135 centers in US, Canada, Belgium, France, Germany, Italy, Korea, Russia, Spain, The Netherlands, UK
Enrollment: Dec 2011 – Aug 2013 Event cutoff: Dec 2014
Primary Endpoint
• Overall Survival
Secondary Endpoints
• PFS, ORR, CBR, DoR, HRQoL
Exploratory Endpoints
• PD Markers in CTC, others
Perez E, et al. Lancet Oncol 2015
Primary Efficacy Endpoint: Overall Survival
1.0
0.8
0.6
0.4
0.2
0.0
0 3 6 9 12 15 18 21 24 27 30
429
423
392
371
331
301
276
229
219
177
161
142
91
93
53
52
25
25
10
9
3
2
Number at Risk:
Months from Randomization
Su
rviv
al P
rob
ab
ility
Events OS (95% CI)
Etirinotecan Pegol (n=429) 318 12.4 mo (11.0-13.6)
TPC (n=423) 329 10.3 mo (9.0-11.3)
HR (95% CI): 0.872 (0.747-1.019)
Log-rank P-value = 0.0835
Perez E, et al. Lancet Oncol 2015
Overall Survival in Patients With History of
Brain Metastases (n=67)
1.0
0.8
0.6
0.4
0.2
0.0
0 3 9 12 15 18 21 24 27 30
36
31
33
27
22
7
16
6
13
4
4
2
3
2
2
1
1
0
0
Months from Randomization
Su
rviv
al P
rob
ab
ility
Events OS (95% CI)
Etirinotecan Pegol (n=36) 31 10.0 mo (7.8-15.7)
TPC (n=31) 29 4.8 mo (3.7-7.3)
HR (95% CI): 0.511 (0.304-0.858)
Log-rank P-value = 0.0099
26
14
Number at Risk:
6
72.2% (54.5-84.0)
45.2% (27.4-61.4)
44.4% (28.0-59.6)
19.4% (7.9-34.6)
Perez E, et al. Lancet Oncol 2015
VINFLUNINE: Phase III Study Design
Cortes J, et al. ASCO 2015
VINFLUNINE: OS
Cortes J, et al. Ann Oncol 2018
HR 0.99 (95% CI 0.82, 1.22)
p value=0.99
Median
OS
Vinflunine 9.7
AA 9.3
Eribulin Mesylate
• Halichondrins ― a new class of antineoplastic agents
• Eribulin is an synthetic analog of halichondrin B, a natural product found in marine sponges
• Non-taxane microtubule dynamics inhibitor
– Inhibits through a novel mode of action distinct from other tubulin-targeting agents
• Potent antiproliferative agent against many human cancer types in vitro and in vivo
• Active against β-tubulin mutated cell lines
• Unusually wide therapeutic window for a chemotherapeutic agent
• Eribulin induces less neuropathy in mice than paclitaxel or ixabepilone
Halichondria okadai
O
O OO
O
O
O
OO
Me
HH
H
H
O
O
O
O
O
O
O
HO
HO
HO Me
Me
H
H H
H
Me
H
H
H
H
H
Halichondrin B
OO
MeO
OO
O
O
O
OO
Me
HH
H
H
H3N
HO
Eribulin Mesylate
1
MsO
Towle et al 2001; Jordan et al 2005; Kuznetsov et al 2004;
Okouneva et al 2008; Smith et al 2010
EMBRACE Study Design
Treatment of Physician’s Choice (TPC)
Any monotherapy (chemotherapy,
hormonal, biological)* or supportive
care only†
Eribulin mesylate
1.4 mg/m2, 2-5 min IV bolus
Day 1, 8 q21 days
Patients (n=762)
• Locally recurrent or
metastatic breast cancer
• 2-5 prior chemotherapies
– ≥2 for advanced disease
– Prior anthracycline and
taxane
• Progression on or within
6 months of last
chemotherapy
• Neuropathy ≤grade 2
• ECOG ≤2
Stratification • Geographic region
• Prior capecitabine treatment
• HER2/neu status
ACCRUAL: Nov 2006 – Nov 2008
Global, randomized, open-label
Phase III trial (Study 305)
2:1
R
* Approved for treatment of cancer and administered according to local practice, if applicable. †Or palliative treatment or radiotherapy.
Cortes J, et al. Lancet. 2011
TPC Treatment Received
Taxanes: paclitaxel, docetaxel, Abraxane
Anthracyclines: doxorubicin, epirubicin, liposomal doxorubicin
25%
19%18%
15%
10% 10%
4%
0%
5%
10%
15%
20%
25%
30%
% o
f P
atie
nts
n=61 n=46 n=44 n=39 n=24 n=25 n=9
96% of patients were treated with chemotherapy
No patients received only best supportive care or biological therapies
Total pts = 247
Cortes J, et al. Lancet. 2011
HER2, human epidermal growth factor receptor type 2; HR, hazard ratio; CI, confidence intervals; TPC, treatment of physician’s choice †HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata ‡Nominal p value from stratified log-rank test.
EMBRACE Updated Survival Analysis:
Overall Survival
Twelves C, et al. San Antonio Breast Cancer Symposium 2010. Abstract P6-14-08
Treatment
Eribulin (n=325)
TPC (n=163)
Study Design (Study 301)
Global, randomized, open-label Phase III trial (Study 301)
Stratification:
– Geographical region, HER2 status
†Equivalent to 1.23 mg/m2 eribulin
Capecitabine 1250 mg/m2 BID orally
Days 1-14, q21 days
Eribulin mesylate
1.4 mg/m2† 2- to 5-min IV
Day 1 & 8 q21 days
Randomization 1:1
Co-primary endpoint
• OS and PFS
Secondary endpoints
• Quality of life
• ORR
• Duration of response
• 1-, 2- and 3-year survival
• Tumor-related symptom
assessments
• Safety parameters
• Population PK (eribulin
arm only)
Patients (N=1102)
Locally advanced or MBC • ≤3 prior chemotherapy
regimens (≤2 for
advanced disease)
• Prior anthracycline and
taxane in (neo)adjuvant
setting or for locally
advanced or MBC
Kaufman P, et al. SABCS 2012
Overall Survival S
urv
iva
l p
rob
ab
ilit
y
Time (months)
0
0.0
0.2
0.4
0.6
0.8
1.0
56 52 48 44 40 36 32 28 24 20 16 12 8 4
HR† 0.879 (95% CI 0.770, 1.003)
p value‡=0.056
Median OS
(months)
Eribulin (n=554) 15.9
Capecitabine (n=548) 14.5
ITT population; †HR Cox model including geographic region and HER2 status as strata ‡p value from stratified log-rank test based on clinical database Kaufman P, et al. SABCS 2012
HR† 0.977 (95% CI 0.857, 1.114)
p value‡=0.736
HR† 1.079 (95% CI 0.932, 1.250)
p value‡=0.305
Time (months)
Investigator Review Independent Review
1.0
0.8
0.6
0.4
0.2
0.0
Su
rviv
al p
rob
ab
ilit
y
Time (months)
0 4 8 12 16 20 24 28 32 36 40 44 0 4 8 12 16 20 24 28 32
1.0
0.8
0.6
0.4
0.2
0.0
Su
rviv
al p
rob
ab
ilit
y
36 40 44
ITT population; †HR Cox model including geographic region and HER2 status as strata ‡p value from stratified log-rank test based on clinical database
Median
(months)
Eribulin (n=554) 4.1
Capecitabine (n=548) 4.2
Median
(months)
Eribulin (n=554) 4.2
Capecitabine (n=548) 4.1
Progression-free Survival
Kaufman P, et al. SABCS 2012
Non-Hematologic Adverse Events†
Safety population †Incidence >10% (all grades) or 1% (Grade 3 or higher) in either arm; ‡Grade 5 events also occurred in 0.7% and 0.5% of patients, respectively
If a subject had two or more AEs in the same system organ class or with the same preferred term with different CTCAE grades, then the event with the
highest grade was used for that subject
Eribulin
(n=544)
Capecitabine
(n=546)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
% % % % % %
Hand-foot syndrome <1 0 0 45 14 0
Alopecia 35 - - 4 - -
Diarrhea 14 1 0 29 5 <1
Nausea 22 <1 0 24 2 0
Vomiting 12 <1 <1 17 2 0
Fatigue 17 2 0 15 2 <1
Asthenia 15 4 <1 15 4 0
Decreased appetite 13 <1 0 15 2 0
Peripheral sensory neuropathy 13 4 0 7 <1 0
Pyrexia 13 <1 0 6 <1 0
Headache 13 <1 0 10 <1 <1
Dyspnea 10 2 <1‡ 11 3 <1‡
Back pain 10 2 0 8 <1 0
This presentation is the intellectual property of the author.
Pre-Specified Subgroup Analysis
Kaufman P, et al. SABCS 2012
Overall 0.879 (0.770, 1.003) 15.9 14.5
HER2 status
Positive 0.965 (0.688, 1.355) 14.3 17.1
Negative 0.838 (0.715, 0.983) 15.9 13.5
ER status
Positive 0.897 (0.737, 1.093) 18.2 16.8
Negative 0.779 (0.635, 0.955) 14.4 10.5
Triple negative
Yes 0.702 (0.545, 0.906) 14.4 9.4
No 0.927 (0.795, 1.081) 17.5 16.6
Subgroup HR (95% CI) Eribulin Capecitabine
Median (months)
ITT population
Overall Survival By Receptor Status
0.2 0.5 1.0 2 5
n=755
n=449
n=284
Favors eribulin Favors capecitabine Kaufman P, et al. SABCS 2012
The Pooled Analysis
Study 3051 EMBRACE (Eisai Metastatic
Breast Cancer Study Assessing
Treatment of Physician’s Choice
(TPC) versus Eribulin E7389)
Study 3012
• Global, open-label, randomised, pivotal Phase III
trial
• First presented 2010
• Used for the regulatory approval of Halaven in
over 55 countries
• Global, open-label, randomised, two-parallel-
arm, pivotal Phase III trial
• First presented 2012
• Didn’t reach primary endpoint
• European Medicines Agency requested further
evaluation
• Pooled analysis requested by EMA as supplementary
information for review of eribulin
• Final decision by EMA based on two Phase III (305 and
301) trials as separate entities1-2
Efficacy of eribulin in MBC by HER2
and triple negative status
Overall HER2− HER2+ TNR
Eribulin C Eribulin C Eribulin C Eribulin C
n 1062 802 748 572 169 123 243 185
HR
(95% CI)a
0.85 (0.77, 0.95) 0.84 (0.72, 0.93) 0.82 (0.62, 1.06) 0.74 (0.60, 0.92)
p 0.003 0.002 0.135 0.006
Eribulin´s Mechanisms of Action
1. Tubulin-based Antimitotic Effects
2. Complex Non-Mitotic Effects on Tumor Biology*
1. Tumor Vasculature Remodeling
2. Reversal of EMT
3. Decrease Capacity for Migration and Invasion
*As shown in preclinical studies
Eribulin blocks mitotic spindle formation, causing
cell death by apoptosis
Towle MJ, et al. Cancer Res 2001; Kuznetsov G, et al. Cancer Res 2004
After a single dose of Eribulin, Perfusion becomes
uniform across tumor core and rim
Funahashi Y, et al. Cancer Sci 2014
Eribulin induces epithelial morphology in surviving
breast cancer cells in vitro
Yoshida T, et al. Br J Cancer 2014
Eribulin reverses EMT in Tumors in vivo
Yoshida T, et al. Br J Cancer 2014
Eribulin decreases in vitro migration and invasion
Yoshida T, et al. Br J Cancer 2014
Experimental metastases in mice
www.benchmarks.cancer.gov
Eribulin prevents experimental metastasis and
increases survival in mice
Yoshida T, et al. Br J Cancer 2014
Eribulin Mesylate:
Ongoing Clinical Trial Programme
NeoEribulin: A Phase II, open-label, single-arm, pharmacogenomic study of
single agent E7389 (eribulin mesylate) as neoadjuvant treatment for operable
Stage I-IIIA HER2 non-overexpressing breast cancer
Pharmacogenomic Study of Eribulin in HER2-ve BC -EISAI
ERIBULIN1.4 mg/m2 D1, D8 Q21days
4 Cycles
I and IIIAOperable HER2 Negative
S
U
R
G
E
R
Y
Post-SurgeryTreatment
as per Investigator
(Anthracyline-based therapy recommended)
Core orIncisionalBiopsy
Imaging Dx
Day 21Core Biopsy
PEMammo/US/MRI pCRB
pCRBLBCR > 60%
N200
Eribulin Safety GeneExpression Profile
ORRBORR
Phase II, open-label, single-arm exploratory study of the safety and pharmacogenomics of single agent E7389 (eribulin mesylate) in patients with operable Stage I-IIIA HER2 non-overexpressing breast cancer (J. Cortés)
C O N F I D E N T I A L
DFS
Eribulin Mesylate:
Ongoing Clinical Trial Programme
Prat A, et al. SABCS 2015
Number of lines of chemotherapy by line and subtype
Median duration of chemotherapy according to line and subtype
Use and Duration of Chemotherapy in Patients With Metastatic Breast Cancer According to
Tumor Subtype and Line of Therapy
Seah DSE et al. J Natl Compr Canc Netw 2014
CASCADE STUDY: Patient Prevalence decay per
line of treatment and tumour immunotype
Chemo-based Treatment Approach for HER2-Negative, Metastatic Breast Cancer
Metastatic Breast Cancer
Scientific approach
•Anthracyclines and taxanes pretreated
Eribulin (TNMBC)
(HER2 neg?)
/IF capecitabine decided)
Progression of disease (after 1 lines)
If disease progresses,
Second/third-line chemo therapy
Eribulin
Capecitabine
Gemcitabine
Vinorelbine
Regulatory approach
•Anthracyclines and taxanes pretreated
