A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment of physician’s choice in patients...
16
A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane Dr Chris Twelves Professor of Clinical Cancer Pharmacology and Oncology University of Leeds & St James’s University Hospital, Leeds, UK On behalf of the abstract co-authors and EMBRACE investigators *Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus Eribulin (E7389)
A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously
A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment
of physicians choice in patients with locally recurrent or
metastatic breast cancer previously treated with an anthracycline
and a taxane Dr Chris Twelves Professor of Clinical Cancer
Pharmacology and Oncology University of Leeds & St Jamess
University Hospital, Leeds, UK On behalf of the abstract co-authors
and EMBRACE investigators *Eisai Metastatic Breast Cancer Study
Assessing Physician's Choice Versus Eribulin (E7389)
Slide 2
Introduction There is a significant need for therapies that
improve overall survival in MBC Several established cytotoxic
therapies for MBC however, many patients do not respond, or become
refractory No single standard of care for heavily pre-treated MBC
depends upon prior treatment, availability, and patient /
oncologist preference To date, no single agent has demonstrated
overall survival benefit in heavily pre-treated MBC MBC, metastatic
breast cancer
Slide 3
Halichondrins a new class of antineoplastic agents Eribulin is
a synthetic analog of halichondrin B, a natural marine sponge
product Non-taxane microtubule dynamics inhibitor with a novel mode
of action Potent anti-proliferative agent in vitro and in vivo
Active against -tubulin mutated cell lines Wide therapeutic window
and induces less neuropathy in mice than paclitaxel Eribulin
mesylate Towle et al 2001; Jordan et al 2005; Kuznetsov et al 2004;
Okouneva et al 2008; Smith et al 2010 Halichondria okadai O O H H O
H H O Me O O O O Halichondrin B H H O O Me O H H H O O O HO Me H H
O O H H 1 O MeO Eribulin Mesylate HO H3NH3N + MsO -
Slide 4
Phase II clinical activity Study 201 (N=87 per protocol) Study
211 (N=269 eligible population) Median number of prior therapies
(range) 4 (1-11) 4 (2-5) ORR, %11.5*9.3* Clinical benefit rate, %
(CR + PR + SD 6 months) 17.217.1 Vahdat et al JCO 2009; 27:
2954-2961 Cortes et al 2010 (accepted for publication by JCO) *No
complete responses Results are based upon independent radiological
review Intent-to-treat population (n=103) ORR, objective response
rate; PR, partial response; SD, stable disease.
Slide 5
Locally recurrent or MBC 2-5 prior chemotherapies Progression 6
months of last chemotherapy Neuropathy grade 2 ECOG 2 Eribulin
mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Treatment of
Physicians Choice (TPC) Any monotherapy (chemotherapy, hormonal,
biological)* or supportive care only Randomization 2:1 PFS ORR
Safety Overall survival Primary endpoint Secondary endpoints
EMBRACE study design Stratification: Geographical region, prior
capecitabine, HER2/neu status Global, randomized, open-label Phase
III trial (Study 305) Patients (N=762) 2 for advanced disease Prior
anthracycline and taxane * Approved for treatment of cancer Or
palliative treatment or radiotherapy administered according to
local practice, if applicable ECOG, Eastern Cooperative Oncology
Group; IV, intravenous; PFS, progression-free survival; HER2/neu,
human epidermal growth factor receptor 2
Slide 6
Statistical plan Primary pre-defined analysis in the ITT
population Two-sided stratified log-rank test by randomization
parameters Overall survival nominal significance level 0.049
(adjusted interim analysis); no other adjustments made Analysis
planned at 411 events (actual number 422 events) Achieved 12 May
2009 Survival follow up analysis ongoing All subset analyses were
pre-planned ITT, intent-to-treat population
Slide 7
Patient characteristics Eribulin (n=508) TPC (n=254) TOTAL
(n=762) Median age (range) 55 (28-85) 56 (27-81) 55 (27-85) ECOG, %
0 1 2 Missing 43 48 8 1.6 41 50 9 1 42 49 8 1 Geographic region, %
I North America, Western Europe, Australia II Eastern Europe,
Russia, Turkey III Latin America, South Africa 64 25 11 64 25 11 64
25 11 Prior capecitabine, % Yes No 73 27 74 26 73 27 Median no.
prior chemotherapy regimens (range)4 (1-7)4 (2-7)4 (1-7) ITT
population
Slide 8
Disease characteristics Eribulin (n=508) TPC (n=254) TOTAL
(n=762) ER positive, %6667 PR positive, %504850 HER2/neu status, %
Positive16 Negative737674 Unknown109 Triple (ER/PR/HER2) negative,
%182120 No. organs involved, % 2514649 >2495451 Sites of
disease,* % Liver586361 Lung393738 Bone606261 ITT population;
*Clinically relevant sites of disease; ER, estrogen receptor; PR,
progesterone receptor
Slide 9
TPC treatment received ITT population; Taxanes: paclitaxel,
docetaxel, abraxane, (ixabepilone) Anthracyclines: doxorubicin,
liposomal doxorubicin, mitoxantrone 96% of patients treated with
chemotherapy % of patients Total patients = 247 n=61 n=46 n=44 n=38
n=24 n=25 n=9 No patient received best supportive care or
biological therapies only
Slide 10
Overall survival (months) 0.0 0.2 0.4 0.6 0.8 1.0
0282624222018161412108642 Survival probability 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
Slide 11
Progression-free survival 20 Eribulin (n=508) TPC (n=254) Time
(months) Independent review (ITT) Proportion progression-free 1.0
0.0 0.2 0.4 0.6 0.8 02468 10 12141618 Eribulin TPC HR 0.87 (95% CI
0.71, 1.05) p-value=0.14 Median (months) 3.7 2.2 PFS in the
per-protocol population was significant with both independent
(p=0.02) and investigator review (p
EMBRACE: conclusions EMBRACE is the first Phase III
single-agent study in heavily pre-treated MBC to meet its primary
endpoint of prolonged overall survival Eribulin demonstrated a
statistically significant improvement in overall survival
Improvement of median overall survival was 2.5 months (23%)
Clinically meaningful in heavily pretreated patients Overall
response rate and progression-free survival also favored eribulin
These benefits were achieved with a manageable safety profile
Acknowledgements We would like to thank all of the patients, as
well as the investigators and their teams, who participated in the
EMBRACE study These results potentially establish eribulin as a new
option for women with heavily pre-treated MBC