Advertisment
Press Release – Halaven® data presented at ECCO 2013
17th ECCO – 38th ESMO – 32nd ESTRO – European Cancer Congress, Amsterdam RAI, 27 Sept – 1 Oct 2013.
Eribulin represents a novel class of antineoplastic agents which targets the microtubule during a critical stage of the cell division process. Eribulin is licensed for the treatment of locally advanced or metastatic breast cancer in patients who have progressed after at least two chemotherapeutic regimens for advanced disease, and whose previous treatment has included included an anthracycline and a taxane. 
Although the mechanism of action of eribulin has not been fully documented, it is known to bind irreversibly to its microtubule target and cause mitotic block and cell death by apoptosis [1]. Further mechanisms of action that have been proposed include increasing the vascular permeability of the tumour and thereby rendering the tumour cells less invasive, and inducing an alteration in the epithelial morphology [2-5].
The clinical efficacy and tolerability of eribulin has been demonstrated in a pivotal phase 3 open-label randomised study, EMBRACE [6]. This study included 762 women with locally recurrent or metastatic breast cancer who were randomised to receive eribulin or treatment of the investigator’s choice, and showed a significantly higher overall survival rate in the eribulin arm (median 13.1 months) compared with the control arm (10.6 months; hazard ratio 0.81; 95% CI 0.66, 0.99; p=0.041) – a clinically meaningful difference according to the investigators, with an acceptable tolerability profile.
A series of abstracts were presented at this year’s ECCO congress in Amsterdam, which provide further evidence on the clinical profile of eribulin; this report provides a summary of these abstracts.
ABSTRACT: First year daily clinical experience with eribulin in Spain; EUFORIA-1 study (Eribulin Use For the treatment of advanced breast cancer: Observational, Retrospective Analysis)
Manuel Ruiz-Borrego et al, Hospital Virgen del Rocio, Seville, Spain
The first of the eribulin abstracts presented at ECCO 2013 showed the results of the first observational study in a European setting, from a retrospective multi-centre study in Spain. Although eribulin received marketing authorisation in April 2011, national pricing negotiations meant hospitals could only access the treatment through a nation-wide compassionate use programme. The objective of the EUFORIA-1 study was to evaluate the experiences gathered during the first year of eribulin use in hospitals where at least three patients had been treated, to determine whether the real-life profile of eribulin matches that seen in the EMBRACE clinical study.
The study included 19 hospitals, providing data for a total of 104 patients with a median age of 57 years, who had (or could have received) ≥3 cycles of treatment by March 2012. 75% of the patients had ECOG status ≤1 in 75.4%; 64% of tumours were ER+; 15.4% of tumours overexpressed Her-2 and 29.8% of patients were triple-negative. Patients received eribulin for a mean treatment duration of three months.
At the end of January 2013, 31% of the patients included in the study were still alive. Median progression-free survival (PFS) was 3.2 months (95% CI 2.7, 4,3) and median overall survival (OS) 8.8 months (95% CI 7.0, 10.0). The overall response rate was defined as patients showing a complete response (CR) or partial response (PR) to treatment; this proportion was 23%. A total of 79% of the patients reported at least one adverse event during the treatment course, most frequently asthenia, neutropenia, anaemia, alopecia, nauseas, and mucositis. Adverse events of severity grade 3 or above occurred in ≤5% of patients. The investigators concluded that the EUFORIA-1 trial adds valuable information to the efficacy and safety evidence base for eribulin, and that confirmatory data can be expected in the planned EUFORIA-2 observational study.
New metastases versus increase in size of pre-existing lesions and its correlation with overall survival in patients with MBC treated with eribulin or capecitabine in study 301, a phase III randomised trial
Edith Perez et al, Mayo Clinic, Jacksonville, USA
The second eribulin abstract to be presented at ECCO 2013 showed the results of an analysis performed on patients included in the recent clinical study 301, which compared the clinical efficacy of eribulin with capecitabine in women with metastatic breast cancer. The primary results of this study revealed that patients treated with eribulin seemed to survive for longer overall than patients treated with capecitabine, but no difference in progression-free survival was seen [7]. The post-hoc analysis presented at ECCO 2013 was performed to clarify whether the nature of an event defining disease progression, defined as the appearance of a ‘new’ lesion or metastasis (NM), an increase in size of pre-existing lesions (IPEL), or other progression event such as death or clinical progression, may predict the overall survival outcome.
Included in the analysis were 832 women whose breast cancer progressed due to new metasases (271 and 285 patients in the eribulin and capecitabine arms, respectively) or pre-existing lesions (147 and 129 patients, respectively). As a general finding, patients who developed new metastases had poorer overall survival than patients in whom pre-existing lesions increased in size (hazard ratio [HR] 2.12; 95%CI 1.84, 2.43; p<0.0001). In the latter group there was no significant difference in overall survival between eribulin and capecitabine; in contrast, patients who developed new metastases and who received eribulin survived for a median of 2.6 months longer than patients who received capecitabine (15.5 months vs 12.9 months; HR 0.81; 95% CI 0.68, 0.97; p=0.02) (Table 1). Amongst patients who developed new metastases, there was no statistically significant difference between the treatment groups in the time to new metastases on the liver, lungs or central nervous system. Based on these findings, the 301 investigators hypothesised that the definition of PFS used in the primary efficacy analysis of the 301 study may have been insufficient to explain the difference in OS but not in PFS, and concluded that further prospective studies are needed to determine the full extent to which different progression events affect influence outcomes [7].
|
Table 1. Results overview. |
||||||
|
|
Progression event |
|||||
|
|
NM |
IPEL |
Other |
|||
|
|
E (n=271) |
C (n=285) |
E (n=147) |
C (n=129) |
E (n=136) |
C (n=134) |
|
Median OS, months (95%CI) |
15.5 (14.2,17.5) |
12.9 (11.3,14.5) |
17.4 (14.4,19.7) |
17.4 (15.3,20.9) |
16.7 (14.8,24.2) |
15.5 (11.7,18.3) |
|
HR (95%CI) |
0.81 (0.68, 0.97) |
1.13 (0.87, 1.46) |
0.78 (0.59, 1.03) |
|||
|
Nominal p-value |
0.02 |
0.35 |
0.08 |
|||
|
Time to NM, months (95%CI) |
5.8 (5.2,6.5) |
5.2 (4.3,5.9) |
||||
|
HR (95%CI) |
0.90 (0.77, 1.05) |
|||||
|
Nominal p-value |
0.17 |
|||||
A post-hoc analysis had also been performed using data from the EMBRACE study, and the results presented in a poster by the study sponsor. The rationale for the study was a hypothesis that the sequence of chemotherapy given prior to eribulin may affect the outcome in terms of overall survival. The analysis explored three prior chemotherapy treatment sequences: capecitabine, vinorelbine, and capecitabine plus vinorelbine and comprised a total of 508 patients. No difference in overall survival was seen between eribulin patients who received either of the three prior treatments and those eribulin patients who did not, and the authors concluded that the only therapies that should be mandatory prior to starting eribulin should be those stated in the study inclusion criteria, ie an anthracycline and a taxane in either the neo/adjuvant and/or metastatic setting.
Last but not least, amongst the eribulin abstracts presented at ECCO 2013 was also a Phase I study documenting combination treatment with eribulin and trastuzumab in Japanese patients with advanced or recurrent HER2-positive breast cancer, which showed that the combination was well tolerated, and a population pharmacokinetics analysis which used data from Phase I-III studies to characterise the pharmacokinetic profile of eribulin and identify factors that predict eribulin exposure. This abstract was also presented by the sponsor and comprised data from 513 individuals, 389 of whom had breast cancer. Body weight and the hepatic function markers albumin, alkaline phosphatase and bilirubin were identified as significant predictors of eribulin clearance.
Bridget Macleod from the UK has metastatic breast cancer and has received eribulin as a clinical study patient. In an interview with Professor Chris Twelves, one of the principal investigators on the EMBRACE study, Miss Macleod explained that the most important thing during cancer treatment was to be able to get on with your life as normal, like it was before the cancer. For her, the experience with eribulin had been largely positive – she kept her hair and experienced only small drops in blood count, which mostly returned to normal before leaving the hospital, and was able to complete all treatment cycles. Participating in clinical studies can make a big difference to the cancer treatment, according to Bridget Macleod – aspects such as receiving treatment in a smaller and friendlier clinic, and getting help with things like travel expenses can be an enormous help when cancer is effecting your life in every way.
References
1. Smith, J.A., et al., Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry, 2010. 49(6): p. 1331-7.
2. McCracken and e. al, Abstract presented at AACR. 2013(Abstract 4502).
3. Dezso and e. al, Abstract presented at AACR. 2013(Abstract 1522).
4. Agoulnik and e. al, Abstract presented at AACR. 2013(Abstract 3830).
5. Matsui and e. al, Abstract presented at AACR. 2013(Abstract 1413).
6. Cortes, J., et al., Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet, 2011. 377(9769): p. 914-23.
7. Kaufman, P. and e. al, Abstract presented at CTRC-AACR. 2012(Abstract S6-6).
