Survival benefits following eribulin in advanced liposarcoma and leiomyosarcoma
Dr Patrick Schöffski - University Hospitals Leuven, Leuven, Belgium
Could you tell me, first of all, a little bit about this agent eribulin?
The investigational agent is called eribulin. Eribulin is a synthetic compound and it’s related to a natural compound which originally comes from a marine sponge and is called halichondrin B. It’s a simplified, optimised halichondrin B drug.
And it is described as a microtubule dynamics inhibitor, what does that mean and why is that significant in cancer?
This drug interferes with tubulin polymerisation which is a target of a number of anti-cancer agents but the mode of action of eribulin is different from other tubulin inhibitors. In addition to the classical anti-mitotic effects that this drug has, it also has a few, let me say, unconventional effects like it can revert the epithelial to mesenchymal transition that we observe in many aggressive advanced types of cancers. It also has effects on the invasiveness of tumours and on the aggressiveness of tumours.
So some very interesting effects. Why did you want to use it in sarcomas?
The study that I’m presenting here at ASCO this year is based on the results of a phase II study that I published in the Lancet Oncology in 2011. We performed a trial through the European Organisation for Research and Treatment of Cancer in four different subtypes of soft tissue sarcoma with eribulin and we came up with promising findings in two of the four subtypes.
And the choice of sarcoma was for what reason?
We started looking at eribulin in trials in soft tissue sarcoma based on very limited preclinical information. The manufacturer of the compound had tested the drug in a number of in vitro models, so in cell lines originating from sarcomas. That was the basis for doing an exploratory phase II study that led to the phase III study that I’m presenting here today.
So in the phase III study could you describe what you were able to do?
The phase III study focussed on two sub-families of soft tissue sarcomas, the liposarcoma family and the leiomyosarcoma family. Within these two subtypes of sarcomas we focussed on tumours with intermediate or high grade, so we are selecting for patients with aggressive cancers. Furthermore, we were selecting for patients who had already failed two or even more lines of prior treatment.
So basically these were difficult to treat cancers and the patients had very few options.
These are very rare cancers and for these types of cancers less than a handful of drugs are approved and can be used. So we were looking into a population with a high unmet medical need.
Rare cancers maybe, but you recruited a good number of patients.
Yes. Soft tissue sarcomas in general are very rare, only one out of a hundred patients treated by oncologists has a mesenchymal tumour or a sarcoma. Then we have to consider the heterogeneity of sarcomas. Soft tissue sarcoma is a family of fifty different diseases and we were only looking at two of the more common subtypes of sarcomas.
And you looked at around 400 patients.
We enrolled in our trial 452 patients, which is a huge trial in the field of soft tissue sarcoma, to make it powered for a very important clinical endpoint that we looked at in this trial which is overall survival.
What did you find?
We found in this study that the investigational agent, eribulin, can prolong overall survival when compared to patients treated with the established cytotoxic compound dacarbazine. The difference in overall survival was two months; the overall survival, the median overall survival, in the eribulin group was 13.5 months and in the dacarbazine group 11.5 months.
What does this mean, then, to doctors who might occasionally have a patient with one of these sarcomas?
In principle sarcomas should be treated in reference sites where the doctors are not only seeing occasionally a patient with sarcoma. So I’m very much in favour of centralising care for patients with such rare diseases. Remember that in this trial we looked at patients who had failed already two or more lines of treatment.
So the criteria for choosing your patients would be previous treatment failure, would it?
Yes. This is what we did in the trial. We looked at patients who had failed two lines of treatment or more, including an anthracycline and anthracyclines are the most commonly used agents in sarcoma in general. Many patients in this trial had received more than two lines of treatment.
So what are the clinical implications coming out of this study, then?
I think the most important implication of our results is that for the first time in the history of clinical research in the field of soft tissue sarcoma we came up with results of a large, well-powered study with a proven overall survival benefit. This is unique to this trial, it has never happened before in the field of sarcoma research.
And it was in refractory or relapsing patients who were heavily pre-treated?
It was done in patients who were heavily pre-treated, had failed a number of other agents. And what we should not forget, we compared against an active drug because dacarbazine is a drug that we use in such patients in clinical routine.
Effective eribulin appears to be but what about toxicity?
This 452 patient trial gave us, of course, an opportunity to look at the safety profile of both agents that we used in this trial. The bottom line is that we did not come up with any surprises. The safety profile of both eribulin and dacarbazine matched our expectations. There were no new safety findings observed in this trial.
Interestingly, you included patient reported outcomes, didn’t you?
Yes. We took the opportunity of this huge trial to also collect patient reported outcomes. I cannot report the outcome here at this meeting but we are planning to present such data at the next large international meetings.
And the significance of doing that is what?
In the field of palliative treatment of patients with advanced metastatic cancers it’s very important not only to look at objective trial readouts like overall survival, that was met in this trial as I told you before, but also to look at the patients’ perspective, the patients’ perception of the actual treatment. So we felt that it was important to compare the quality of life, the health-related quality of life of patients entered into the two arms of this trial.
So what is the bottom line message that clinicians need to take home from this study that you’ve just been talking about here at the ASCO meeting?
The bottom line of this study is that eribulin is capable of prolonging overall survival in patients with metastatic soft tissue sarcoma after failure of two or more lines of systemic treatment, including an anthracycline.