ECC 2013

FLIMS workshop: Methods in clinical cancer research

Dr Piotr Rutkowski - Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

Methods in clinical cancer research, you’re talking about the workshop on this, FLIMS workshop; it’s a joint effort between a number of distinguished cancer bodies. Why is it necessary to have a workshop on methods in clinical cancer research?

That’s true but this is a joint effort of some European and American associations and the problem is that the number of young clinical scientists is decreasing. Moreover, as one of the directors of this workshop told me, Patrick Schöffski from the University of Leuven, that the number of PIs below 40 is very, very low. So because oncology, we need evidenced based medicine in oncology so we need more clinical trials; we need more clinical trials which are not only pharma sponsored but very well designed by universities, by investigators. So this kind of workshop is very important because we want to give a basic knowledge for young oncologists how to design and how to implement the trial.

Now for how long has the idea of this FLIMS workshop?

Next year it will be the sixteenth edition of it. So this a very young tradition but very effective because every year about 70 Fellows are attending this workshop, this is the competitive way, and during one week they are preparing a full protocol of the new clinical trial. Moreover, many of them are implemented so they are really working. This is a joint effort, as I told some of the bodies, which can perform clinical trials like the EORTC, for example.

Clearly method is very important because if you want to get hard data you’ve got to have good method. What have you identified as the most crucial factors that need to be focussed on?

First is a good aim of the study, this is very important. And second is it real to perform the study because if you have a brilliant idea, sometimes, and a trial is not possible to perform in reality you will fail. So the faculty of the FLIMS is completely multidisciplinary, this is very good, because we have the greatest, probably in the world, concentration of statisticians involved in clinical trials but not only we have medical oncologists, clinical oncologists, radiation oncologists, paediatric oncologists together and we are working in small groups. We are preparing the design of the trials but also we are giving lectures and we are completely interactive during one week.

Now oncological scientists all over the world will be waiting with baited breath to hear what we’ve got to say about how you do this so that you get your project accepted and so that you do generate hard data. To begin with, what are the pitfalls?

The pitfalls of the workshop or the clinical trial?

The pitfalls of cancer research. How can you go wrong? What are the things to make sure you don’t do?

Of course the pitfalls, the major pitfalls are financing, this is the major problem probably, and sometimes too much bureaucracy as yesterday the President of the EORTC told. So we need clinical trials, we need investigator initiated clinical trials but the bureaucracy is killing the clinical trials. But also we are looking for new funds for it.

So number one, make sure you’ve got money for your project.

Yes and second bureaucracy.

And you need to have some ideas, have you got any ideas for how you generate that money? Talk to the right people, I suppose.

I think that there are some promising facts from new EU projects like Horizon 2020 because we know that as from FP7 there are some funds for clinical trials. For example, I’m now a member of one of the consortium for so-called Eurostars and we are performing clinical trials, completely academic clinical trials, in the frame of a consortium which is financed by the European Union in rare tumours and sarcomas because usually trials in rare tumours are very difficult to perform when we want to get the financing from pharma. So the European Union understood that it is necessary to perform clinical trials in rare tumours also.

Could you give me some examples of the sorts of things that have, in the past, gone wrong and the sorts of things that have gone right and made a trial hugely successful?

The most difficult things are trials for local treatment. So surgery, I’m a surgical oncologist so I know it very well, or radiation oncology because it’s completely outside of pharma, this is completely academic. And the problem is also with recruitment of patients because some of us, some physicians, have their own ideas how to treat the patients not based completely on the evidence base. So we need to perform the trials in surgical oncology and radiation oncology. This is one of the pitfalls but what is going better, this is an example of Eurostars because we are performing now the trial with retroperitoneal sarcomas with radiotherapy versus observation, so surgery only and the recruitment for this trial is going extremely well. So in rare indications with good financing and with a brilliant idea and with a good network we can do it.

So doing local things, local treatments, quite difficult so think your research out very carefully. What’s the sort of research project that will really fly and is really needed at the moment?

Of course research projects which are really flying are projects, are tumours which have bad results, bad outcomes until now, and it’s really an unmet need. So a great example is melanoma trials now. We have enormous recruitment because for the last twenty years we had nothing and the last two years everything is working, everything is working but the patients still are not cured. This year results are showing that probably advanced melanoma can be disease curable in some percentage, or at least it will be chronic disease. So this is what we worked for years but now we have results and the recruitment for the trials is very good.

Each of the companies making those agents is very happy about that agent and will tell you this particular pathway or this particular mechanism is the one to go for but you, the investigator, can only choose one of those agents. How do you choose between the potential agents?

Of course in an ideal world it would be best to have access to different companies’ products and to make the trials for a combination of different agents, that’s true.

It never happens, though, the head to head, does it?

Usually it happens a head to head comparison only, not a combination, that’s true. But now we have some tools how to distinguish the patients for proper clinical trials because now we know more about etiopathogenesis in molecular point of melanoma so we can very well select the patients for NRAS mutants, for BRAF mutants. But also we know that some very slowly or slowly progressive tumours are very good candidates for immunotherapy up front and very fast progressive tumours probably should receive targeted therapy from up front. So now we know more after these two years how to select the candidates for good trials.

So are you saying that in this era of individualised therapy and even molecularly individualised therapy it’s easier because there won’t be many agents to choose from?

Absolutely, that’s true. But also we are waiting for some combination of the agents which are going against some pathways or the same pathways on different stages. This is an example of BRAF and MEK inhibitors, for example, and we are eagerly waiting for the results of BRAF plus MEK inhibitors versus BRAF inhibitors. This is one idea and the second idea is the sequential or combination of BRAF inhibitors plus immunotherapy and there are some examples, there are some trials on-going now so the future is very interesting in melanoma.

And a hot tip, maybe? Because I know you’re working on the GRID study…

GIST.

In GIST, of course, and that’s an unmet need, there are things needed to be done, you’ve got a multi-kinase inhibitor there. What’s happening there and is that a good candidate, typical candidate of a good study to do?

Of course gastrointestinal stromal tumours, or GIST, are the great example of the success of targeted therapy over the last twelve years. However, after years of enthusiasm around imatinib and sunitinib we know that, well perfectly, from the beginning we have the population of patients who progress after these two drugs and have resistance to imatinib and sunitinib. From a phase II trial we knew that some drugs, like sorafenib, act very well and the derivative of sorafenib called regorafenib was designed and the trial was working on the population of imatinib and sunitinib resistant patients.

And you and your fellow investigators chose regorafenib because it floated to the top?

Absolutely, this was a multi-kinase inhibitor because we know that very selective inhibitors in the resistant population is too little so regorafenib showed a clear improvement in progression free survival but not only the patients who were in the placebo arm could go crossing over when progressed on the placebo arm to regorafenib and regorafenib was also active. So overall survival in this group is very nice because we haven’t reached even median overall survival in third line therapy. So regorafenib is a really active drug and recently registered in the US, we are waiting for registration in the EU.

OK, so final words of advice for your investigators, especially young investigators, looking to choose the right study?

First go to a workshop in FLIMS because this is a unique experience and you will be a light of oncology after years. This is why during the ECCO Congress we have a FLIMS alumni club meeting so we are keeping in touch our oncologists and, as I know, many of them are really prominent oncologists now and they are designing new trials.