Thank you for the introduction. I’ll take you into a completely different area and a little bit out of the box. It’s not going to be less complicated but somewhat different. These are my disclosures, I think the only relevant disclosure to this presentation is that I received travel assistance for this meeting and other meetings from the sponsor of the trial.
What I’m going to talk to you is about a disease called glioblastoma. Glioblastoma is the most aggressive and actually deadly brain tumour we have in adults. It arises in the brain and it stays usually in the brain. It used to kill patients within less than a year but there has been progress made over the last twenty years and some of the progress I want to show you today.
One of the challenges when you want to treat the tumour in the brain is that actually many of our drugs do not penetrate the brain so standard treatment is surgery, is radiation therapy and to radiation therapy a chemotherapy agent called temozolomide that my colleagues and myself in EORTC and NCIC, so the European and the Canadian co-operative groups, established in 2005 as the standard of care. But it’s just a standard of care for the time being, it just showed us that we can improve.
Now, I told you that one of the challenges is to get the drugs into the brain. So the monoclonal antibodies you’ve heard of just a moment ago, they would not penetrate through the blood-brain barrier so we can’t use those agents. Sometime you need to think outside the box and tumour treating fields is a treatment somewhat outside the box. So rather than using drugs, chemotherapy, cytotoxic agents or targeted agents, as you just heard, targeting specific aberrations, or immunotherapy with the immune system, here the approach was using physical properties, physical force to actually interact and affect tumour growth.
Researchers in Israel came up with the concept and the idea by exposing cells to an electrical field that you would actually affect cell properties. When you have an electrical field you have an energy, you have a potential between the plus and the minus and when we have a dividing cell we have a lot of polar molecules in the dividing cell. And in the dividing cell you need what we call the spindle apparatus to actually build up to have the chromosomes align and then duplicate the chromosomes and separate into two cells. Now these tubulins are highly polar. If you come with an electrical field that is going to change direction many times these tubulins, these polar molecules, will adapt to the direction. If you do that at a certain frequency all the time you’re actually going to perturb the tubulins in a way that the spindle apparatus cannot build up correctly and cannot actually do its function correctly. This ultimately will lead to disruption of the spindle apparatus, to cell cycle arrest and it will have unequal distribution of chromosomes, it will have other errors and error messages that will ultimately lead into what we call programmed cell death, so apoptosis.
How is this done and how do you deliver these electrical fields? You deliver it through a device, so we’re not talking about a drug, we’re talking about a device, a portable device that is attached to these kinds of arrays of electrodes. The patient has these electrodes on their shaved skull, as you can see on this picture. This picture is actually an actor, it’s not a real patient but you can find, but I cannot show that to you, on the internet plenty of real patients’ pictures which they have posted themselves. This is attached to a device generator. Here you see the first generation, so the trials were done with this type of generator. Cell phones have become smaller so the device has also become smaller so this is now about 3lbs. These are batteries; the patient has about four of these battery packs which you put in and each one gives you about 3-4 hours of independence. You can afterwards touch it, it’s in a little backpack or in a bag, patients carry that and you see one of the bags on this image.
So that was on one side the theory, on the other side how you would want to administer that. Why glioblastoma? There was a good reason for that, as explained to you: a) it’s an organ where we don’t have easy drug penetration so drugs need to have specific properties otherwise they would not reach; there was a demand there. Second, we have a disease that is usually local regional, it’s a disease of the brain. So unlike other cancers that readily metastasise, as breast cancer as you have heard, this is a disease that usually is not going outside the brain so it was a perfect clinical situation, not to call it a model, that a local treatment makes sense.
So at some point, and that’s where I come in to the picture, that’s all fine in theory but we need to now see can we actually make sense of that in practice in the clinic. So after some preliminary trials this was the trial to be set up where the patients were randomised, so attributed by chance in a 2:1 randomisation after they had completed their first course of radiation therapy which is about six weeks plus temozolomide but have not progressed. So what we would call newly diagnosed patients after they had the first six weeks of treatment behind them and surgery behind them and then it was randomised to either temozolomide chemotherapy alone, that’s worldwide the standard, in Europe it’s more six months, that’s the way it’s also approved by the FDA, actually in the US often it’s even given for twelve months of temozolomide, versus temozolomide plus tumour treating fields. Tumour treating fields, for this to work, and also with the mechanism of action I just explained to you, it is given permanently, I would say almost 24/7, actually patients are suggested that they would wear it about eighteen hours a day. Some wear it at night they have it plugged in so they don’t have to get up at night to change the battery and so on, others will turn it off. You will change the electrodes every 3-4 days, maybe reshave the head a little bit. So it’s a permanent electronic treatment with the aim also of making glioblastoma a chronic disease.
So we had randomised a total of 695 patients to either temozolomide alone, the control arm, or temozolomide plus tumour treating fields. For patient characteristics suffice it to say it’s well comparable, you have the slides, you have in your handouts a few more slides than I present here in the interests of time, but that’s the point of randomisation that you get balanced. When you have 700 patients you randomise you should get a balance between the two arms, there is no obvious difference between the two groups.
If you look at safety as it is a completely different mechanism of action most of the side effects observed were actually due to the chemotherapy we give and not to the device. You see that on the blood haematological side effects are the same between the two arms; also fatigue, asthenia, about the same, maybe slightly more but still nothing significant with the device. What you will see with the device is, of course, a reaction on the skin. This is placed so there may be a reaction to these electrodes to some extent, it’s usually mild so most of the time patients were able to manage it themselves. To be honest, personally, over ten years of experience I’ve seen very little patients with major reactions. This they dealt with it, they kept maybe the device off two or three days, got some air, some local ointments and they get instructions.
This is the main outcome. If you want still a curve far from where I want it to be up here but the blue curve, that’s the patients who got the device, clearly better and above the red curve and this even at a longer term like three and four years out. That’s what we call the hazard ratio, risk reduction of 37% or a hazard ratio of 0.63. So if you want to have that in numbers it’s 30.7% without tumour treating fields whereas it was 43% with tumour treating fields at two years. So a clear improvement. We did some landmark analyses just because it speaks more than a hazard ratio. So at three years 16% to 26%, at four years 8% to 20% and a few patients out at five years.
When you have a new treatment, and you’ve seen it from the previous presentations, we always want to know who are the ones who benefit. That’s our biggest challenge. I don’t care if a treatment works only in 3% if I can actually identify those 3%; what I don’t want is to treat 100. Now we’re not yet there. From also the mechanism of action which is specific to growing cells but not necessarily to molecular properties, as from as much we know, you see it works in all subgroups. Important enough, and especially for our brain tumour patients, it works in the patients who have the worst prognostic factors like unmethylated tumours, biopsy only patients, the ones we could not resect, and also elderly patients who by many of my colleagues until recently were considered you should not do anything and they do not merit any aggressive or intensive treatment. I think here, once again, we proved that wrong, it’s worse if the general condition is fine to treat them adequately.
We have presented some of this data before and I’m thankful to AACR for giving us the opportunity to present here the full data. When you have a new treatment you build in in a trial interim analyses, a) for futility to show that something does not work, you don’t want to expose more patients to something, or to have an early look if it works. So two years ago there was an interim analysis that was pre-planned and we looked at the first 315 patients, that has been published. At that time we didn’t look at any subgroups, that was too early to do so, and we already at that time saw a benefit and saw the independent data monitoring committee imposed on us that the data is immediately released which happened at that time. You see that from here to here the hazard ratio has further improved. Overall the outcome, the message, remains the same and we have it in the subgroups.
What I want to show you here, that’s the one I told you at the very beginning when temozolomide was established ten years ago, actually we have, interestingly enough, exactly the same magnitude of benefit. So this is, in my opinion, a meaningful additional benefit. Far from where I want to be, far from being able to retire, that’s why I’m moving to Chicago rather than retirement which I thought that’s going to be the next step, so we need to further improve. But it’s another step for the patients, another step in this deadly disease.
So let me conclude. We have shown that adjuvant treatment with tumour treating fields in addition to standard temozolomide improves survival. I’ve shown you the landmark analysis; I’ve shown you that all subgroups do benefit. I cannot show you yet, and we’ll work hard to next year or the year after come up and tell you who are the patients who are most likely to benefit. The beauty of this is that it has a completely different toxicity profile than all the other treatments so we can actually combine it. To me, what is very important, what I’ve shown you today that there is also a new treatment modality born. So surgery, radiation, chemotherapy, targeted treatment, immunotherapy and now tumour treating fields. Now we have to figure out as oncologists how we integrate that in all of the care like other diseases – mesothelioma, pancreatic cancer, malignant ascites, these are other opportunities where possibly this can help the quality of life and the benefit of our patients. Thank you very much.
Thank you, Dr Stupp. Questions to the middle but I will ask the first one – the mechanism is still a little fuzzy in my head. I can imagine lots but what’s your sense and the fact that people are getting rashes? I hate to plug into the immuno-oncology hype but is there a chance that we’re waking up the immune system and that it’s going after those MGMT signatures in the brain tumours that are left? What do you think?
There is some preclinical evidence that this could be the case and that in immunotherapy checkpoint inhibitors combined with this. I’m not the right person to give you all the insights there; there are smarter people, some are here in the room, who could help out with that. Because I was afraid of some of the mechanisms of action question I have for you a summary on the mechanism of action. Now, let’s be honest, the mechanism of action of many of our chemotherapy agents twenty years and thirty, forty years later, we don’t fully understand either.
Agreed, thank you. First question.
[Audience member] Charles Bankhead, MedPage Today. Does this mechanism apply to other types of chemotherapy, other types of systemic therapy, or do you see it as being specific to temozolomide? And beyond that does this open up the possibility of using other systemic agents for treating glioblastoma as opposed to temozolomide being the standard?
I don’t think it is at all specific to temozolomide. You show synergy with cytotoxic agents and you possibly show synergy with other treatments we can imagine. That’s the beauty and that’s the intriguing thing about this. So it’s not specific to temozolomide.
[Audience member] Lynne Peterson with Trends in Medicine again. So maybe I’m missing something here but the comparison is TTF plus tem versus tem, not a sham? You could, you could. You can still give the temozolomide but couldn’t you shave the person’s head and put a fake device on it? Other than that this isn’t really a good comparison.
I take that. If this is true half of the clinical science we present at this meeting and surely at ASCO, most of the treatments are without a placebo control. Temozolomide was established without placebo.
No, I’m not suggesting without a placebo, I’m suggesting a sham device with tem.
A sham is a placebo.
That’s what I’m saying but temozolomide, when we established it there was no placebo there. We’re looking here, and please note I present here overall survival, none of the soft endpoints, not progression free survival which was also prolonged consistently, but we look here at the four month overall survival benefit. If this is only the placebo effect, which you’re asking with the sham device I think that would be a very first in oncology. So that’s not the case. So we have here survival benefit. Why didn’t we use in oncology sham devices? It felt, for many reasons, that this is not really ethical, feasible for the patients, it would be too much of a burden. Secondly, these are electrodes so it doesn’t take much to figure out whether there is a voltage, a power, attached to it or not even if you would come up with the perfect device, so it would probably not work.
One way that we treat our patients is that we have an honest interaction with them. Because this question comes up again and again. We have done trials without placebo in all the glioblastoma, many of the trials; we have done a trial which also I was heading called Cilengitide, a CENTRIC trial, where we gave a drug IV twice a week and it was not placebo controlled. So only the patients on the experimental arm came in twice a week to the clinic, here they were independent, the patients were at home. We got a hazard ratio of 1.0, no effect whatsoever, in a large randomised phase III trial. So here I have a hazard ratio of 0.63.
