ELCC 2021 | Combining immunotherapy and radiotherapy to improve mesothelioma outcomes

So, I’ll be talking about the role of radiation therapy in mesothelioma and, more specifically, how it integrates with immunotherapy. We don’t have a lot of data yet, but it is a very rapidly emerging field. And so, I broke down my presentation first to talk about the different radiation techniques that are available right now.

A lot of time is spent and a lot of experience has been built around the technique targeting the entire pleura, which is really the area at risk in pleural mesothelioma and is technologically extremely challenging. And so, we, as well as a group in Italy have developed a technique that is able to do that and spare the underlying lung, because the lung is a radiosensitive organ and can only take so much radiation before we cause excessive toxicity. And so technologically that is now possible that we can deliver that safely. And that’s been demonstrated in multiple Phase II trials and is currently under investigation in a cooperative group, Phase III trial in North America. And the Italian group has also done a single institution Phase III trial, even showing a very promising survival benefit that needs to be substantiated and validated in a multicenter trial.

So, certainly a technique that is up and rising and has been coming along in the last 10 to 15 years, can, at this point, only be done in experienced hands because it’s still a challenging treatment to put patients through and to also manage them in terms of after effects, but at least it’s technologically possible in experienced centers.

Now, that technique has not been combined with immunotherapy yet. There is a SWOG trial that is led by Anne Tsao at MD Anderson, where immunotherapy is given sequentially to radiation as well as chemotherapy and surgery, so that will be one of the first trials to look at that. We are looking at combining it directly with this type of radiation, which, by the way, we call IMPRINT, that’s Intensity-Modulated Pleural Radiation Therapy. And so, we are launching a Phase I study to combine immunotherapy with this technique in patients that cannot have surgery. So, that’s the first direct combination of immunotherapy with this type of radiation.

On the other hand, there are many other radiation techniques that are actually in some ways more commonly employed because it’s quite common that radiation therapy is used for palliative purposes and many patients are not candidates for this radiation that targets the entire pleura because it’s too tough, they may be too frail for it, or it may be too risky, or it may be technologically not possible because of how extensive the disease is.

And so, very commonly, we actually offer radiation to areas that are causing symptoms really for pain control, to improve quality of life, for any areas where the tumor is pressing on nearby organs and causing airway compression or pressing on blood vessels, pressing on nerves. And that’s where radiation can be very helpful and is standardly employed. And so, in that setting, of course, immunotherapy is playing also an increased role like in many disease sites, immunotherapy has made its inroads in the more advanced setting.

So, they were at first single agent trials, and now there was, just in January, published a dual checkpoint inhibition trial with ipilimumab and nivolumab by Paul Baas. And that showed actually a survival benefit compared to a regular conventional chemotherapy. So, we only expect that the role of immunotherapy will continue to expand and so we need to learn how to safely combine it with palliative radiation therapy.

And so, we’ve done a trial looking at avelumab and stereotactic radiation, and that seemed to be safe. And that was published earlier this year at the World Lung Cancer Conference. And in the UK there’s a similar trial, ongoing, I believe, with pembrolizumab, so another immuno anti-PD-L1 drug. And so, we’re beginning to explore that combination and see whether it is safe. It seems to be, and in some ways it’s anticipated to be because, from other disease sites, we have some experience combining radiation and immunotherapy, even in the thorax, but not specifically for mesothelioma that we were just beginning to do those trials.

And then lastly, maybe proton therapy or some really advanced, modern radiation technologies can, of course, be combined. There’s nothing fundamentally different in terms of the interaction that we expect between that type of radiation therapy and immunotherapy, but it is a different way of delivering radiation that is potentially able to avoid more normal organs nearby. It all depends on the geometry, the anatomy and the physics behind it, but it is another tool in the box that we have to combine with immunotherapy.