ASTRO 2015
Combining immunotherapy with stereotactic body radiotherapy
Dr James Welsh - MD Anderson Cancer Center, Houston, USA
One of the main things that we work on is how to combine radiation with immunotherapy agents. The point of that is to try to get radiation to help prime an immune response. Classically radiation is used to control the tumour locally, so we aim at it, we hope, get local control and radiation is very good for that, it has been used for the last hundred years and really refined to perform local control and it’s wonderful at that. We’re trying to take it in a new direction where we can help with systemic control, so disease throughout the body. We irradiate one area of the tumour, combine it with an immunotherapy agent to prime T-cells that can then travel throughout the body and help other spots that have not been irradiated to then reduce in size.
What are some of the studies that are being performed at the MD Anderson Cancer Center?
At MD Anderson we have about four or five trials where we’re doing this in different disease types. We have patients in the phase I group, so they’re any tumour type with metastatic disease that have progressed where we do ipilimumab plus radiation therapy where we treat in the lung or the liver. We also have studies for patients purely with metastatic non-small cell lung cancer where we do PD1 inhibitors with radiation. We have studies for small cell lung cancer as well. What’s interesting is a lot of this data initially came out of melanoma and we’ve seen recently the drugs are working quite well in non-small cell. We now have FDA approved drugs for adeno and squamous and it looks like, based on preliminary data from the last ASCO conferences, that these drugs also work in small cell and mesothelioma and other tumour sites in the thoracic area. So there’s a lot of interest to see if we can make those work better by adding in radiation.
Is there a particular reason why ipilimumab is being used?
We do trials with both ipilimumab and the PD1 inhibitors. Ipilimumab was the first drug on the scene that was FDA approved for this in melanoma and so we started our trials with ipilimumab. Now that it’s going forward we’re also doing studies with PD1 inhibitors and in the future the combination of the two is very effective, although increased toxicity, so the future for immunoradiation oncology is really figuring out the right sequence of all these different immune drugs. Ipilimumab, CTLA4 inhibitors and PD1 are really the tip of the iceberg and now there are about 15-20 new agents that hit different parts of the immunologic pathways and trying to figure out the correct ones to combine with radiation and the correct timing and the dose of radiation. So there are a lot of questions that remain to be answered.
What are some of the results seen so far?
It’s still pretty new. Since we’ve been doing this the main thing for our initial studies is really safety, to make sure it’s safe to combine immunotherapy with radiation which is a new thing. The immunotherapies have different side effects than chemos or TKI type drugs so they can cause some bowel toxicity, colitis, and they can cause pneumonitis in the lung. One of our initial concerns and questions was if we combine it with radiation therapy in the lung could we make the pneumonitis worse. So that’s one of the points of the studies that we do. Initially we started with very small pinpoint stereotactic or SABR radiation and so we’ve treated quite a few patients with that. Those studies are, again, still ongoing but so far they seem like it’s been reasonably well tolerated. Also very important for radiation is studying side effects in short term and long term toxicities. So we’re getting some good signals for short term but long term it’s going to take a longer follow up to really learn the safety. Then the next part is what’s the response rate and if we’re increasing anything on top of drug alone which was what we’re really trying to figure out.
What about the safety and tolerability of combining immunotherapies with radiation, are you seeing any synergistic effects?
The combinations we’re most concerned about are ones that would be a synergy between the two, particularly pneumonitis since I specialise in thoracic tumours. So far we haven’t seen a really big change in the pneumonitis but it’s still early and we’ll have to wait and see how that goes. As we progress in our trials we’re getting bigger and bigger fields of radiation so we’re starting with pinpoint stereotactic radiation therapy which is certainly the safest and now I have trials going on with larger fields of radiation therapy, more fractionated, larger doses and so now we have to evaluate those with these checkpoint inhibitors.
Is there a way to pre-empt or prevent toxicities?
The way we address these side effects is with steroids which blunts their immune response which unfortunately would keep the drugs from working. So it’s a delicate balance, sometimes we do have to initiate steroids when we see toxicity in these patients. Obviously the first rule of medicine, ‘do no harm’, but we have to use these in a very reserved fashion and sparingly and try to get them off because the steroids can ironically blunt the immune response that we’re trying to stimulate. So we do have a back-up if we do get into trouble, if we got a revved up immune response you can stop the drug, let it wash out and then, if needed, give steroids to really reverse the inflammation.
Are there any specific data presented at ASCO 2015 you could highlight?
At this meeting we have a poster talking about ipilimumab plus radiation therapy, the first safety data. It looks at the sequencing of the ipilimumab plus radiation therapy and doing lung versus liver radiation therapy. So far in that initial data that will be presented here in a poster we did not see an increase in toxicity that was additive. We see a toxicity from ipilimumab alone, skin rash is the most common thing we see, but the sites where we added in radiation we did not see a major increase in any other toxicity so far. Again, that’s with pinpoint radiation therapy and a limited dataset so we’ll keep following that. But so far we’re off to a good start.
Are there other research groups looking at combining immunotherapy and radiotherapy?
Silvia Formenti in New York is probably the pioneer in this field who really did a lot of the preliminary data and provided a lot of the insights of why this works and how it works. She’s been doing several studies for this and published some very nice case reports that demonstrate this benefit. So she really deserves a lot of credit for spearheading this field and also has some very good data on how these agents work with immunotherapy.
Is there anything else you would like to highlight?
Just the importance of doing this in an organised fashion so that we can learn from the safety data. In oncology immunotherapy is a massive paradigm shift, it will change everything that we do and it’s a disruptive change which can also be good but it can also be scary for radiation oncology. So, for example, we can start using potentially immunotherapies in stage 4 patients and provide abscopal responses and systemic benefits. So if we can figure that out and do it on a consistent basis that’s safe then we will extend the benefits of radiation therapy to a much larger patient population which would be wonderful. But, on the flipside, these immunotherapy drugs, particularly melanoma, we’ve seen controlled data out to fourteen years. So people are really starting to question have you cured metastatic melanoma in certain patient populations. If that’s the case and you have a systemic agent that can do that, that appears now to be working in other solid tumours as well, could that go up front for localised tumours. So could some of the indications that currently now get radiation as definitive therapy or with chemoradiation therapy, could they be replaced in the future with immunotherapy and that’s very possible. There’s a lot of money and resources going into new ways to develop DNA vaccines, cancer vaccines, that could replace radiation if we’re not successful at showing how to integrate radiation with immunotherapy. So it’s really upon us in the greater community at ASTRO and NRG to do this in an efficient manner so that we remain relevant and we have a clear rationale of how we combine radiation with immunotherapy.
