Will Immunotherapy and Radiation Be Combined in Lung Cancer Treatment?

Checkpoint inhibitors continue to show promise in the treatment of patients with non-small cell lung cancer (NSCLC), but researchers are now exploring the efficacy of these agents when combined with radiation therapy (RT).

This is similar to the synergistic effect of immunotherapy and chemotherapy combined in these patients, as experts are questioning whether administering RT while patients are receiving treatment with a PD-1/PD-L1 inhibitor could improve the significant, albeit often short, responses seen with checkpoint blockade.

“We are only beginning to scratch the surface with regards to combining these two independently potent modalities,” said Sagus Sampath, M.D. “Secondly, this is touching all stages of lung cancer…which is exciting. We are not just talking a small population of lung cancer patients who could benefit from this; this could really touch all of lung cancer.”

In an interview with CURE, Sampath, an associate clinical professor of radiation oncology, City of Hope, discussed the ongoing studies exploring checkpoint inhibitions with RT and the promise of integrating these two treatments in the field of NSCLC.

What combinations are being studied with these two modalities?

Basically, there are two main classes of immunotherapies. Now, people are focused on the PD-1/PD-L1 pathway so the drug therapies that are out there are mainly using mainly those two ligand and receptors. Targeting that with radiation is essentially where we are headed. It has been tested in a few clinical trials [across] a few patient populations. I spoke about that and the exciting possibilities of combining the two treatments, perhaps in stage IV patients.

Why might be there synergy with checkpoint inhibitors and RT?

A lot of people don’t know too much about RT, other than it sounds really scary. However, it’s a focused treatment that is usually directed to a specific area in the body. For example, for lung cancer, the intuitive thing is to usually treat the chest. However, as we know, lung cancer can go to different places and, once that happens, we want to figure out — besides just giving drug therapies — is there something else we can give to make the systemic therapy better?

What we are trying to scratch the surface of is to understand, hopefully more as time goes on, is if we give RT to a distant spot at the same time the patient is getting their systemic therapy, perhaps we could make the drug therapy work even better. That [involves] understanding the biology and the underlying mechanisms behind that; that is where the current research is being done. It’s an exciting time.

There is a lot there that we don’t really understand. Will we be able to extend patients’ lives? That will be the bottom line as to how this combination gets judged. In the next three to five years, we will be able to have an answer.

Do we have an idea of what the safety profile of this combination looks like?

For now, it depends on the organ that is being radiated. In the end, when we think of RT and adverse effects, we limit it to where the radiation took place, so we can keep that answer straightforward. We know that immunotherapy independently can cause some lung side effects and lung inflammation; we know radiation can do that, too. Of course, we want cancer cells to die, but then we also worry about the surrounding normal cells. Obviously, if you get too potent for the normal cells around it, then that can be a problem, too. Pneumonitis is one common thing that we look at, especially when it comes to radiation.

As far as other organs go, that is another area that people are slowly reporting about. What are the toxicities when people are combining the two treatments? The lung is what comes to mind, but as we get more and more experience combining them, we will be able to understand a little bit more.

The brain is another area where we often treat a lot of patients who are already on immunotherapy and have brain metastases. The other thing we know is that RT can cause some temporary leakage or disruption of the blood-brain barrier, so the idea is that maybe that can allow the immunotherapy to work even better in the brain. It may be a synergistic thing—better than what immunotherapy and RT can do by themselves. That is what the exciting part is behind that.

Are there any other ongoing trials exploring this combination?

I presented a few published or mature studies that have been out there. Right now, for the stage 4 population, we do have a national trial that is currently open at City of Hope looking at patients with limited metastatic disease. It is a select group within the stage 4 population. Drug therapy could include immunotherapy or chemotherapy.

The trial is open now and is looking for somewhere on the order of 300 patients. We’re hoping in the next four or five years we will have the trial completed; that is a randomized study so that will be a gold standard for us to judge whether an intervention is useful. We are hoping that will give us some useful information.