Expert Explains Work Needed for Immunotherapy/RT Approaches in NSCLC

James Larner, MD

In non—small cell lung cancer (NSCLC), determining whether radiation can truly potentiate response to immunotherapy requires a better understanding of underlying permutations and pathways, explained James Larner, MD.

Following findings of the phase III PACIFIC trial, which showed an improvement in overall survival for durvalumab (Imfinzi) as consolidation therapy after definitive chemoradiotherapy in patients with unresectable stage III NSCLC, other studies are looking at how to use radiation to trigger the immune system.

“An optimist would say that the glass is three-quarters full,” said Larner, professor and chair of Radiation Oncology, University of Virginia Health System. “We’ve made huge inroads. Radiation is a potent stimulator of the immune system and most, if not all, patients should get radiation to potentiate immune checkpoint blockade.”

OncLive: What is the role of radiation therapy in combination with immune-oncology agents?

In an interview during the 2018 OncLive State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Larner discussed the process by which radiation interacts with the immune system and how physicians are working to improve treatment responses for patients with NSCLC.Larner: Immunotherapy has had a tremendous impact on lung cancer and other solid tumors. The real question in my mind is, “Why do patients become resistant to immunotherapy?” If we can figure out the mechanisms of resistance, we have the potential to manipulate the system, invert resistance, and increase response rates. Historically, radiation has been thought of as a DNA-damaging agent.

Over the past decade or so, there has been interest in the use of radiation therapy to stimulate the immune system. Radiation has tremendous potential in that regard. Radiation increases antigen presentation. It increases dendritic cell activity through the damage-associated molecular pattern with the release of ATP and calreticulin, high mobility group proteins, and so forth. This results in the so-called abscopal effect, whereby if you radiate a lung cancer or a metastatic deposit in the left lung, you can see regression in the right lung or the liver. It's potentiating immune checkpoint blockade.

There are a lot of unknowns in terms of how to integrate radiation with immune checkpoint blockade. Do you give radiation first, or do you give immunotherapy first? What dose of radiation is optimal? Recently, there have been several molecular pathways that have been identified. These include the cGAS-STING pathway where damaged DNA goes into the cytosol and turns on an interferon response that leads to dendritic cell stimulation. If you give too high or too low of a dose you may not get that response.

How does the PACIFIC trial play into this?

Have any other trials examined immunotherapy alongside chemoradiotherapy?

Are any trials set to open?

What is another area of research you would like to see addressed?

Will chemoradiotherapy remain a go-to regimen moving forward?

The real future is understanding the many potential permutations and pathways that are involved in potentiating the immune response and whether radiation can contribute to autovaccination. That releases the individual antigens of a patient's tumor to produce a systemic effect.There was one subset analysis suggesting that if you give immunotherapy within 2 weeks of chemoradiation, it is more effective. The obvious biological explanation is that there are more neoantigens and priming of dendritic cells close to radiation and chemotherapy as opposed to distant to it. That is just conjecture.There have been small single-arm trials. What's missing are trials that conclusively show that radiation is acting synergistically with immune checkpoint blockade. You have to look not at radiation plus immune checkpoint blockade, but radiation plus immune checkpoint blockade versus immune checkpoint blockade as the control. Randomized high-quality trials that demonstrate that radiation is potentiating the activity of immune checkpoint blockade are still lacking.There are several that are pending, but I haven't seen any compelling evidence. There are case reports showing that when you radiate a site, you see unbelievable remote responses. I'm a cynic. I don't know if those remote responses would have occurred in the absence of radiation and whether that patient's individual tumor just happened to be susceptible to that ligand.Ultimately, this is going to take a big data approach. There are so many pathways involved and so many different genetic and epigenetic variations. To get to personalized therapy, you're going to have to find the critical tumor antigen that determines outcome. You're going to have to find a way to maximize the host’s response to that tumor antigen. That may or may not have to be coupled with something else. That's the future of personalized medicine vis-a-vis immunotherapy.There is compelling evidence that chemotherapy and radiation therapy is better than either modality alone. The downside is that it's more toxic. You have a doubling or tripling of the grade 3 toxicity when you give radiotherapy concurrently with chemotherapy, principally in terms of myelosuppression and esophagitis. If you look at the number of grade 3 events, it's 2 to 3 times [greater]. That's the price you pay for a statistically significant increase in overall survival.