Ezra Cohen, MD: Barbara, I want to turn to you and ask, what are the next steps? We’ve talked about integrating these agents with standards of care, but there are a lot of unanswered questions. What are the next steps in research?

Barbara A. Burtness, MD: There are 2 ways you can build on what you learn about who’s responsive and who’s resistant. You can look to see what predicts responsiveness and try to mimic that tumor microenvironment in your patient or you can see what predicts resistance and see if it’s something that’s targetable. So, I think that there are a lot of ways that we can use existing targeted therapies and standard therapies to improve the environment for immunotherapy.

It appears as if high mutational load is associated with more responsiveness. That’s certainly something that can be manipulated with DNA-damaging agents and perhaps other strategies. There is reason to think that antiangiogenics will lead to a DNA damage response that might do this as well. And then, there’s reason to think that some of our conventional targeted therapies—PI3 kinase and EGFR inhibitors among them—actually have downstream effects, which regulate tumor-associated macrophages and other tumor-infiltrating lymphocytes.

So, I think that there’s going to be a lot of room for looking at combinations of existing therapies, whether they’re conventional DNA damage approaches or they’re targeted therapies with immunotherapy. I would encourage the people who are watching this video to know, when you have a patient who progresses on nivolumab or pembrolizumab, your local cancer center may well have a phase I trial that’s doing exactly this. We’ve been seeing how accelerated drug development is. These answers are coming back to the clinic in a patient’s survival timeframe. So, I think that there’s a lot that’s going to be done just from the correlatives that we have from the first generation of studies.

Ezra Cohen, MD: Absolutely. And speaking to that, Barbara, if I may add, we also have a lot of trials now ongoing looking specifically at patients who are refractory to the existing agents, pembrolizumab and nivolumab, trying to ask the question, “Well, how can we overcome resistance?” How can we understand resistance and then overcome it with many of the modalities that you discussed? Hopefully, we’ll have answers to those questions in the near future. Go ahead, Barbara.

Barbara A. Burtness, MD: The other group of patients who have not really been able to benefit from these agents are those patients who have preexisting immunologic disorders. So, we’ve been extremely worried about giving these agents to patients who are on immunosuppressive therapy who have an active flare of a rheumatologic disease or who have underlying interstitial lung disease. And although those patients may be at higher risk for immune-related adverse events, it doesn’t look as if those underlying conditions necessarily guarantee it.

And just to follow up on the biomarker conversation we’ve been having all morning, I think that we are really going to want a signature for the patient who is going to just get macrophage activation syndrome from these agents and who’s the patient who—with a low dose of steroid, methotrexate, or something like that, Plaquenil—could be treated with one of these agents. Because I think, maybe, in lung cancer they see that more, but we certainly have patients with joint disease who are precluded from benefitting now.

Ezra Cohen, MD: Yes, bringing in more patients who could potentially benefit.

Transcript Edited for Clarity