Naiyer Rizvi, MD: Again, around the newly diagnosed patients and what we do, Tim, tell me about brain mets [metastasis]. I know that for some of the targeted therapies, we'll start with the targeted therapies and forego radiation up front. What's your thinking about brain metastasis in a newly diagnosed patient, how we do that in the context of immunotherapy? Do we radiate them first? Can we do them at the same time? Do you wait for the immunotherapy to work and hold the radiation? What's your approach?

Tim Kruser, MD: I urge my medical oncology colleagues to have me see these patients, because there are differences in terms of size, location, symptom burden that drive that decision. I see a lot of patients with melanoma brain metastasis, and unlike that scenario where the response rates are 55%, 60% to dual-agent checkpoint inhibition, the data for response in single-agent immunotherapy in lung cancer is more 20%, 25%. So we have a lower threshold for using radiation up front. Now, if we see 2-mm, 3-mm brain metastasis in non-eloquent locations, I'll watch those, and we'll get a 6- or 8-week MRI [magnetic resonance imaging] and see where things are going. It's case by case depending on the disease burden, and also performance status and the extracranial disease burden of the patient as well.

Naiyer Rizvi, MD: Can we give immunotherapy at the same time as radiation? That's often a call from the community: “I need to radiate a lung lesion, or a brain lesion, or a bone lesion. Can we do it at the same time, or do we need to hold treatment or delay treatment?”

Tim Kruser, MD: We've gotten increasingly comfortable giving it simultaneously. There are a lot of retrospective data looking at palliative radiation in the setting of people on immunotherapy that suggests non-overlapping toxicity and increasingly prospective data looking at high-dose radiation in the setting of even chemoimmunotherapy. A phase I study just came out looking at that in locally advanced patients. So we essentially radiate away based on the clinical scenario without too much concern for immunotherapy related reactions.

Jacob Sands, MD Tim if I can ask, this topic is so important. Radiating a bone is different than radiating the brain or lung. With your answer, is that across the board, or are there specifics to that? Do you feel as comfortable with the brain as you do with bone, or are there differences?

Tim Kruser, MD: Well, I only choose to irradiate things for which I'm going to potentially clinically benefit the patient. If there's a symptomatic brain metastasis or a brain metastasis that's growing through systemic therapy, my thought is that the benefit of the local control is going to outweigh some potential risk of radiation necrosis, which does seem to be augmented by immunotherapy. So your point is not without merit, but we can salvage radiation necrosis down the road with steroids or Avastin.

Tim Kruser, MD: Concurrent with checkpoint inhibitor is what you'd be doing. So generally, if someone is getting a checkpoint inhibitor, and they're going to get radiation to their brain, I've held the checkpoint inhibitor. If someone is getting even SBRT [stereotactic body radiation therapy] to a bone metastasis, I'm more comfortable continuing the checkpoint through that. We certainly have concurrent therapy in lung cancer, and we're actually getting more comfortable with this as well, and there are trials now where we're seeing concurrent radiation with checkpoint and even chemotherapy during that time. But the brain I've been more hesitant about.

Joshua Bauml, MD: But if we looked at the pharmacology here, the drug is in their system. If somebody is on a checkpoint inhibitor, it's a long half-life.

Tim Kruser, MD: Right.

Joshua Bauml, MD: So I can hold the drug on the day of their SRS [stereotactic radiosurgery], but I'm not changing the steady state in their body by doing so. Also their T cells are activated, according to some data, for a year. So I don't know that I'm doing anything if I hold the drug. So I tend not to.

Jacob Sands, MD: That's been my rationale as well. If there's a clinical indication and we know the immunotherapy is in their system and active, and we seem to think they're benefiting from the immunotherapy, we continue it, radiate, and watch. And if we need to withhold at some point because of irradiation-related adverse effects that warrant steroids, we do that reactively, rather than proactively, to try and minimize that.

Leora Horn, MD, MSc: Yes, I agree. We don't tend to hold back because we haven't really seen that holding makes much difference.

Tim Kruser, MD: I guess the other side of that is if someone misses a dose, for the same reasons you are probably not harming them in any way by missing one. So if I'm seeing someone when they're getting whole brain radiation, or even SRS to the brain or something, to hold the dose of pembrolizumab during that time I see as minimal risk as well. I don't think we quite know the answer, particularly around the brain, but I agree that we're getting more and more comfortable with radiation along with checkpoint inhibitors.

Transcript Edited for Clarity