Durvalumab in Stage III NSCLC Based on Performance Status

Mark Socinski, MD: Do you stretch the performance status [PS] rules? Obviously, PACIFIC was PS0 to PS1, but pretty positive results. Do you think those can be extrapolated to the poor performance status population, or what would you consider as a standard of care in a PS2, or dare I say, PS2.5?

Stephen Liu, MD: I probably do stretch it a bit. Part of it depends on why the performance status is low, and chemoradiation is a tough treatment. I think it’s not unusual to have patients who are pretty tired, pretty weak from that therapy. And the first thing I do is try to wait, try to give them a little time to recover, maybe IV [intravenous] hydration, focus on nutrition and see if we can get some of that performance status back.

I’m balancing the potential improvement in outcomes with the toxicity, and durvalumab monotherapy in this consolidation setting is pretty well tolerated. I found it pretty easy to deliver, and I’m not really concerned that I’ll take someone who is PS2 and make them a lot sicker by delivering durvalumab. I suspect the outcomes are going to be worse than the PS0 to PS1, but I suspect the outcomes would be better in the PS2 compared to not giving it to them.

Mark Socinski, MD: Roy, any different thoughts?

Roy S. Herbst, MD, PhD: No, I agree. Few things have changed practice as rapidly as the PACIFIC results. The 2 papers back to back, first the PFS [progression-free survival]; we were using it based on the PFS, then OS [overall survival] came right on the tail, that’s such a good survival benefit. I try to give it everyone. We talk to everyone about it now at the beginning of the chemoradiation, so they're prepared for it. We try to give it as often as possible. Yes, I wouldn’t give it to someone who’s a PS3, but if someone is PS2, and you saw them a few times, and they're a PS2 and not a PS3, I’ve given it, and I think it does improve outcome.

I agree with what was said earlier, if you don’t get through a year, that’s OK. You do as much as you can, and when you stop you usually don’t retreat after that.

Mark Socinski, MD: Kristin, your thoughts on the performance status issue.

Kristin Higgins, MD: For PS2/3 I think the hardest part of treatment is definitely the chemoradiation. For those patients, we are typically giving hypofractionated radiation alone, so it’s 60 gray in 15 fractions. And a case-by-case basis, if we think they can tolerate durvalumab, we occasionally will do sequential chemotherapy followed by radiation. I think there is an AstraZeneca trial underway that’s testing sequential chemoradiation followed by durvalumab for poor performers. Again, I think it’s the chemoradiation piece they struggle with, and we haven't seen very many new therapies for the PS2/3 patient. So I think it’s important to mount a trial that tests immunotherapy for that patient population.

Mark Socinski, MD: One of the things that I think was reassuring about the PACIFIC trial is this issue of pneumonitis, that there didn’t seem to be an excessive amount of pneumonitis. Of course, one of the things we don’t know is the radiation parameters for the patients who were treated on both arms. Give us your perspective as a radiation oncologist, the issues around immune- mediated pneumonitis, radiation-mediated pneumonitis.

Kristin Higgins, MD: If you look at the contemporary chemoradiation trials, for example, R2GO617, the rate of grade 3 or higher radiation pneumonitis was about 6% or 7%. It’s gotten so much lower over the years because of improved technology. We can handle these bigger tumors. If we see changes on imaging that are within a treated radiation field, and the patient is symptomatic with increasing hypoxia, then we think this is likely due to the radiation. If imaging findings tend to be more widespread throughout the lung, I tend to think that would be more of an immunotherapy-driven pneumonitis. Sometimes it can be difficult to differentiate. We still don’t have any great biomarkers for this toxicity. I think it’s something that people worried about at the onset of chemoradiation followed by immunotherapy in stage III disease. But clinically it doesn’t happen that often, and I think that the oncology community is getting more comfortable with managing these toxicities, and our patients do overall pretty well.

Mark Socinski, MD: I think in the PACIFIC trial they topped the radiation dose up at 66 gray. Is that correct?

Kristin Higgins, MD: The PACIFIC trial patients enrolled after they finished radiation, so the radiation dose wasn’t specified. You had to get at least 54 gray, so everybody got at least 54 gray, but there wasn’t a stopping point in terms of where everybody stopped. It was sort of dealer’s choice. If you look at PACIFIC-2 that’s enrolling internationally, patients obviously are getting just 60 gray, so the radiation parameters will be controlled for.

Mark Socinski, MD: What is the standard?

Kristin Higgins, MD: I would say the standard is 60 gray, based on R2GO617. Certainly, you can get better doses to your lungs with 60 gray as opposed to 66 or 70 gray. I never push it over 60 gray for non–small cell lung cancer.

Mark Socinski, MD: I guess you would conclude that from the R2GO617 trial, but I still see our radiation oncologist going to 66, 70 gray. That’s probably based on volumes, but I was wondering if there's an accepted standard in the radiation oncology community.

Kristin Higgins, MD: I would say 60 gray.

Mark Socinski, MD: Sixty. Great.

Transcript Edited for Clarity