Treating for Stage III NSCLC After Progression on Durvalumab

Mark Socinski, MD: Let’s get back to these patients. They get on durvalumab, 6 months into treatment they progress. Roy, what do you do in that situation?

Roy S. Herbst, MD, PhD: Well, they just won. But in clinical practice, then you’re usually in a tough situation because not only have they progressed pretty early on durvalumab, but they’ve progressed pretty early from their chemoradiation. You’re not left with that many options in those patients. I’ll often try to rebiopsy, see if there's some sort of action with a mutation of some sort, maybe that’s not been done. As we said, we don’t always profile early stage patients. At that point, assuming a reasonable performance status, try to find some trial. Maybe it’s an I-O combination or an I-O plus chemotherapy combination. It depends what their toxicity profile is to the chemotherapy, the radiation, and the I-O.

Mark Socinski, MD: How would you look at a patient on the opposite end of the spectrum, where they got the PACIFIC regimen, completed a year of treatment, and then 18 months later had evidence of disease progression? Would you look at that patient differently than the patients who progressed while they're receiving durvalumab?

Roy S. Herbst, MD, PhD: That’s a tough one, but the answer is probably yes. They’re not prior refractory to durvalumab, although it could have been the chemoradiation effect. In a patient like that, the trials would have let them on, but I think in practice one could consider a rechallenge with immunotherapy, absolutely. Assuming there are no toxicities that would prohibit that.

Mark Socinski, MD: Stephen, your thoughts on that?

Stephen Liu, MD: Yes, I agree. When you start that late after the durvalumab, I think you start fresh as we would approach our typical stage IVs. You do full molecular profiling and NGS [next-generation sequencing], maybe rebiopsy to confirm this isn't some separate primary or another lung cancer, and if there are no driver alterations, I would challenge with immunotherapy-based treatment. Probably in that setting I’m more likely to go with some sort of combination, either dual checkpoint or chemoimmunotherapy.

Mark Socinski, MD: One of the issues that we alluded to before, I think Stephen you said this, that the duration of a year of treatment was arbitrary. It is amazing to me that when we saw the 3-year overall survival curves that the difference was maintained despite getting that 1 year. Do you think there is opportunity, or we should think about longer duration because typically in stage IV disease we are wedded to this 2-year duration of treatment, and then wondering what to do at that point? Any thoughts? I’ll ask Roy to chime in on that too in terms of is there room for longer durations?

Stephen Liu, MD: I think it’s a setting where you’re talking about generating a durable, immune-mediated, antitumor response. Ultimately, it’s not going to be a one-size-fits-all. I think there are going to be some people who need very little of the checkpoint inhibitor to induce T-cell memory, and some who may need more constant. I’ve had some very late relapses, for example, in small cell that I wouldn’t necessarily expect in a lot of my non–small cell cases. We've seen a lot of data, some presented by Dr Herbst, that showed when you stop after 2 years you can rechallenge with some success, but I think ultimately, we’re still looking for patient-based biomarkers that are going to help guide us. I am comfortable stopping and watching closely, but I’ll tell you that some of my patients are not comfortable stopping.

Mark Socinski, MD: Roy?

Roy S. Herbst, MD, PhD: It can go both ways. I’ve had people who have gotten 2 or 3 doses of immunotherapy. They come off from toxicity, and we’re managing their toxicity with steroids for years, but their cancer never recurs. Then, there are some where we treat to progression, oftentimes in those cases, patients will say, “I’ve had enough.” Now, the intervals are stretching out. Six weeks now with pembrolizumab, and so forth, so it’s easier to do maintenance.

I like the 2-year mark as we heard from Stephen. That came out of KEYNOTE-010. We looked at those patients who had PR [partial response] or response in the [Journal of Clinical Oncology] paper from earlier this year, and very few of them relapsed after 2 years of treatment if they were in that group. And when they did, about half of them responded again. A similar analysis is going on now for KEYNOTE-024, so we’ll see that soon as well.

Again, I think it’s each patient individualized, and in the absence of measuring memory T cells and knowing what's going on, it’s a bit empirical, obviously.

Transcript Edited for Clarity