Considerations for accurately predicting and identifying response to tebentafusp in uveal melanoma, and insight regarding the appropriate length of treatment for patients with disease progression.
Richard D. Carvajal, MD: You're right, this is reminiscent to me of the ipilimumab experience where you get the survival benefit despite the low response rate. But even more so here, we've both had patients that we've treated where the radiographic disease course has been remarkable, right? Where it's significant progression and then a flattening of the curve. I'd love to hear your experience of treating patients beyond progression and the benefit that we've seen as presented by Anthony Joshua, MD [head, Department of Medical Oncology, Kinghorn Cancer Centre, Sydney, Australia].
Marlana M. Orloff, MD: Yes, when you see progression early on and then stabilization, or you see progression early on and then shrinkage in immunotherapy, there's that term pseudoprogression that's been coined, but I don't even think we really know. Without biopsying, which we actually did early on in 102 [IMCgp100-10 phase 2 study], we had a few patients that had really significant progression of some pretty easily accessible tumors. I'm thinking of one as a larger kind of neck mass, and we did see necrosis early on. It's possible that there are patients that either truly have pseudoprogression and it's an immune phenomenon, or it just takes a little while longer to work, because I know that even patients with initially kind of stable disease, sometimes you may see responses first starting at 6 or 9 months—maybe just a delay in response. The interesting thing is there is one abstract at ASCO [American Society of Clinical Oncology meeting] that talked about overall survival in patients whose best overall response was progressive disease. That's it; they had progressive disease from the get-go, and a lot of these patients were treated beyond progressions actually in both arms. There was some treatment beyond progression, but more so in the tebe [tebentafusp.] arm. And their overall survival holds up. They showed that either progressive disease, stable disease, or a PrCR [programmed cell removal] all had better survival than any arm in investigator choice. I think there is something to it. We're still trying to tease that out. Do you have any thoughts about what we could be seeing here?
Richard D. Carvajal, MD: No, this is a remarkable example of how RECIST [Response Evaluation Criteria in Solid Tumors] fails us. This is a case where we cannot make decisions based upon RECIST. It just does not predict overall benefits. As you brought out, one of the striking curves from Dr Joshua's presentation was that if you look at the tebe survival curve for those just who've progressed, it's higher than the investigator's choice arm, whether they do well or not. And it's just this remarkable decoupling of what the scans are telling us and the true benefit. There's interesting work going on and other changes beyond size that may be able to help us predict which patients are going to benefit or not, but RECIST by itself in this case is not helpful.
Marlana M. Orloff, MD: Yes, and even what has been coined as kind of IR [interventional radiology] recess, which is basically repeating a scan at 4 weeks, that either confirms what you previously saw or not, also sometimes still doesn't totally help in these scenarios. It is kind of food for thought, moving forward, that we do need to do a better job at using radiology, like you said, radio density of lesions, if there are some other clues we can get. Certainly, we use a lot of MRI [magnetic resonance imaging] of the liver in this. Looking at different aspects of these tumors to help predict which ones maybe more just go into a dormant phase or if there is actually some response that’s happening within the tumors that would then predict that survival.
Richard D. Carvajal, MD: Some of the challenges then are, I mean over 50% of the patients on 202 were treated beyond progression—and they get benefit—but it’s still unclear to me how to determine how long patients need to be treated beyond progression. Would they have derived the same benefit if we stopped? Because right now, I still have patients on weekly treatment 2 years out. How long do we have to do that for?
Marlana M. Orloff, MD: That’s a whole other question. Those are patients who you’re saying even had some treatment beyond progression. But even patients who have best overall response of stable disease or PR, weekly treatment is a commitment and there are patients that have gone very long getting this therapy. That’s probably another question we’re going to need to ask ourselves, certainly soon enough.
Richard D. Carvajal, MD: The last bit on the radiographic findings I found interesting is that the ctDNA [circulating tumor DNA] data that was collected from the 102 trial might be predictive of benefit. I think Dr Joshua presented this as well, where they looked at the patients who progressed and looked at the ctDNA findings. What was interesting is in, a small proportion, in 4 of the patients who had radiographically progressed, they completely cleared their ctDNA. And if you look at the patients who had some odd-fold decrease in the ctDNA, that seem to predict benefit. So maybe there will be ways for us to predict beyond scans.
Marlana M. Orloff, MD: Yes. And just a little anecdote, again, how scans are kind of what we use to guide ourselves. We see these patients weekly, and you do physical exams, and we have had a handful of patients that something that was palpable was a certain size on the scan, and it was a different size on physical exam about a week later. There is something also dynamically happening in these tumors, so things like ctDNA, where maybe you can map even more consistently, may be helpful in these scenarios because you can’t get scans every week.
Transcript Edited for Clarity