Reactions to Phase 3 THOR Study: Primary End Point Not Met

By Peter O'Donnell, MD, Terence Friedlander, MD, Matthew D. Galsky, MD, Jonathan Rosenberg, MD - Last Updated: November 17, 2023

A roundtable discussion, moderated by Peter O’Donnell, MD, discussed the advanced urothelial treatment landscape, as well as recent trial data from ESMO 2023. Dr. O’Donnell was joined by Terence Friedlander, MD; Matthew Galsky, MD; and Jonathan Rosenberg, MD.

In the next segment of the roundtable series, the panel shares lessons learned from the phase THOR study, in which erdafitinib showed benefit in patients with an FGFR mutation.

Watch the next segment in this series.

Dr. O’Donnell: Let’s shift to one of the other datasets that was presented, the THOR data, looking at erdafitinib. We’ve heard about erdafitinib a couple times this year already. Earlier this year, looking at erdafitinib in the refractory space against taxane-like chemotherapy where it looked quite good. Then now at ESMO, we saw in the refractory space again, erdafitinib, this time against pembrolizumab, with a negative trial. I’ll go this way this time, Terry. Erdafitinib, I think is a drug a lot of us are struggling to find a place for it in urothelial cancer. Does this dataset affect you in any way?

Dr. Friedlander: I think the phase 3 data in the late-line setting where erdafitinib was compared to sort of later-line chemotherapy and was shown to be beneficial in patients with the FGFR mutation, I think that’s very important. Almost we could call it transformative, because it’s the first positive phase 3 of a molecularly targeted therapy. It really does have benefit, about 40% or so patients have good responses, some deep and durable. I think the data that was presented at ESMO was a slightly funny study, because the study was designed back when pembrolizumab was the second-line regimen. We’re trying to understand what the positioning of a FGFR inhibitor should be. They say in hockey, “You need to skate to where the puck’s going, not where the puck is.” I think this is an example of that, where it answered a very good question from 2017 or so, 2018, about which drug you should use. Actually, it didn’t really answer the question, because both groups seem to do okay with therapy. I’d love to hear your thoughts.

I don’t really know what to take away from that in terms of a prescriptive clinical take-home point. But it’s enough to say that there’s activity with both of these agents. I just don’t think we’re going to be using that much single-agent pembrolizumab going forward, unless we’re in a resource-poor environment where you really can’t give combination therapy upfront.

Dr. O’Donnell: Matt?

Dr. Galsky: I think erdafitinib performed consistently with other studies, and I think this study helps establish that the presence of FGFR3 mutations do not confer resistance to immune checkpoint blockade, which had been suggested in retrospective looks, but this establishes that prospectively. It’s not to say that erdafitinib didn’t work well. It’s not to say that the response rates weren’t higher. It’s just to say that pembrolizumab works in this subset of patients about as well as it works in other patients in that the drivers of resistance to immune checkpoint blockade that are enriched in luminal tumors are probably not causally linked to FGFR activation. It’s probably something else.

Dr. Rosenberg: My 1 take-home point is that if a patient hasn’t had immune checkpoint blockade for some reason and they have an FGFR3 inhibitor, I would likely give it to them first based on the way the data has fallen out. The cohort where there was real benefit were in the people who had prior checkpoint inhibitors. In the cohort, where it wasn’t worse, but wasn’t better, in fact, in some ways was worse, was the people who never had a checkpoint inhibitor. But now we’re probably going to see everybody having had a checkpoint inhibitor, so it doesn’t matter.

Dr. Friedlander: The data’s a little less salient.

Dr. Rosenberg: Right. For the second part of the trial that they reported, yes.

Dr. Friedlander:  Yeah, I will say just also, the data was also consistent in terms of the side effects, the adverse event profile of Erdafitinib, which in my experience, has been challenging for a lot of patients. Going back to this question of if you had a patient and you had to choose between one or the other, I would very likely choose a checkpoint inhibitor, both for the durability of response, but also just for the tolerability to keep patients on therapy. I think, at least in my experience, it’s easier with a checkpoint inhibitor compared to erdafitinib, at least.

Dr. O’Donnell: Great points.

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