ONCAlert | Upfront Therapy for mRCC

The Future of FGFR Inhibitor Treatment

Targeted Oncology
Published Online:12:46 PM, Wed July 31, 2019

Sumanta Pal, MD: I think that FGFR [fibroblast growth factor receptor] is a very valid target, not just in the context of advanced bladder cancer but in cholangiocarcinoma and a subset of lung cancers that are driven by FGFR mutations. I really think in the same way that we’ve looked, for instance, at inhibiting NTRK across a wide spectrum of different tumor types, maybe the premise of hitting FGFR across a multitude of malignancies will stand as well. So I’m excited to see agents like infigratinib develop in multiple diseases simultaneously.

We published the data for infigratinib in Cancer Discovery. Again, I was really impressed with the response rates—25%, a very heavily pretreated population of patients. And in my mind, it’s impossible to compare apples and oranges with different studies. I think it ranks right up there with erdafitinib, which obviously gained its approval for advanced bladder cancer recently. So I’m really intent on seeing infigratinib developed further.

An interesting thing happened though. Infigratinib actually passed hands. It was originally owned by Novartis. The agent was then shifted over to QED Therapeutics, a much smaller company. And funny enough, on the day that this transition happened, I happened to be in San Francisco at ASCO GU [American Society of Clinical Oncology, Genitoruinary Cancers Symposium]. I actually e-mailed the folks at the company, and at the time they had 2 employees, and so we had a conversation over coffee. I said I’d really like to see this compound develop in a different niche, and that niche should really be upper tract bladder cancer. And I didn’t expect much out of the conversation. But now, I guess it’s about a year later, we’re on the brink of hopefully launching a phase III clinical trial in upper tract disease. So I’m very thankful to the company, obviously, for taking this advice seriously.

In this clinical trial, we’re actually going to be looking at a comparison of infigratinib against placebo in patients who have resected upper tract disease. The trial is going to permit a small handful of individuals who have lower tract disease as well. But I like to think of this as being a trial that’s really going to test this premise of the relevance of FGFR biology in upper tract patients.

There’s been a lot of discussion about different molecular subtypes of bladder cancer. We talk about the FGFR3-driven subtype, and I certainly think that there’s some rationale to conceive of bladder cancer that way. But I think over the years what we’ve really learned is that there’s no perfect subtyping of the disease, at least according to response to therapy. And to account for that overlap and because bladder cancer is such an aggressive and rapid disease, it might actually make sense to take the “kitchen sink” approach and lump together multiple therapies.

With that in mind, I would be excited to see agents like infigratinib paired with immunotherapy [I/O]. I definitely think that the combination should be tested first for safety, of course. But provided that that’s the case, I think that we need to very quickly move forward to more definitive studies that look at these combinations. In my experience, in the situation of bladder cancer, it’s not the scenario in which all patients will easily shift from first-line therapy to second-line therapy and on to a third-line regimen. You really have to look to make each line of treatment very impactful, and perhaps combinations are the best way to do that.

Rachna Shroff, MD, MS: So where do we go from here? What do you think are some of the ongoing challenges in terms of research for FGFR inhibitors and what the next steps should and could be for their role in cholangiocarcinoma?

Richard Kim, MD: Most of the studies currently being published are in second-line setting, refractory setting. And we know that as a single agent, it does have activity for sure, and I think those patients would benefit. But I think looking forward, there are already studies going on in first-line. Can you spare these patients chemotherapy, right? Everybody wants that personalized medicine. They want their actual mutation to be tested and to be given that drug that targets that.

So I think we’re heading in the right pathway, doing a first-line study comparing against active chemotherapy. That’s one area that we’re still eagerly anticipating. The second thing that we are looking for is, can we combine this with other drugs, I/O, chemotherapy, so to enhance the activity of that drug? Third is to understand better the resistant pattern. We know that these FGFR fusions, they work but they will eventually stop responding. So the question is what can you do when they stop responding? Do we understand enough to say we could go from one FGFR inhibitor to another one and go on trying to attack the same area? So I think those are the 3 main areas of interest and moving forward in terms of managing those FGFR fusion cholangiocarcinoma cases.

Rachna Shroff, MD, MS: Yes, and I think that the resistance question is such an important one. There’s some really elegant and interesting research that is looking at these gatekeeper mutations that are developing with, after infigratinib exposure, for instance. And this kind of change in the binding pocket. So once we better understand those implications, I think we can then begin to understand if there’s a role for any and all of these inhibitors in these patients’ treatment options.

Richard Kim, MD: Thank you Dr Shroff and Dr Pal for this insightful discussion. And thank you to our audience for watching this Targeted Oncology presentation on precision medicine.

Transcript edited for clarity.

Sumanta Pal, MD: I think that FGFR [fibroblast growth factor receptor] is a very valid target, not just in the context of advanced bladder cancer but in cholangiocarcinoma and a subset of lung cancers that are driven by FGFR mutations. I really think in the same way that we’ve looked, for instance, at inhibiting NTRK across a wide spectrum of different tumor types, maybe the premise of hitting FGFR across a multitude of malignancies will stand as well. So I’m excited to see agents like infigratinib develop in multiple diseases simultaneously.

We published the data for infigratinib in Cancer Discovery. Again, I was really impressed with the response rates—25%, a very heavily pretreated population of patients. And in my mind, it’s impossible to compare apples and oranges with different studies. I think it ranks right up there with erdafitinib, which obviously gained its approval for advanced bladder cancer recently. So I’m really intent on seeing infigratinib developed further.

An interesting thing happened though. Infigratinib actually passed hands. It was originally owned by Novartis. The agent was then shifted over to QED Therapeutics, a much smaller company. And funny enough, on the day that this transition happened, I happened to be in San Francisco at ASCO GU [American Society of Clinical Oncology, Genitoruinary Cancers Symposium]. I actually e-mailed the folks at the company, and at the time they had 2 employees, and so we had a conversation over coffee. I said I’d really like to see this compound develop in a different niche, and that niche should really be upper tract bladder cancer. And I didn’t expect much out of the conversation. But now, I guess it’s about a year later, we’re on the brink of hopefully launching a phase III clinical trial in upper tract disease. So I’m very thankful to the company, obviously, for taking this advice seriously.

In this clinical trial, we’re actually going to be looking at a comparison of infigratinib against placebo in patients who have resected upper tract disease. The trial is going to permit a small handful of individuals who have lower tract disease as well. But I like to think of this as being a trial that’s really going to test this premise of the relevance of FGFR biology in upper tract patients.

There’s been a lot of discussion about different molecular subtypes of bladder cancer. We talk about the FGFR3-driven subtype, and I certainly think that there’s some rationale to conceive of bladder cancer that way. But I think over the years what we’ve really learned is that there’s no perfect subtyping of the disease, at least according to response to therapy. And to account for that overlap and because bladder cancer is such an aggressive and rapid disease, it might actually make sense to take the “kitchen sink” approach and lump together multiple therapies.

With that in mind, I would be excited to see agents like infigratinib paired with immunotherapy [I/O]. I definitely think that the combination should be tested first for safety, of course. But provided that that’s the case, I think that we need to very quickly move forward to more definitive studies that look at these combinations. In my experience, in the situation of bladder cancer, it’s not the scenario in which all patients will easily shift from first-line therapy to second-line therapy and on to a third-line regimen. You really have to look to make each line of treatment very impactful, and perhaps combinations are the best way to do that.

Rachna Shroff, MD, MS: So where do we go from here? What do you think are some of the ongoing challenges in terms of research for FGFR inhibitors and what the next steps should and could be for their role in cholangiocarcinoma?

Richard Kim, MD: Most of the studies currently being published are in second-line setting, refractory setting. And we know that as a single agent, it does have activity for sure, and I think those patients would benefit. But I think looking forward, there are already studies going on in first-line. Can you spare these patients chemotherapy, right? Everybody wants that personalized medicine. They want their actual mutation to be tested and to be given that drug that targets that.

So I think we’re heading in the right pathway, doing a first-line study comparing against active chemotherapy. That’s one area that we’re still eagerly anticipating. The second thing that we are looking for is, can we combine this with other drugs, I/O, chemotherapy, so to enhance the activity of that drug? Third is to understand better the resistant pattern. We know that these FGFR fusions, they work but they will eventually stop responding. So the question is what can you do when they stop responding? Do we understand enough to say we could go from one FGFR inhibitor to another one and go on trying to attack the same area? So I think those are the 3 main areas of interest and moving forward in terms of managing those FGFR fusion cholangiocarcinoma cases.

Rachna Shroff, MD, MS: Yes, and I think that the resistance question is such an important one. There’s some really elegant and interesting research that is looking at these gatekeeper mutations that are developing with, after infigratinib exposure, for instance. And this kind of change in the binding pocket. So once we better understand those implications, I think we can then begin to understand if there’s a role for any and all of these inhibitors in these patients’ treatment options.

Richard Kim, MD: Thank you Dr Shroff and Dr Pal for this insightful discussion. And thank you to our audience for watching this Targeted Oncology presentation on precision medicine.

Transcript edited for clarity.
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