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FGFR Inhibitors in Development for CCA

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Center; Martin Gutierrez, MD, Hackensack University Medical Center; Teresa Macarulla, MD, PhD, Vall d'Hebron Institute; Andrea Wang-Gilliam, MD, PhD, Washington University ; Andrew Zhu, MD, PhD, Massachusetts General Hospital
Published: Monday, Nov 25, 2019



Transcript:

Ghassan Abou-Alfa, MD, MBA: Back to you Teresa, we heard while we were at ESMO [the European Society for Medical Oncology annual meeting] here in Barcelona, about the FIGHT-202 study of the Incyte Corp drug. Tell us more about this study.

Teresa Macarulla, MD, PhD: This is a single arm phase II trial with another FGFR2 [fibroblast growth factor receptor 2] inhibitor, Incyte’s drug, pemigatinib. They reported on more than 100 patients with cholangiocarcinoma and the FGFR2 fusion.

Ghassan Abou-Alfa, MD, MBA: Yes, 146 actually, which is quite a bit.

Teresa Macarulla, MD, PhD: The response rate was 35%.

Ghassan Abou-Alfa, MD, MBA: Correct.

Teresa Macarulla, MD, PhD: This was in second-line or beyond that. I think it is a very impressive result for this population. Again, the progression-free survival was pretty high, and the overall survival, that is completely mature, was 21 months. This opens light in this type of patient. For me, they were incredible results.

Ghassan Abou-Alfa, MD, MBA: Sure, by all means. Martin, however, they reported on 3 cohorts. This was with the FGR fusion, mutations or other alterations, and nothing at all. Tell us the report about those 3.

Martin Gutierrez, MD: Actually it’s reaffirmed what we have been talking about for the last hour, hour and a half; it’s the intrahepatic diffusion, which is a narrow, tunnel view, what the responses were. We find out that the mutations, and obviously the ones that doen’t carry that driver mutation, their response rates were nonexistent. So it just reinforced what the population should be for the next study.

Ghassan Abou-Alfa, MD, MBA: Fair enough. We’re happy to see that data. In full disclosure, again, many of us were involved with this effort, the same for the BGJ398 trial. I would say that definitely it’s quite intriguing as we just heard from Teresa, the response rate, more than 36%. In addition to that, yes, there was a delineation to see what other changes genetically that could occur that could have influenced the choice of therapy, being the fusion proteins or anagenic changes, or even no genetic changes. Which by the way, does not mean no genetic changes, but it means something that we don’t yet understand or know, per se.

But now we know very well that the pemigatinib is also moving on with a phase II trial, again in first-line therapy versus GemCis [gemcitabine-cisplatin]. Quite a bit of action is happening in that early game.

Andrea Wang-Gilliam, MD, PhD: May I ask a question?

Ghassan Abou-Alfa, MD, MBA: Please go ahead, Andrea.

Andrea Wang-Gilliam, MD, PhD: Why not combination, since we’re talking about gemcitabine-cisplatin versus a front-line targeted therapy? Is there a thought of doing a combination, versus we think there’s not synergy, versus we think it’s too much toxicity?

Ghassan Abou-Alfa, MD, MBA: My simple answer to that is that first you want to know what your asset knows, or what it does by itself before you start combining it, because otherwise you don’t want to piggyback on something else. In other words, I would say presumably, yes, it might be worth looking into the future of that. But we also want to make sure whether there is a potential or no potential synergistic effect.

Martin, you seem you have some thoughts on that.

Martin Gutierrez, MD: Yes, right. I also think the same. I think it’s better to know the activity on a single agent upfront in the first line, when these studies are moving. We learned from some of the other diseases that when we start to combine some of the TKIs [tyrosine kinase inhibitors] and chemotherapy, they were not necessarily better. Specifically in the lung cancer area, they actually increased toxicities, and responses…the same. So it’s actually worth it to just look at it as a single agent upfront.

Ghassan Abou-Alfa, MD, MBA: Absolutely, fair enough. Andrew, back to you. This is something that I have to admit, it continues to intrigue me quite a bit, and it’s nice work that was brought up by your group with Lipika Goyal, MD, and yourself. Interestingly when you give the BGJ398 [infigratinib] to certain patients, if they were to progress on the therapy, you were able to delineate that there were genetic changes that occurred to stress out the tumor 1 way or the other. Tell us a little bit more about this finding.

Andrew Zhu, MD, PhD: Yes. We have learned quite a lot from targeted therapy development in oncology, period. We definitely know that these targeted agents, even though they work well, they almost invariably will develop resistance. The resistance can be further classified by intrinsic resistance, meaning, they just don’t respond to the drug in the first place. Or more commonly, or meaningfully, they will actually respond to the treatment. But then because of the very significant molecular heterogeneity occurring while the patient is receiving the drug, the tumor actually develops the acquired resistance. As a result, that contributes to the therapeutic failure.

So understanding this mechanism obviously has a significant impact. We have learned from targeted therapy development in lung cancer, melanoma, and figuring out this mechanism really can guide further therapeutic intervention.

In the case of the BGJ FGFR inhibitor in cholangiocarcinoma, we were able to demonstrate, as you’re getting the treatment response, and the tumor is actually starting to emerge with very meaningful mutations, the specific mutations that we identified are actually in the FGFR kinase domain. These are the mutations that actually have the theoretical consideration of altering the binding of the drug with the emergence of the mutation.

The implication, with identification of these mutations, is that we are able to guide these patients with additional therapeutic interventions. Particularly we have the next generation of the FGFR inhibitors, that they may actually overcome the mutation that’s already emerging in this setting. Clearly this is something that’s definitely doable, but also that has clinical implication.

Ghassan Abou-Alfa, MD, MBA: Absolutely, it’s quite fascinating work. I strongly recommend too that you look at this manuscript by Dr Lipika Goyal, and with senior authorship by Dr Andrew Zhu, because it’s quite fascinating. I have great admiration. They actually did…autopsies on patients with cholangiocarcinoma to be able to dissect the tumors from different sites in the liver, and then…the genetic changes that occurred upon progression, or of course, sadly, upon death. If anything, yes, they were able to delineate some of them.

Admittedly we still have a lot to cover in that regard because the question is, is it a hazard to stress a gatekeeper mutation, which is, for example, the V154C? Or could it be some evolution that’s happening on different models that are yet to be discovered? Something that we’ll wait and see where this is going to take us.

With this said, however, I’ll go back to Teresa. In your perspective, in regard to the FGFR2 fusion, there are a lot of other efforts going on. Actually, it’s a very busy field. Tell us a little bit more about your perception at least on this.

Teresa Macarulla, MD, PhD: Yes. In fact, in the moment, all our new compounds are in the same setting. It seems complicated to understand what is the exact place for all of these new drugs. Because it’s only a small percentage of patients with intrahepatic cholangiocarcinoma. This is a rare disease. So it seems incredible. But they are there. There are some of these compounds, for example, the TAS compound that seem to have some differences. For example, it seems it could work in these resistant patients previously treated with the FGFR2 and who become resistant. We have some examples of patients who respond to this because there are some differences in the drugs, that they are irreversible. So maybe we can have these small differences. If not, they are in the same setting in this moment.

Ghassan Abou-Alfa, MD, MBA: Absolutely. Martin, back to you on this issue of the different therapies for the FGFR, and of course, alterations that can occur based on thresholds of the tumor by certain therapies. How often do you see the, not specifically the fusions, but the mutations, other alterations with regard to FGFR2?

Martin Gutierrez, MD: Feel free to correct me, it’s probably around 15% or 20% when you start to see the other mutations. What is fascinating to me is that the fusions, the patterns of the fusions are so large and so variable, and I’m not sure we have really dissected that yet, that it has different meanings. It depends on the partner.

Ghassan Abou-Alfa, MD, MBA: I’d glad you brought this up, this is exactly what you just spoke about. There are so many alterations occurring of the FGFR2 fusions that, number 1, where does it start? How does it get stressed out by the tumors? I think Andrew already brought up a very important point, which is what other therapies can come into play afterward to see where things are?

To wrap up the FGFR2 story, at the moment we have many products. We heard about several of them. We know that 2 of them at least are moving into a phase III trial, among which is the BGJ398, which has plenty of data that as we heard, many of us have collaborated on. We’re doing it all collaboratively. The other one is, of course, the pemigatinib from Incyte that we also heard about here in Barcelona yesterday with the FIGHT-202 study. This again is intriguing, especially because of the perspective, not only looking at this nice high response rate of 36%, which is applicable to the fusion cohort A, but also the intriguing part in regard to the mutations as well.

Transcript Edited for Clarity

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Transcript:

Ghassan Abou-Alfa, MD, MBA: Back to you Teresa, we heard while we were at ESMO [the European Society for Medical Oncology annual meeting] here in Barcelona, about the FIGHT-202 study of the Incyte Corp drug. Tell us more about this study.

Teresa Macarulla, MD, PhD: This is a single arm phase II trial with another FGFR2 [fibroblast growth factor receptor 2] inhibitor, Incyte’s drug, pemigatinib. They reported on more than 100 patients with cholangiocarcinoma and the FGFR2 fusion.

Ghassan Abou-Alfa, MD, MBA: Yes, 146 actually, which is quite a bit.

Teresa Macarulla, MD, PhD: The response rate was 35%.

Ghassan Abou-Alfa, MD, MBA: Correct.

Teresa Macarulla, MD, PhD: This was in second-line or beyond that. I think it is a very impressive result for this population. Again, the progression-free survival was pretty high, and the overall survival, that is completely mature, was 21 months. This opens light in this type of patient. For me, they were incredible results.

Ghassan Abou-Alfa, MD, MBA: Sure, by all means. Martin, however, they reported on 3 cohorts. This was with the FGR fusion, mutations or other alterations, and nothing at all. Tell us the report about those 3.

Martin Gutierrez, MD: Actually it’s reaffirmed what we have been talking about for the last hour, hour and a half; it’s the intrahepatic diffusion, which is a narrow, tunnel view, what the responses were. We find out that the mutations, and obviously the ones that doen’t carry that driver mutation, their response rates were nonexistent. So it just reinforced what the population should be for the next study.

Ghassan Abou-Alfa, MD, MBA: Fair enough. We’re happy to see that data. In full disclosure, again, many of us were involved with this effort, the same for the BGJ398 trial. I would say that definitely it’s quite intriguing as we just heard from Teresa, the response rate, more than 36%. In addition to that, yes, there was a delineation to see what other changes genetically that could occur that could have influenced the choice of therapy, being the fusion proteins or anagenic changes, or even no genetic changes. Which by the way, does not mean no genetic changes, but it means something that we don’t yet understand or know, per se.

But now we know very well that the pemigatinib is also moving on with a phase II trial, again in first-line therapy versus GemCis [gemcitabine-cisplatin]. Quite a bit of action is happening in that early game.

Andrea Wang-Gilliam, MD, PhD: May I ask a question?

Ghassan Abou-Alfa, MD, MBA: Please go ahead, Andrea.

Andrea Wang-Gilliam, MD, PhD: Why not combination, since we’re talking about gemcitabine-cisplatin versus a front-line targeted therapy? Is there a thought of doing a combination, versus we think there’s not synergy, versus we think it’s too much toxicity?

Ghassan Abou-Alfa, MD, MBA: My simple answer to that is that first you want to know what your asset knows, or what it does by itself before you start combining it, because otherwise you don’t want to piggyback on something else. In other words, I would say presumably, yes, it might be worth looking into the future of that. But we also want to make sure whether there is a potential or no potential synergistic effect.

Martin, you seem you have some thoughts on that.

Martin Gutierrez, MD: Yes, right. I also think the same. I think it’s better to know the activity on a single agent upfront in the first line, when these studies are moving. We learned from some of the other diseases that when we start to combine some of the TKIs [tyrosine kinase inhibitors] and chemotherapy, they were not necessarily better. Specifically in the lung cancer area, they actually increased toxicities, and responses…the same. So it’s actually worth it to just look at it as a single agent upfront.

Ghassan Abou-Alfa, MD, MBA: Absolutely, fair enough. Andrew, back to you. This is something that I have to admit, it continues to intrigue me quite a bit, and it’s nice work that was brought up by your group with Lipika Goyal, MD, and yourself. Interestingly when you give the BGJ398 [infigratinib] to certain patients, if they were to progress on the therapy, you were able to delineate that there were genetic changes that occurred to stress out the tumor 1 way or the other. Tell us a little bit more about this finding.

Andrew Zhu, MD, PhD: Yes. We have learned quite a lot from targeted therapy development in oncology, period. We definitely know that these targeted agents, even though they work well, they almost invariably will develop resistance. The resistance can be further classified by intrinsic resistance, meaning, they just don’t respond to the drug in the first place. Or more commonly, or meaningfully, they will actually respond to the treatment. But then because of the very significant molecular heterogeneity occurring while the patient is receiving the drug, the tumor actually develops the acquired resistance. As a result, that contributes to the therapeutic failure.

So understanding this mechanism obviously has a significant impact. We have learned from targeted therapy development in lung cancer, melanoma, and figuring out this mechanism really can guide further therapeutic intervention.

In the case of the BGJ FGFR inhibitor in cholangiocarcinoma, we were able to demonstrate, as you’re getting the treatment response, and the tumor is actually starting to emerge with very meaningful mutations, the specific mutations that we identified are actually in the FGFR kinase domain. These are the mutations that actually have the theoretical consideration of altering the binding of the drug with the emergence of the mutation.

The implication, with identification of these mutations, is that we are able to guide these patients with additional therapeutic interventions. Particularly we have the next generation of the FGFR inhibitors, that they may actually overcome the mutation that’s already emerging in this setting. Clearly this is something that’s definitely doable, but also that has clinical implication.

Ghassan Abou-Alfa, MD, MBA: Absolutely, it’s quite fascinating work. I strongly recommend too that you look at this manuscript by Dr Lipika Goyal, and with senior authorship by Dr Andrew Zhu, because it’s quite fascinating. I have great admiration. They actually did…autopsies on patients with cholangiocarcinoma to be able to dissect the tumors from different sites in the liver, and then…the genetic changes that occurred upon progression, or of course, sadly, upon death. If anything, yes, they were able to delineate some of them.

Admittedly we still have a lot to cover in that regard because the question is, is it a hazard to stress a gatekeeper mutation, which is, for example, the V154C? Or could it be some evolution that’s happening on different models that are yet to be discovered? Something that we’ll wait and see where this is going to take us.

With this said, however, I’ll go back to Teresa. In your perspective, in regard to the FGFR2 fusion, there are a lot of other efforts going on. Actually, it’s a very busy field. Tell us a little bit more about your perception at least on this.

Teresa Macarulla, MD, PhD: Yes. In fact, in the moment, all our new compounds are in the same setting. It seems complicated to understand what is the exact place for all of these new drugs. Because it’s only a small percentage of patients with intrahepatic cholangiocarcinoma. This is a rare disease. So it seems incredible. But they are there. There are some of these compounds, for example, the TAS compound that seem to have some differences. For example, it seems it could work in these resistant patients previously treated with the FGFR2 and who become resistant. We have some examples of patients who respond to this because there are some differences in the drugs, that they are irreversible. So maybe we can have these small differences. If not, they are in the same setting in this moment.

Ghassan Abou-Alfa, MD, MBA: Absolutely. Martin, back to you on this issue of the different therapies for the FGFR, and of course, alterations that can occur based on thresholds of the tumor by certain therapies. How often do you see the, not specifically the fusions, but the mutations, other alterations with regard to FGFR2?

Martin Gutierrez, MD: Feel free to correct me, it’s probably around 15% or 20% when you start to see the other mutations. What is fascinating to me is that the fusions, the patterns of the fusions are so large and so variable, and I’m not sure we have really dissected that yet, that it has different meanings. It depends on the partner.

Ghassan Abou-Alfa, MD, MBA: I’d glad you brought this up, this is exactly what you just spoke about. There are so many alterations occurring of the FGFR2 fusions that, number 1, where does it start? How does it get stressed out by the tumors? I think Andrew already brought up a very important point, which is what other therapies can come into play afterward to see where things are?

To wrap up the FGFR2 story, at the moment we have many products. We heard about several of them. We know that 2 of them at least are moving into a phase III trial, among which is the BGJ398, which has plenty of data that as we heard, many of us have collaborated on. We’re doing it all collaboratively. The other one is, of course, the pemigatinib from Incyte that we also heard about here in Barcelona yesterday with the FIGHT-202 study. This again is intriguing, especially because of the perspective, not only looking at this nice high response rate of 36%, which is applicable to the fusion cohort A, but also the intriguing part in regard to the mutations as well.

Transcript Edited for Clarity
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