ONCAlert | Upfront Therapy for mRCC

The Development of FGFR Inhibitors

Targeted Oncology
Published Online:12:33 PM, Wed July 10, 2019

Sumanta Pal, MD: I think for years we’ve really been craving some strategy in which we can inhibit FGFR [fibroblast growth factor receptor] in bladder cancer, again recognizing that 20% of folks have mutations, 50% to 70% in upper tract disease have mutations. We’ve always tried to conceive of a way to block these entities, and now we have 2 broad classes of drugs that can do this. We have small molecule inhibitors, and we have monoclonal antibodies. In that small molecule inhibitor category are agents such as erdafitinib and infigratinib. We have perhaps more recently a compound out of Debiopharm Group as well that inhibits that pathway. In the monoclonal antibody category from Rainier Therapeutics, we have a drug called B-701.

Rachna Shroff, MD, MS: In terms of the development for FGFR inhibitors, can you talk about what their impact is in the new era of precision medicine and personalized therapy, and just in general their mechanism of action—how do these drugs work?

Richard Kim, MD: As you mentioned, there are 4 FGF receptors out there, FGFR1, 2, 3, and 4. And we know that the aberration of FGFR2, you could have amplification, you could have mutation, and you could have fusion. Those are the things that occur. But currently the drugs bind FGFR2, or a pan-FGFR inhibitor that blocks 1, 2, 3, and 4. And some are more selective than the others, we have to point that out.

If you do have the FGFR fusion, those are the patients that tend to respond to this inhibitor. And response rate, depending on the data set you look at range anywhere from 25% to 40%. That makes sense because that’s on oncogenic driver. It is what drives the tumor in those highly targeted patients. Therefore, I think that’s the rationale for using those FGFR fusion inhibitors in those patients who have those fusions.

Rachna Shroff, MD, MS: Yes, and the ease of administration. These are oral drugs, and so for patients who’ve been on IV [intravenous] chemotherapy and such, it was a really nice break in terms of being able to take these drugs on the go and to not come in for infusions and things like that, which is, from a quality of life perspective, an added benefit to something like this.

Sumanta Pal, MD: I think that one of the key differences among targeted therapies in general, whether we’re looking at agents that hit HER2 [human epidermal growth factor receptor 2] or EGFR is drug potency and specificity. Potency and specificity is a key differentiator for all compounds that sit within the same class. I’m really excited about infigratinib in particular among the FGFR inhibitors because it seems to have, in the context of bladder cancer cell lines, the most specificity for FGFR receptors 1 through 3. As opposed to other agents that target 4 as well, this seems to really home in on those 3 specific targets. And it does so at nanomolar concentrations. These concentrations are an order of magnitude lower than what we see, for instance, with erdafitinib and some of the other agents in this category. So I think that really positions infigratinib quite nicely among the other agents within this category.

Transcript edited for clarity.

Sumanta Pal, MD: I think for years we’ve really been craving some strategy in which we can inhibit FGFR [fibroblast growth factor receptor] in bladder cancer, again recognizing that 20% of folks have mutations, 50% to 70% in upper tract disease have mutations. We’ve always tried to conceive of a way to block these entities, and now we have 2 broad classes of drugs that can do this. We have small molecule inhibitors, and we have monoclonal antibodies. In that small molecule inhibitor category are agents such as erdafitinib and infigratinib. We have perhaps more recently a compound out of Debiopharm Group as well that inhibits that pathway. In the monoclonal antibody category from Rainier Therapeutics, we have a drug called B-701.

Rachna Shroff, MD, MS: In terms of the development for FGFR inhibitors, can you talk about what their impact is in the new era of precision medicine and personalized therapy, and just in general their mechanism of action—how do these drugs work?

Richard Kim, MD: As you mentioned, there are 4 FGF receptors out there, FGFR1, 2, 3, and 4. And we know that the aberration of FGFR2, you could have amplification, you could have mutation, and you could have fusion. Those are the things that occur. But currently the drugs bind FGFR2, or a pan-FGFR inhibitor that blocks 1, 2, 3, and 4. And some are more selective than the others, we have to point that out.

If you do have the FGFR fusion, those are the patients that tend to respond to this inhibitor. And response rate, depending on the data set you look at range anywhere from 25% to 40%. That makes sense because that’s on oncogenic driver. It is what drives the tumor in those highly targeted patients. Therefore, I think that’s the rationale for using those FGFR fusion inhibitors in those patients who have those fusions.

Rachna Shroff, MD, MS: Yes, and the ease of administration. These are oral drugs, and so for patients who’ve been on IV [intravenous] chemotherapy and such, it was a really nice break in terms of being able to take these drugs on the go and to not come in for infusions and things like that, which is, from a quality of life perspective, an added benefit to something like this.

Sumanta Pal, MD: I think that one of the key differences among targeted therapies in general, whether we’re looking at agents that hit HER2 [human epidermal growth factor receptor 2] or EGFR is drug potency and specificity. Potency and specificity is a key differentiator for all compounds that sit within the same class. I’m really excited about infigratinib in particular among the FGFR inhibitors because it seems to have, in the context of bladder cancer cell lines, the most specificity for FGFR receptors 1 through 3. As opposed to other agents that target 4 as well, this seems to really home in on those 3 specific targets. And it does so at nanomolar concentrations. These concentrations are an order of magnitude lower than what we see, for instance, with erdafitinib and some of the other agents in this category. So I think that really positions infigratinib quite nicely among the other agents within this category.

Transcript edited for clarity.
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