FGFR Inhibition: A Novel Therapeutic Strategy - Episode 5

FGFR Inhibitor Clinical Trials

June 21, 2019

Sumanta Pal, MD:A lot of this development for FGFR [fibroblast growth factor receptor] inhibitors in bladder cancers happened in at the same time. We had studies for erdafitinib and infigratinib really happening more or less at the same time course. For erdafitinib, we achieved response rates on the order of around 40%, and progression-free survival [PFS] of around 5 months or so. And this really triggered some enthusiasm for the compound, and led to an FDA approval. I will say that there’s still a confirmatory phase III trial of erdafitinib that we’re going to have to wait on before I feel that this approval is really going to hold a lot of water. And that trial is actually comparing erdafitinib against standard chemotherapy in individuals that have previously received checkpoint inhibition. It’s also going to look at the comparison of erdafitinib versus checkpoint inhibition in folks who haven’t been exposed to checkpoint inhibitors to date. So I think that’s an important trial.

Infigratinib, in my mind, has produced relatively similar data in the sense that we see great response rates. In a very heavily pretreated population, we see response rates approximately of around 25%. Most of the patients in this early-phase experience that I led along with my colleagues at Memorial Sloan Kettering Cancer Center, really seemed to indicate that about 70% to 80% of patients were heavily pretreated. And despite that, we had appreciable response rates.

I’ve had the opportunity to lead the phase I clinical trial looking at infigratinib in the context of bladder cancer. This was a phase IB study that dovetailed on a phase I experience that encompassed multiple histologies. And what we saw in this particular arm of the study in patients withFGFR-mutated or fused bladder cancer is that we achieved response rates, despite multiple lines of prior therapy in most patients, of around 25%, very impressive responses. In fact, I have a patient myself with bony metastatic disease that developed a complete response, which I really haven't seen before in the context of other existing therapies, including checkpoint inhibitors. I’m really hoping that we’re going to be able to look at infigratinib further in a context of advanced bladder cancer. And we certainly do have a couple of potential trial designs moving forward with this compound.

So, at this year’s ASCO [American Society of Clinical Oncology] Annual Meeting, I had the privilege of having one of my fellows, in fact, present some of the subset analyses for an initial report for infigratinib. We’re specifically going to look at that population of patients with upper tract disease, and this is predicated on the fact that some of our earlier work shows that upper tract disease seems to be heavily enriched with mutations and fusions inFGFR3. And perhaps those patients have a more relevant biology driven by that molecule. What we in fact saw is that all patients in this series acquired some clinical benefit from infigratinib, either disease stabilization or response in the context of upper tract disease. And furthermore, we had about a 50% response rate. So seeing this makes me particularly excited about a plan to develop infigratinib for upper tract patients.

Richard Kim, MD:So let’s go into more depth in terms of some of the trials that have been published and will be presented at the ASCO 2019 Annual Meeting as well. And one of the trials that Dr. Rachna Shroff, MD, MS, said you were involved in is an FGFR inhibitor called infigratinib, which is a pan-FGFR. It mostly blocks 1, 2, and 3, some 4 as well, that you’re part of the phase II data also. Can you tell us a little bit more about that data that has been published in the JCO [Journal of Clinical Oncology]?

Rachna Shroff, MD, MS:When the original data was published it the Journal of Clinical Oncology it included 61 patients. And the first thing that I have to say is I still remember when we were discussing this study with a company that had infigratinib, and they said, “We’re talking about 15% of a rare tumor type.” So a rare finding in a rare tumor type—how are we going to do this? Tt was amazing how 61 patients were accrued in under 18 months. It just goes to show what collaboration across institutions can do and what these patients are motivated to do.

In the original data there was 61 patients and in the initial data set, the majority of patients hadFGFR2fusions, but there was a subset of patients that had other FGFR alterations. And since then the data has been updated, which was presented at the 2018 ESMO [European Society of Medical Oncology] Annual Meeting, there is a slightly larger group of patients and they’re actually still accruing for that phase II population. But the dataset that was presented, the overall response rate of the entire group of justFGFR2-fusion patients was 30%, which was in a very refractory patient population. So the patients received gemcitabine with platinum, but they could be anywhere from second-line therapy all the way up to any number of lines. And so to see that type of response rate in a refractory population was very exciting.

And if you looked specifically at just the patients who received it in the second line, the response rate was even higher, it was 39%. Regarding prior retrospective data, if you look at some of the pooled analyses, most of these patient’s prior responses are in the single digits.

Richard Kim, MD:So based on that data there’s a phase III study going on right now called the PROOF study that is comparing the standard arm of GEM [gemcitabine ] and CIS [cisplatin] versus the FGFR inhibitor, infigratinib, also allows crossover. The primary endpoint of the study was PFS. And I believe that study is ongoing right now and hopefully with that result maybe the landscape of the first-line FGFR fusion driven tumor will change.

So another abstract that was presented, that will be presented at ASCO on Monday, is a trial done in Asia using another pan-FGFR inhibitor called erdafitinib, which is

a pan-FGFR inhibitor 1 through 4. So can you comment on any of the results of that?

Rachna Shroff, MD, MS:Well you know this is a drug that was developed again, and a lot of these FGFR inhibitors are initially used across different tumor types. There was a subset of patients with cholangiocarcinoma, and what I’ll say is that at this point we have data with a lot of different FGFR inhibitors, and you mentioned,FGFR2fusions are clearly oncogenic drivers. Across the board these inhibitors, whether it be erdafitinib, infigratinib, and some of the other ones that are in ongoing studies, their respective patients are responding, and they’re all in the 20% to 30% up to 35% range. So it’s nice to see that that response across different drugs, because it just shows that this is a very targetable alteration.

Richard Kim, MD:So the other drug that I want to mention is the drug called pemigatinib, which was presented last year at the 2018 ESMO Annual Meeting, and that was a study with 3 different arms. The first arm had an arm withFGFRfusion only. The second one was FGFR or other aberrations and a fusion that had none of the FGFR aberration.

And they presented the 45-patient study with the FGFR aberration, withFGFRfusion only, and the response rate was pretty remarkable at 40%, around 45%, with a very high disease control rate as well. And just like was mentioned, it seems to have activity in those subtype of tumor. And based on that promising data, once again, they’re also conducting a first-line study as well comparing against GEM and CIS versus the pemigatinib in patients withFGFRfusion.

Transcript edited for clarity.