JCO PO author Dr. Shilpa Gupta at Cleveland Clinic Children's Hospital shares insights into her article, "Fibroblast Growth Factor Receptor 3 (FGFR3) Alteration Status and Outcomes on Immune Checkpoint Inhibitors (ICPI) in Patients with Metastatic Urothelial Carcinoma". Host Dr. Rafeh Naqash and Dr. Gupta discuss how FGFR3 combined with TMB emerged as a biomarker that may be predictive for response to ICPI in mUC.

TRANSCRIPT

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center.

Today I am excited to be joined by Dr. Shilpa Gupta, Director of Genitourinary Medical Oncology at the Cancer Institute and co-leader of the GU Oncology Program at the Cleveland Clinic, and also lead author of the JCO PO article titled "Fibroblast Growth Factor Receptor 3 Alteration Status and Outcomes on Immune Checkpoint Inhibitors in Patients With Metastatic Urothelial Carcinoma."

At the time of this recording, our guest's disclosures will be linked in the transcript.

Shilpa, welcome again to the podcast. Thank you for joining us today.

Dr. Shilpa Gupta: Thank you, Rafeh. Honor to be here with you again.

Dr. Rafeh Naqash: It is nice to connect with you again after two years, approximately. I think we were in our infancy of our JCO PO podcast when we had you first time, and it has been an interesting journey since then.

Dr. Shilpa Gupta: Absolutely.

Dr. Rafeh Naqash: Well, excited to talk to you about this article that you published. Wanted to first understand what is the genomic landscape of urothelial cancer in general, and why should we be interested in FGFR3 alterations specifically?

Dr. Shilpa Gupta: Bladder cancer or urothelial cancer is a very heterogeneous cancer. And while we find there is a lot of mutations can be there, you know, like BRCA1, 2, in HER2, in FGFR, we never really understood what is driving the cancer. Like a lot of old studies with targeted therapies did not really work. For example, we think VEGF can be upregulated, but VEGF inhibitors have not really shown definite promise so far.

Now, FGFR3 receptor is the only therapeutic target so far that has an FDA approved therapy for treating metastatic urothelial cancer patients, and erdafitinib was approved in 2019 for patients whose tumors overexpressed FGFR3 mutations, alterations, or fusions. And in the landscape of bladder cancer, it is important because in patients with non-muscle invasive bladder cancer, about 70 to 80% patients can have this FGFR3. But as patients become metastatic, the alterations are seen in, you know, only about 10% of patients. So the clinical trials that got the erdafitinib approved actually used archival tumor from local cancer. So when in the real world, we don't see a lot of patients if we are trying to do metastatic lesion biopsies. And why it is important to know this is because that is the only targeted therapy available for our patients right now.

Dr. Rafeh Naqash: Thank you for giving us that overview. Now, on the clinical side, there is obviously some interesting data for FGFR3 on the mutation side and the fusion side. In your clinical practice, do you tend to approach these patients differently when you have a mutation versus when you have a fusion?

Dr. Shilpa Gupta: We can use the treatment regardless of that.

Dr. Rafeh Naqash: I recently remember I had a patient with lung cancer, squamous lung cancer, who also had a synchronous bladder mass. And the first thought from multiple colleagues was that this is metastatic lung. And interestingly, the liquid biopsy ended up showing an FGFR3-TACC fusion, which we generally don't see in squamous lung cancers. And then eventually, I was able to convince our GU colleagues, urologists, to get a biopsy. They did a transurethral resection of this tumor, ended up being primary urothelial and synchronous lung, which again, going back to the FGFR3 story, I saw in your paper there is a mention of FGFR3-TACC fusions. Anything interesting that you find with these fusions as far as biology or tumor behavior is concerned?

Dr. Shilpa Gupta: We found in our paper of all the patients that were sequenced that 20% had the pathognomonic FGFR3 alteration, and the most common were the S249C, and the FGFR3-TACC3 fusion was in 45 patients. And basically I will say that we didn't want to generate too much as to fusion or the differences in that.

The key aspect of this paper was that historically there were these anecdotal reports saying that patients who have FGFR alterations or mutations, they may not respond well to checkpoint inhibitors because they have the luminal subtype. And these were backed by some preclinical data and small anecdotal reports. But since then, we have seen that, and that's why a lot of people would say that if somebody's tumor has FGFR3, don't give them immunotherapy, give them erdafitinib first, right?

So then we had this Phase 3 trial called the THOR trial, which actually showed that giving erdafitinib before pembrolizumab was not better. That debunked that myth, and we are actually reiterating that because in our work we found that patients who had FGFR3 alterations or fusions, and if they also have TMB-high, they actually respond very well to single agent immunotherapy. And that is, I think, very important because it tells us that we are not really seeing that so-called potential of resistance to immunotherapy in these patients. So to answer your question, yeah, we did see those differences, but I wouldn't say that any one marker is more prominent.

Dr. Rafeh Naqash: The analogy is kind of similar to what we see in lung cancer with these mutations called STK11/KEAP1, which are also present in some other tumors. And one of the questions that I don't think has been answered is when you have in lung cancer, if you extrapolate this, where doublet or single agent immunotherapy doesn't do as well in tumors that are STK11 mutated. But then if you have a high TMB, question is does that TMB supersede or trump the actual mutation? Could that be one reason why you see the TMB-high but FGFR3 altered tumors in your dataset responding or having better outcomes to immunotherapy where potentially there is just more neoantigens and that results in a more durable or perhaps better response to checkpoint therapy?

Dr. Shilpa Gupta: It could be. But you know, the patients who have FGFR alterations are not that many, right? So we have already seen that just patients with TMB-high respond very well to immunotherapy. Our last podcast was actually on that, regardless of PD-L1 that was a better predictor of response to immunotherapy. So I think it's not clear if this is adding more chances of response or not, because either way they would respond. But what we didn't see, which was good, that if they had FGFR3, it's not really downplaying the fact that they have TMB-high and that patients are not responding to immunotherapy. So we saw that regardless, and that was very reassuring.

Dr. Rafeh Naqash: So if tomorrow in your clinic you had an individual with an FGFR3 alteration but TMB-high, I guess one could be comfortable just going ahead with immunotherapy, which is what the THOR trial as you mentioned.

Dr. Shilpa Gupta: Yes, absolutely. And you know, when you look at the toxicity profiles of pembrolizumab and erdafitinib, really patients really struggle with using the FGFR3 inhibitors. And of course, if they have to use it, we have to, and we reserve it for patients. But it's not an easy drug to tolerate. Currently the landscape is such that, you know, frontline therapy has now evolved with an ADC and immunotherapy combinations. So really if patients progress and have FGFR3 alterations, we are using erdafitinib. But let's say if there were a situation where a patient has had chemotherapy, no immunotherapy, and they have FGFR3 upregulation and TMB-high, yes, I would be comfortable with using only pembrolizumab. And that really ties well together what we saw in the THOR trial as well.

Dr. Rafeh Naqash: Going to the clinical applications, you mentioned a little bit of this in the manuscript, is combination therapies. You alluded to it a second back. Everything tends to get combined with checkpoint therapy these days, as you've seen with the frontline urothelial, pembrolizumab with an ADC. What is the landscape like as far as some of these FGFR alterations are concerned? Is it reasonable to combine some of those drugs with immune checkpoint therapy? And what are some of the toxicity patterns that you've potentially seen in your experience?

Dr. Shilpa Gupta: So there was indeed a trial called the NORSE trial. It was a randomized trial but not a comparative cohort, where they looked at FGFR altered patients. And when they combined erdafitinib plus cetrelimab, that did numerically the response rates were much higher than those who got just erdafitinib. So yeah, the combination is definitely doable. There is no overlapping toxicities.

But unfortunately that combination has not really moved forward to a Phase 3 trial because it's so challenging to enroll patients with such kind of rare mutations on large trials, especially to do registration trials. And since then the frontline therapy has evolved to enfortumab vedotin and pembrolizumab. I know there is an early phase trial looking at a next generation FGFR inhibitor. There is a triplet combination looking in Phase 1 setting with a next generation FGFR inhibitor with EV-pembro. However, it's not a randomized trial. So you know, I worry about such kinds of combinations where we don't have a path for registration.

And in the four patients that have been treated, four or five patients in the early phase as a part of basket trial, the toxicities were a lot, you know, when you combine the EV-pembro and an FGFR3 inhibitor, we see more and more toxicity. So the big question is do we really need the "kitchen sink" approach when we have a very good doublet, or unless the bar is so high with the doublet, like what are we trying to add at the expense of patient toxicity and quality of life is the big question in my mind.

Dr. Rafeh Naqash: Going back to your manuscript specifically, there could be a composite biomarker. You point out like FGFR in addition to FGFR TMB ends up being predictive prognostic there. So that could potentially be used as an approach to stratify patients as far as treatment, whether it's a single agent versus combination. Maybe the TMB-low/FGFR3 mutated require a combination, but the TMB-high/FGFR mutated don't require a combination, right?

Dr. Shilpa Gupta: No, that's a great point, yeah.

Dr. Rafeh Naqash: But again, very interesting, intriguing concepts that you've alluded to and described in this manuscript.

Now, a quick take on how things have changed in the bladder cancer space in the last two years. We did a podcast with you regarding some biomarkers as you mentioned two years back. So I really would like to spend the next minute to two to understand how have things changed in the bladder cancer space? What are some of the exciting things that were not there two years back that are in practice now? And how do you anticipate the next two years to be like? Maybe we'll have another podcast with you in another two years when the space will have changed even more.

Dr. Shilpa Gupta: Certainly a lot has happened in the two years, you know. EV-pembro became the universal frontline standard, right? We have really moved away from cisplatin eligibility in metastatic setting because anybody would benefit from EV-pembro regardless of whether they are candidates for cisplatin or not, which historically was relevant. And just two days ago, we saw that EV-pembro has now been approved for localized bladder cancer for patients who are cisplatin ineligible or refusing. So, you know, this very effective regimen moving into earlier setting, we now have to really think of good treatment options in the metastatic setting, right? So I think that's where a lot of these novel combinations may come up.

And what else we've seen is in a tumor agnostic trial called the DESTINY-PanTumor trial, patients who had HER2 3+ on immunohistochemistry, we saw the drug approval for T-DXd, and I think that has kind of reinvigorated the interest in HER2 in bladder cancer, because in the past targeting HER2 really didn't work. And we still don't know if HER2 is a driver or not. And at ESMO this year, we saw an excellent study coming out of China with DV which is targeting HER2, and toripalimab, which is a Chinese checkpoint inhibitor, showing pretty much similar results to what we saw with EV-pembro.

Now, you know, not to do cross-trial comparisons, but that was really an amazing, amazing study. It was in the presidential session. And I think the big question is: does that really tell us that HER2-low patients will not benefit? Because that included 1+, 2+, 3+. So that part we really don't know, and I think we want to study from the EV-302 how the HER2 positive patients did with EV and pembro. So that's an additional option, at least in China, and hopefully if it gets approved here, there is a trial going on with DV and pembro.

And lastly, we've seen a very promising biomarker, like ctDNA, for the first time in bladder cancer in the adjuvant setting guiding treatment with adjuvant atezolizumab. So patients who were ctDNA positive derived overall survival and recurrence-free survival benefit. So that could help us select moving forward with more studies. We can spare unnecessary checkpoint inhibitors in patients who are not going to benefit.

So I think there is a lot happening in our field, and this will help do more studies because we already have the next generation FGFR inhibitors which don't have the toxicities that erdafitinib comes with. And combining those with these novel ADCs and checkpoint inhibitors, you know, using maybe TMB as a biomarker, because we really need to move away from PD-L1 in bladder cancer. It's shown no utility whatsoever, but TMB has.

Dr. Rafeh Naqash: Well, thank you so much, Shilpa, for that tour de force of how things have changed in bladder cancer. There used to be a time when lung and melanoma used to lead this space in terms of the number of approvals, the biomarker development. It looks like bladder cancer is shifting the trend at this stage. So definitely exciting to see all the new changes that are coming up.

I'd like to spend another minute and a half on your career. You've obviously been a leader and example for many people in the GU space and beyond. Could you, for the sake of our early career especially, the trainees and other listeners, describe how you focused on things that you're currently leading as a leader, and how you shaped your career trajectory over the last 10 years?

Dr. Shilpa Gupta: That's a really important question, Rafeh, and you and I have had these discussions before, you know, being an IMG on visas like you, and being in different places. I think I try to make the most of it, you know, instead of focusing on the setbacks or the negative things. Like tried to grab the opportunities that came along. When I was at Moffitt, got to get involved with the Phase 1 trial of pembrolizumab in different tumor types. And just keeping my options open, you know, getting into the bladder cancer at that time when I wanted to really do only prostate, but it was a good idea for me to keep my options open and got all these opportunities that I made use of.

I think an important thing is to, like you said, you know, have a focus. So I am trying to focus more on biomarkers that, you know, we know that 70% patients will respond to EV-pembro, right? But what about the remaining 30%? Like, so I'm really trying to understand what determines hyperprogressors with such effective regimens who we really struggle with in the clinic. They really don't do well with anything we give them after that. So we are doing some work with that and also trying to focus on PROs and kind of patient-reported outcomes.

And a special interest that I've now developed and working on it is young-onset bladder cancer. You know, the colorectal cancer world has made a lot of progress and we are really far behind. And bladder cancer has historically been a disease of the elderly, which is not the case anymore. We are seeing patients in their 30s and 40s. So we launched this young-onset bladder cancer initiative at a Bladder Cancer Advocacy Network meeting and now looking at more deep dive and creating a working group around that.

But yeah, you know, I would say that my philosophy has been to just take the best out of the situation I'm in, no matter where I am. And it has just helped shape my career where I am, despite everything.

Dr. Rafeh Naqash: Well, thank you again. It is always a pleasure to learn from your experiences and things that you have helped lead. Appreciate all your insights, and thank you for publishing with JCO PO. Hopefully we will see more of your biomarker work being published and perhaps bring you for another podcast in a couple of years.

Dr. Shilpa Gupta: Yeah, thank you, Rafeh, for the opportunity. And thanks to JCO PO for making these podcasts for our readers. So thanks a lot.

Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.

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DISCLOSURES

Dr. Shilpa Gupta

Stock and Other Ownership Interests:
Company: BioNTech SE, Nektar

Consulting or Advisory Role:
Company: Gilead Sciences, Pfizer, Merck, Foundation Medicine, Bristol-Myers Squibb/Medarex, Natera, Astellas Pharma, AstraZeneca, Novartis, Johnson & Johnson/Janssen

Research Funding:
Recipient: Your Institution
Company: Bristol Myers Squibb Foundation, Merck, Roche/Genentech, EMD Serono, Exelixis, Novartis, Tyra Biosciences, Pfizer, Convergent Therapeutics, Acrivon Therapeutics, Flare Therapeutics, Amgen

Travel, Accommodations, Expenses:
Company: Pfizer, Astellas Pharma, Merck

Podcast: FGFR3 Alteration Status and Immunotherapy in Urothelial Cancer

JCO Precision Oncology Conversations