Futibatinib and Pembrolizumab in FGFR-Altered Urothelial Cancer - Vadim Koshkin

January 29, 2025

Vadim Koshkin discusses a phase II study of combination therapy using futibatinib and pembrolizumab in advanced metastatic urothelial cancer. The study explores two patient cohorts: those with FGFR3 mutations or FGFR fusions, and those without these biomarkers. The results show promising anti-tumor activity, particularly in the biomarker-defined cohort, with encouraging response rates and survival outcomes. The combination demonstrates a favorable safety profile compared to existing FGFR inhibitors, with notably lower rates of certain side effects like retinal toxicity and nail changes. The discussion highlights the potential of this combination therapy as a treatment option for cisplatin-ineligible patients, while also raising interesting questions about the mechanism of response in biomarker-negative patients and the future development of this therapeutic approach.

Biographies:

Vadim Koshkin, MD, Assistant Professor, Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA

Shilpa Gupta, MD, Director, Genitourinary Medical Oncology, Taussig Cancer Institute, Co-Leader of the Genitourinary Oncology Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH


Read the Full Video Transcript

Shilpa Gupta: Hello, everyone. I'm Shilpa Gupta. I'm a GU medical oncologist at the Cleveland Clinic. I'm delighted to be joined by Dr. Vadim Koshkin, who's an associate professor at UCSF in GU oncology, and a former Cleveland Clinic fellow. Vadim, welcome. Great to have you here.

Vadim Koshkin: Thank you, Shilpa. Great to be here as well.

Shilpa Gupta: Vadim, we want to discuss the study that you presented at ESMO 2020 for the phase II study of futibatinib and pembrolizumab in advanced metastatic urothelial cancer. Can you give us a brief overview of what this study entailed? What were the cohorts, and what you saw?

Vadim Koshkin: Yeah, absolutely. So this was a global two-cohort phase II study of patients with metastatic urothelial cancer, specifically who were platinum-ineligible, or specifically cisplatin-ineligible. So major eligibility criteria, of course, included histologically confirmed metastatic urothelial cancer, no prior therapy in the metastatic setting, and being ineligible for or declining platinum-based chemotherapy.

The trial enrolled two cohorts in parallel. So the first cohort, or cohort A, was the biomarker-defined cohort and included patients with FGFR3 mutations or FGFR1 through 4 fusions. The other cohort, cohort B, included the remaining patients—in other words, wild-type patients or patients with other alterations that were not included in cohort A.

In both cohorts—again, this was not randomized but assessed in parallel—a patient received futibatinib (the oral FGFR inhibitor) 20 milligrams once daily orally, and pembrolizumab 200 milligrams IV every three weeks.

I will maybe briefly just highlight the outcomes in both cohorts, and then we can, of course, delve into specific questions. Cohort A—again, that's the biomarker-defined cohort—enrolled a total of 17 patients. The remaining 26 patients (this was overall a 43-patient study) were enrolled in cohort B.

But in cohort A, the objective response rate to the combination was 47%. Disease control rate was just over 80%. Median progression-free survival was 8.3 months. Median overall survival was actually not reached in cohort A after a median follow-up of about a year and a half.

In cohort B—that’s mostly the wild-type cohort—responses were a bit more modest, in the high 20s (around 27% response rate), about 52–54% disease control rate, and then the median progression-free survival and median overall survival were 4.1 months and 18.3 months, respectively.

Overall, from this trial, we concluded that certainly the combination of futibatinib and pembrolizumab demonstrates encouraging anti-tumor activity—clinically meaningful activity—in particular in the biomarker-defined cohort of patients with FGFR3 mutations or FGFR1 through 4 fusions. And overall, it was also a fairly well-tolerated combination, with toxicity really as expected with this respective class of each agent (FGFR inhibitor and immune checkpoint inhibitor). No new safety signals were observed, and there were no grade 4 or 5 events, which was also important to highlight. So it seems to be a fairly effective and viable combination in this setting.

Shilpa Gupta: Thank you for the great overview, Vadim. And this is certainly—we've seen the NORSE trial in the past with erdafitinib and another checkpoint inhibitor showing activity of about mid-50s in response rates. And this one is—granted it's a much smaller trial—but this is very encouraging activity. Regarding the side effect profile, is this any different from erdafitinib? Would you say this is better tolerated?

Vadim Koshkin: That's a great question because erdafitinib is, of course, as we know, the only approved FGFR inhibitor in urothelial cancer right now. It's a very effective drug, often, of course, challenging to give because of the associated toxicity.

Comparing the toxicity side by side of erdafitinib and checkpoint inhibitor combination in NORSE—which was erda and cetrelimab—versus this trial, futibatinib and pembrolizumab, there are, of course, the usual caveats that apply: we can't quite compare across trials. These were different populations enrolled in different places and times.

But I will highlight that while overall the rate of grade 3 events was about similar in the two trials (in both trials, it was around 40% or a bit above 40%), there were some toxicities more commonly seen with erdafitinib that we saw less in this trial—in particular, retinal toxicity. So central serous retinopathy, which is again a known class effect of these drugs, was not seen as much with futibatinib here, only really in single digits of patients. And then nail changes, which are quite bothersome for many patients on erdafitinib, we did not see as much here.

So I will highlight those as differences—potentially suggesting maybe somewhat better tolerability of futibatinib. But again, it's challenging to compare across these two trials.

Shilpa Gupta: Yeah, I agree. And there's a lot of newer FGFR inhibitors out there whose toxicity profiles are certainly more appealing. I also wanted to ask you, Vadim—in cohort B, there was activity of about 27% response rates and even complete responses, around 11%. What do you think the main driver of these responses was in this cohort, since it’s the unselected cohort?

Vadim Koshkin: That's a great question. And also, I mean, one of the differences in this trial with some of the other trials, including NORSE that combined a checkpoint inhibitor and FGFR inhibitor, but only in the biomarker-selected patients with FGFR3 alterations, is that here we did have a biomarker-unselected cohort, so to say—mostly a wild-type cohort or a cohort with other FGF/FGFR alterations where maybe we don't expect an FGFR3 inhibitor to work in quite as well.

I would say the overall response rate/disease control rate in this cohort was fairly consistent with what we expect with pembro. So with pembro, we expect in the treatment-naive population probably somewhere between 27–30% responses, and that's really what we saw here—a disease control rate of just over 50%. But there were certainly some durable responses in this cohort as well. Whether that's driven by pembro alone—and it would have happened anyway with pembro monotherapy—or whether there really is a change in the tumor microenvironment with FGFR inhibition that drives greater benefit from pembro, I think it's hard to say.

But one of the rationales for including this cohort is that there is some preclinical data, again, suggesting that FGFR inhibition does prime the tumor microenvironment potentially to respond to checkpoint inhibitors a bit better. So potentially some of the more durable responses could be driven by that as well.

Shilpa Gupta: That's great. What are the next steps with this combination, Vadim? Any insights on that?

Vadim Koshkin: Well, I think a lot of that is still in the works and being planned. But certainly, I think exploring this combination further in urothelial cancer is viable. This trial did highlight that combining futibatinib with pembro is safe. It's certainly beneficial for a significant proportion of patients. And I think it's an open question whether we can build on this more—maybe with some of the even currently available combination regimens across the urothelial cancer landscape—whether we can add on a drug like futibatinib, probably for biomarker-selected patients, for those with FGFR alterations. So I think probably more to come there still.

Shilpa Gupta: Great. And has there been any data with futibatinib in the refractory setting, Vadim, so far?

Vadim Koshkin: Well, only in earlier-phase trials, which led to this. And there, it’s as you expect, the FGFR-altered patients.

Shilpa Gupta: I think it's always great to have multiple options. Just like in prostate cancer, we have so many different PARP inhibitors, and there's always that option. I think that's the way bladder cancer is going to. And congratulations on your presentation, and thank you for joining us.

Vadim Koshkin: Thank you so much, Shilpa. I really appreciate it.