Results from the Phase 1b/2 FIDES-02 Study: Derazantinib for Metastatic Bladder Cancer with Activating FGFR1/2/3 Genetic Aberrations - Andrea Necchi

March 16, 2023

Andrea Necchi joins Alicia Morgans in a conversation about the FIDES-02 Study.  This Phase 1b/2 study evaluated the efficacy and safety of derazantinib, a multi-TKI oral inhibitor that targets FGF receptor genomic alteration 1, 2, 3, and 4 genomic alterations, in patients with metastatic urothelial carcinoma. The focus is metastatic local advanced or metastatic patients with urothelial carcinoma of either bladder or upper tract tumor in different disease settings. The study investigated different dose levels of derazantinib monotherapy and the combination of derazantinib-atezolizumab in various disease settings. However, the study was closed in advance due to inactivity. The study revealed an 8% partial response rate, lower than other similar inhibitors, like erdafitinib. It did not meet the cutoff of activity regarding the response rate, allowing any further development of derazantinib, at least as a single agent in this disease. 


Andrea Necchi, MD, Medical Oncologist, Associate Professor of Oncology, Vita-Salute San Raffaele University, Chief of Genitourinary, Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi. I'm so excited to be here with Dr. Andrea Necchi, speaking about the FIDES-02 Study. This is a Phase 1b/2 study that you presented at GU ASCO 2023. Thank you so much for talking with me.

Andrea Necchi: Thank you, Alicia. And thank you UroToday people for inviting me.

Alicia Morgans: Always happy to talk to you. So tell me a little bit about the FIDES study.

Andrea Necchi: Well, the FIDES-02 Study is a platform study with the multi arm opportunities to evaluate derazantinib, which is a multi-TKI oral available inhibitor targeting FGF receptor genomic alteration 1, 2, 3, and 4 genomic alteration among other alterations in urothelial cancer. So the focus is metastatic local advanced or metastatic patients with urothelial carcinoma of either bladder or upper tract tumor in different disease settings. So there are subgroups investigating different dose levels of a single arm, of single agent study, is with atezolizumab monotherapy as a second line, or for later line therapy, in patients who had already received and experienced chemotherapy with or without immunotherapy. There is an arm investigating monotherapy in patient with, in frontline for Cisplatin ineligible. And there are also arms investigating the combination of the derazantinib-atezolizumab, so the combination of FGF receptor inhibition and immune checkpoint inhibitors.

The study was closed in advance due to inactivity. So basically, the main data they will present are relative to the summary of the two cohorts that it investigated to different levels of their derazantinib monotherapy as second line, or later line therapy, in patients with the metastatic urothelial carcinoma.

... About 50%, if 50 patients were included in these subgroup analysis. And of course, the objective response rate, that was a primary endpoint of the study overall, revealed an 8% partial responses, so quite a few partial responses, as compared to other similar inhibitors that worked very well in this disease, like erdafitinib, which was set as a newer standard of care by the USFDA. The safety signals was good. So, in particular, the rate of hyperphosphatemia, which was a targeted side effects for this class of agents was quite low. So the main toxicity with this drug was elevation of transaminase and anemia. But the drug did not meet the cutoff of activity in terms of the response rate, allowing any further development of the, at least as single agent, in this disease.

So the question now is why have we seen such a difference in the response rates between similar agents, between erdafitinib and derazantinib, as well as other similar compounds in the same patient population? So I think that the data will generate a huge discussion around the activity of different agents, or apparently similar agents in this disease, in the targeted population of patients with FGF receptor alterations, and that the question related to the biomarker for selecting patients that are direct candidate for this kind of approach will be another important key to develop this drug further in this disease.

Alicia Morgans: Well, very, very interesting and important, though not necessarily moving forward. What does this mean for FGFR approaches? Is this something that we've kind of finished with erdafitinib, or is this something that we still need to investigate? As you said, I think there's going to be a lot of discussion, but where do we go from here?

Andrea Necchi: I think most of the developments, the development possibilities of agents targeting FGF receptor, genomic alteration, plays into a round the role of biomarkers and the type of this alteration that are targeted as biomarker for patient selection. There is a huge heterogenity between studies, according to the type of mutations that are included, that are considered to select patients for trials. And of course, there are different ways of evaluating these mutations, targeted approach, or more extensive approach, like with the comprehensive genomic profiling tests, and so on. All these ways may have influenced somehow the quality of the patients that have been included, and may, at least in part, justify the difference in the inactivity that we have seen. Of course, there may be a, of course, an issue related to the activity of the drugs, and since so far dovitinib is the only drug that provided outstanding activity, 40% response rate in the chemotherapy pretreated patients, with the FGF receptor alterations.

Of course, we are waiting for more mature data from trials, from validation trials, in particular, the THOR Study, which will validate the role over erdafitinib in the comparison with the standard of care investigator choice chemotherapy or pembrolizumab in the second line or third line setting with these patients. But waiting for this data, what we have today is that 40% response rate with erdafitinib, and the far less response rate with any other agents, including pemigatinib, including afatinib, including now derazantinib, which sets far below the cut point of 20%, 15% activity response rate, which may justify further development, at least at monotherapy again in this disease.

Alicia Morgans: Well, I think that's a wonderful way to think it through. So thank you for that. At least we do have erdafitinib, as you said, and we are waiting for those confirmatory trials to help us really understand that landscape better, and really understand versus these other comparators how to best integrate that drug. So I just really appreciate the time that you took. Thank you so much for sharing this exciting, interesting data, which we will learn from, even if the drug itself is not moving forward. And I appreciate your expertise as always.

Andrea Necchi: Thank you.