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David Quinn, PhD, on FGFR-Targeted Therapy in Urothelial Cancer

<ѻý class="mpt-content-deck">– FORT-1 showed similar efficacy to chemo, other trials continue

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The FORT-1 trial was the first to compare a fibroblast growth factor receptor (FGFR) inhibitor, rogaratinib, with standard-of-care therapy. As David Quinn, MBBS, PhD, of the Keck School of Medicine at the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, and colleagues explained in the , their hope was that FGFR mRNA-positivity would identify a group of patients in whom rogaratinib was more efficacious than chemotherapy. That proved not to be the case, but studies of this class of drug in this patient group are continuing.

The phase II, open-label FORT-1 trial included 175 patients with locally advanced or metastatic FGFR mRNA-positive cancer previously treated with at least one platinum chemotherapy regimen. Patients were randomized to receive rogaratinib or chemotherapy with docetaxel, paclitaxel, or vinflunine.

"To our knowledge, these are the first reported data comparing FGFR-targeted therapy with standard-of-care chemotherapy in patients selected on the basis of FGFR mRNA-positive urothelial carcinoma," the authors wrote.

Although the study was designed to be a phase II/III trial, following a potential imbalance of deaths, the Data Monitoring Committee recommended pausing enrollment and reducing the daily dose of rogaratinib for further evaluation. The trial's sponsor, Bayer AG, decided to stop further enrollment because of similar efficacy between the treatment groups.

The team therefore presented an interim phase II analysis with a median 10.8 months of follow-up. The objective response rate (ORR) was 20.7% for patients who received rogaratinib and 19.3% for those on chemotherapy (P=0.48). Median overall survival was 8.3 months for rogaratinib and 9.8 months for chemotherapy (P=0.67). An exploratory analysis of patients with FGFR3 tumor DNA alterations, however, found an ORR of 52.4% for rogaratinib vs 26.7% for chemotherapy (P not given).

"Overall, the improved ORR with rogaratinib seen in this study in FGFR mRNA-positive patients with FGFR genetic DNA alterations is of interest and may warrant further evaluation," the study authors concluded.

In the following interview, Quinn, who is medical director of the Norris Cancer Hospital and Clinics and head of the Section of Genitourinary Medical Oncology, discussed additional details of the study and ongoing research in this area.

What would you say is the main implication of FORT-1?

Quinn: Essentially it is a negative trial. It's noteworthy because it's the first comparison of this class of drugs to a standard-of-care therapy, and it accrued very quickly -- we were successful in that regard, but the primary biomarker did not pan out. I think the lesson here is that it's likely this drug or group of drugs are active in patients with the FGF receptor mutation, but the biomarker we used was not useful or discriminatory in this case.

Why do you think the drug had better efficacy in patients with the FGFR3 tumor DNA alterations?

Quinn: The mutational translocation activates FGF, and in that setting this drug and others in the group, including erdafitinib, inhibit the activity of that mutation specifically. It's a mutation-specific effect that we see.

About how many patients have this DNA alteration?

Quinn: FGFR3 mutations are present in about 20% of patients with metastatic urothelial cancer -- that's overall in a variety of cohorts. In our study of 175 patients, there were 33 with this mutation, so that's roughly 20%.

The important point here is what we did was not the same thing as taking a whole bunch of people with urothelial cancer and screening for the mutation. In this study, we used the mRNA assessment to screen patients, and we were very successful in that. There was a question before about how quickly it would accrue, and it actually accrued extremely quickly.

Given that rogaratinib showed better efficacy in patients with the FGFR3 alterations, are you planning any further study in this patient group?

Quinn: This drug is going to be studied further in combination with immunotherapy. There are a series of trials with the PDL-1 inhibitor atezolizumab that are ongoing where there's some interesting activity.

But we had a discussion about whether we would do FORT-2 and look at the mutation and erdafitinib, which is an FGF receptor inhibitor, same class, and has accelerated approval with the FDA based on a study of about 80 patients, single-arm, with FGF receptor mutation.

Erdafitinib is being developed by Janssen, and they're well advanced in the phase III, and we didn't think it was worth trying to do a "me too" study in that group if there wasn't an advantage in terms of having a larger population, which is what was expected with the mRNA and didn't pan out.

Read the study here.

The study was sponsored by Bayer AG.

Quinn disclosed employment with AbbVie and relationships with Pfizer, Bristol Myers Squibb, Genentech/Roche, Merck Sharp & Dohme, Bayer, Exelixis, Eisai, US Biotest, Seattle Genetics, Myovant Sciences, Aveo, and the Clinigen Group.

Primary Source

Journal of Clinical Oncology

Source Reference:

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ASCO Publications Corner