2. UroToday Home
  3. Clinical Trials
  4. From the Editor
Back to From the Editor Articles    

Fibroblast Growth Factor Receptor 3 (FGFR3) Specificity, Promise of Efficacy with Less Toxicity for Patients with Urothelial Carcinomas?

It has been almost 6 years, since I’ve talked about the fibroblast growth factor receptor (FGFR) family in the Urotoday Clinical Trials Portal.1 Since then, the United States Food and Drug Administration granted accelerated approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alteration, that has progressed during or following platinum-containing chemotherapy, including within 12 months of perioperative platinum-containing chemotherapy.2 This accelerated approval was based on tumor response rate from the phase 2 trial,3 and required confirmation of clinical benefit from additional clinical trials.

At the 2023 annual American Society of Clinical Oncology (ASCO) meeting this year, we saw results from the randomized phase 3 THOR trial in patients with select FGFR2 or 3 mutations/fusions.4 Note that this trial has 2 randomizations, and we saw results of the comparison between erdafitinib (n=136) and taxane chemotherapy of choice (n=130), which was docetaxel or vinflunine. All patients had previously received 1-2 lines of systemic therapy, and prior anti-PD-(L)-1 therapy was mandatory for enrollment. The other randomization component of the THOR trial is for patients who are naïve to anti-PD-(L)-1 therapy, and results are still pending from this randomization between erdafitinib and pembrolizumab.

The data from ASCO 2023, showed that patients who received erdafitinib had a statistically significant overall survival benefit over chemotherapy, median 12.1 vs. 7.8 months, respectively. This translated into a hazard ratio of 0.64 (p=0.0050), a 36% reduction in the risk of death. Objective response rate was 46% vs. 12%, respectively. This trial data supports the role of erdafitinib in the post-PD-(L)-1 antibody-treated population. The current accelerated approval is for the post-platinum-treated population, therefore, it will be interesting to see what regulators do with a potential confirmatory label. Of course, if erdafitinib demonstrates overall survival benefit over pembrolizumab in the other randomization component of the trial, that would likely lead to a much broader label.

The previous Urotoday Clinical Trials Article, almost 6 years ago, focused on FGFR non-selective and -selective small molecules and monoclonal antibodies. Although we’ve seen results from many of these other agents over time, none, other than erdafitinib, have risen to standard of care, clinical use status for our patients. We must recognize, however, that FGFR non-selective and even FGFR-selective agents offer a significant toxicity profile, including hyperphosphatemia, tissue calcification, nail and hair changes, mucositis, retinal detachment and arthralgias.5 This brings us to the question of what type of FGFR selectivity does each compound has, and whether different cancer types may require even more specific FGFR subtype selectivity for enhanced efficacy. For example, it is thought that many of the toxicities mentioned above are likely due to FGFR2 inhibition. This may be very important for cancers like intrahepatic cholangiocarcinoma, where FGFR2 fusions are common. Yet, urothelial carcinoma tends to have higher rates of FGFR3 mutation, and early hints are that the FGFR3 mutation patients may have better response rates to erdafitinib.3 It is possible that FGFR3 specific targeting, might lead to fewer off-target effects and potentially less toxicity.

There have been some attempts to inhibit FGFR3, specifically, in the past. For instance, Vofatamab (B-701) is a FGFR3 specific monoclonal antibody that was tested with pembrolizumab, and it yielded objective response rates of 29.6% in a small patient population (n=28).6 Efforts for further development of Vofatamab for advanced metastatic urothelial carcinoma have been terminated, although there may still be efforts for non-muscle invasive bladder cancer and multiple myeloma. Other newer small molecules with greater FGFR3 selectivity offer the promise of a wider therapeutic window, less toxicity, and the ability to dose higher, which could lead to greater efficacy than a broad FGFR inhibitor. At this time, both TYRA-300 and LOXO-435 are being studied in actively accruing clinical trials, and purportedly, have up to 63- and 361-fold preclinical selectivity for FGFR3 over other FGFR isoforms, respectively. This certainly warrants further investigation with the accrual of our patients, with hopes for improved side effect profile and efficacy.

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Yu EY. Fibroblast Growth Factor Receptors, a New Hope for Patients with Urothelial Carcinomas. Urotoday Clinical Trials Portal; December 6, 2017.
  2. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma
  3. Loriot Y, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2019; 381:338-48.
  4. Loriot Y, et al. Phase 3 THOR study: Results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt). J Clin Oncol 41, no. 17_suppl (June 10, 2023) LBA4619-LBA4619.
  5. Tabernero J, et al. Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol 2015; 33:3401-8.
  6. Siefker-Radtke AO, et al. Clinical activity of vofatamab (V), an FGFR3 selective antibody in combination with pembrolizumab (P) in metastatic urothelial carcinoma (mUC), updated interim analysis of FIERCE-22. Ann Oncol 2019; 30 (Suppl 5) V365.