Erdafitinib’s ‘Time to Shine’ in FGFR-Altered Urothelial Cancer


In an interview with Targeted Oncology, Arlene O. Siefker-Radtke, MD, discusses the findings from 3 trials of erdafitinib and explains the next steps for evaluating the agent.

Arlene O. Siefker-Radtke, MD

Arlene O. Siefker-Radtke, MD

According to Arlene O. Siefker-Radtke, MD, erdafitinib (Balversa) represents a potentially groundbreaking advancement for the treatment of metastatic urothelial carcinoma (mUC).

Erdafitinib is an FGFR1-4 inhibitor being evaluated for the treatment of patients with urothelial cancer. As a pan-FGFR inhibitor, erdafitinib marks the first biomarker targeted therapy for patients with mUC. Previously, the therapy demonstrated efficacy in the open-label, non-comparator, phase 2 BLC2001 study (NCT02365597) for patients who had received 1-3 or more prior lines of therapy.

Now, erdafitinib is being further evaluated in 3 trials; NORSE (NCT03473743), THOR (NCT03390504), and RAGNAR (NCT04083976). Each of these 3 studies resulted in promising data, including benefits in overall survival, progression-free survival, and objective response rate.1-3

In an interview with Targeted OncologyTM, Siefker-Radtke, professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, discusses the findings from these 3 trials of erdafitinib and explains the next steps for evaluating the agent.

Targeted Oncology: Can you discuss the mechanism of action of erdafitinib?

Siefker-Radtke: Erdafitinib is an FGFR1-4 inhibitor, so it inhibits all 4 FGF receptors, and it inhibits them in the single digit nanomolar range. It is very effective at targeting these, and this may be important because in the lab, we saw we only blocked FGFR3, and we saw 1,2, and 4 come up. If you inhibit more, perhaps you could enhance the clinical activity using pan inhibition of FGF.

Can you discuss some of the trials the agent is being evaluated in?

It is edrafininib’s time to shine. [At ASCO], we saw 3 major trials presented. The first 1 is the NORSE clinical trial. You may notice the different names of the trial is a sign that Janssen likes her Norse gods. We have erdafitinib itself, which is named after the goddess Erda the Norse goddess for the Earth. Then we have the THOR clinical trial, and the RAGNAR trial. The trial that it was my pleasure to present [at ASCO was] the NORSE clinical trial.

What did the NORSE study evaluate and what was the design of the study?

This clinical trial was designed to test the combination of erdafitinib with the PD-1 inhibitor cetrelimab [JNJ-63723283] in the frontline treatment of patients with metastatic surgically unresectable urothelial carcinoma. This trial was designed as a randomized yet non-comparative cohort trial with erdafitinib as a single-agent, and then the combination of erdafitinib with cetrelimab.

If we look at the biology behind the design, there's been historic literature suggesting that the FGFR3 alterations are present in more immunologically cold tumors. The goal was to see if this combination could overcome any potential immune resistance, or perhaps enhance the clinical activity of erdafitinib in the FGFR3-altered urothelial carcinoma population.

Please discuss the results of the NORSE trial.

The results of this trial are quite promising. It was a frontline trial, no prior therapy for patients who are ineligible for cisplatin-based chemotherapy. The treatment of these patients has long been an unmet need, with over 50% of patients not eligible for standard-of-care cisplatin-based regimens, so developing alternatives would be very important to enhance activity.

The results appeared quite compelling. Single-agent erdafitinib had an objective response rate of around 45%. The combination of erdafitinib with cetrelimab had an objective response rate of around 55%. We also saw deeper and more durable responses with the combination, and we saw nearly a 14% complete response rate with the combination treatment. This also translated to an impact in progression-free survival with single-agent erdafitinib having a progression-free survival around 5 and a half months, and the combination arm having a median survival of around 11 months. The median overall survival for erdafitinib alone was around 16 months, whereas the combination had a median overall survival of around 20.8 months.

As a result of this trial, we see that single-agent erdafitinib has similar clinical activity to what has been reported previously in the second-line treatment of urothelial carcinoma. The combination appears promising as well with an objective response rate around 55%, deeper and more durable responses that also translated to a survival of around 20.8 months. I feel the combination is worth further study as well. But our ultimate goal is to come up with strategies that enhance the life expectancy and the treatment options for our patients with urothelial cancer.

What are the next steps for this research?

The next steps for this research are understanding how to sequence it with combination strategies that are currently being used in urothelial carcinoma. Also important is studying erdafitinib earlier in the disease space. We see the presence of FGFR3 alterations in about 15% to 20% of metastatic urothelial tumors of the bladder. However, in superficial bladder cancer, we see the frequency of mutations of around 60%. The ability to use this therapy to control tumors in earlier stage disease, well, it would be awesome if it would put me out of a job by preventing the development of metastases, but it may enhance the control of tumors inside the bladder, and help patients keep their bladders for much longer.

Is there anything else in this space that has caught your eye?

The THOR clinical trial was designed to confirm evidence of benefit from erdafitinib in the urothelial cancer population. This trial was designed in patients who receive prior chemotherapy, and in the cohort presented at [ASCO], all patients received a prior immune checkpoint inhibitor. Patients were randomized between treatment with erdafitinib alone, or with docetaxel or vinflunine, which is used in Europe.

When we look at the results, the results appear quite promising on all 3 fronts, with an improvement in response rate, progression-free survival, and overall survival, meeting its clinical end point. If we look at the objective response rate, it was 45% compared with 11% with single-agent taxane. The progression-free survival was around 5 months compared with around 2 months with single-agent taxane, translating to that median overall survival of around 1 year, compared with around 7 months with single-agent taxane. Erdafitinib is here to stay as a recommended treatment for our [patients with] urothelial cancer.

In addition to both the THOR and NORSE clinical trials, we have an additional trial being presented, the RAGNAR trial. It's a tumor agnostic trial. It took any patient who had an FGF alteration present. This is so important because most tumor types don't have a high enough frequency of these mutations to do a large randomized clinical trial. If we see efficacy, we have to find a way of benefiting this patient population. The results were quite promising with an objective response rate tumor agnostic across all tumor types of around 30%. There were also selected tumor types that showed even higher responses with salivary tumors showing a 100% response rate, endometrial tumors around 50%, and cholangiocarcinomas around 50%, as well. There's clearly benefit in helping control tumors and have FGFR3 alterations present by using this pan-FGF1-4 inhibitor, erdafitinib, for treatment across multiple tumor types.

  1. Siefker-Radtke A, Powles T, Moreno V, et al. Erdafitinib (ERDA) vs ERDA plus cetrelimab (ERDA+CET) for patients (pts) with metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa): Final results from the phase 2 Norse study. J Clin Oncol. 2023;41(suppl 16):4504.
  2. Loriot Y, Matsubara N, Park SH, 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. 2023;41(suppl 17):LBA4619.
  3. Pant S, Schuler M, Iyer G, et al. Erdafitinib in patients with advanced solid tumors with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study. Lancet Oncol. 2023;24(8):925-935. doi:10.1016/S1470-2045(23)00275-9
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