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<i>FGFR</i> Alterations in Bladder
How I Test for FGFR Alterations in Bladder Cancer and Manage Targeted Therapies

Released: April 30, 2021

Expiration: April 29, 2022

Andrea Necchi
Andrea Necchi, MD
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The therapeutic landscape for bladder cancer is rapidly shifting due to the advent of novel therapies. Immunotherapies were initially approved for later-stage disease, but we are now seeing approvals for early disease stages as well. In the United States, pembrolizumab has been approved for patients with non‑muscle‑invasive disease, and in the first‑line metastatic setting, atezolizumab and pembrolizumab have been approved for cisplatin‑ineligible patients.

The data concerning the efficacy of immunotherapies for patients with high‑risk disease post cystectomy have been mixed. In the Imvigor010 trial, patients with high-risk muscle-invasive bladder cancer or cancer of the upper urinary tract received adjuvant atezolizumab or observation. However, the trial did not show a disease-free survival (DFS) improvement in either the all‑comer or PD-L1–high patient populations with atezolizumab. By contrast, the phase III CheckMate 274 study of adjuvant nivolumab was designed similarly to IMvigor010 but included a placebo control. All‑comer and PD-L1–high patients who received nivolumab had significantly improved DFS vs those who received placebo (median DFS: 21 vs 10.9 months, respectively; HR: 0.70; 95% CI: 0.54-0.89; P = .0006).

Antibody–drug conjugates (ADCs) that deliver chemotherapy with antibodies while targeting specific antigens are also currently being investigated. There are 2 potential key ADCs for bladder cancer. Enfortumab vedotin, which targets nectin‑4, and sacituzumab govitecan, which targets TROP2, is now approved in the United States in the postchemotherapy and postimmunotherapy setting. It is evident that the field is expected to change in the next few years, perhaps more in the early-stage non-muscle-invasive and muscle-invasive disease than the later disease stages.

BCL2001 Study
In urothelial cancer, FGFR3 mutations occur mainly in low-grade noninvasive papillary tumors, which have a relatively stable genome with few other alterations. FGFR3 alterations are detected in 60% to 70% of these non-muscle-invasive carcinomas, but FGFR3 alterations are also detected in approximately 15% to 20% of more advanced, invasive urothelial carcinoma as well. Although the frequency of FGFR3 mutations is relatively low, they are recognized drivers of bladder cancer.

Drugs targeting FGFR3 are mainly tyrosine kinase inhibitors, and some are being investigated in patients with metastatic disease in phase I and phase II trials. Erdafitinib, a pan‑FGFR inhibitor that targets FGFR3 and FGFR2 alterations, was investigated in the open-label phase II BLC2001 (NCT02365597) study. Patients (N = 101) enrolled on this trial had metastatic or unresectable locally advanced urothelial carcinoma, ≥1 previous chemotherapy, and ≥1 FGFR3 mutation or rearrangement. In this trial, erdafitinib showed an objective response rate of 40%, with 31% of responders having a duration of response ≥1 year. The median progression-free survival was 5.5 months, and the median overall survival was 13.8 months. This is quite promising in the salvage setting for patients with metastatic disease. Based on these results, erdafitinib was approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma that have a susceptible FGF3 or FGF2 genetic alteration and progression during or following previous platinum-based chemotherapy including within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

Treating physicians should be aware of the adverse events associated with erdafitinib and be prepared to manage them. The most common adverse event occurring with drugs like erdafitinib is hyperphosphatemia. In the BLC2001 study, a very small proportion of patients (2%) developed grade 3/4 hyperphosphatemia, but it should be managed when occurring as a grade 1/2 event. Another potential treatment-related adverse event is central serous retinopathy, and less serious and less frequent adverse events include palmar–plantar erythrodysesthesia syndrome (or hand–foot syndrome), nausea, and vomiting. Consultations with a nephrologist, nutritionist, or ophthalmologist are likely required when dealing with patients receiving erdafitinib. I advise establishing a multidisciplinary management team before the occurrence of the more serious adverse events to optimize treatment compliance and minimize the risk of treatment interruption or suspension due to adverse events.

Erdafitinib Compared With Other FGFR Inhibitors
There are other FGFR inhibitors under development for treating patients with bladder cancer, but erdafitinib provides the highest levels of objective responses and durable survival compared with all the other compounds for which we have preliminary results. It is intriguing that the objective response rate of erdafitinib nearly doubles that of any other FGFR inhibitor. Infigratinib, pemigatinib, vofatamab, and rogaratinib have provided response rates approximating 20% to 25% compared with 40% seen with erdafitinib.

The reason for the differences in response rates has not been fully explained. Differences may be due to the mechanism of action of each drug or the ways patients with FGFR alterations were selected for each study. In some trials, like the open-label phase II/III FORT-1, which studied rogaratinib vs chemotherapy, tumors were tested for FGF1/3 mRNA expression, whereas the BCL2001 trial used a polymerase chain reaction–based assay for identifying FGFR2 or FGFR3 alterations. Other trials tested for alterations with more generalized next-generation sequencing tests that identify a higher number of mutations.

Testing for FGFR Alterations: Timing
In general, I suggest testing for FGFR alterations as soon as possible, especially for patients diagnosed with advanced-stage tumors. Knowing that there is an opportunity to use erdafitinib may be key when managing sequential therapies that may involve immunotherapy, an FGFR inhibitor in second line, and then an ADC. It is also important to keep in mind that if there is an FGFR alteration in the primary bladder tumor, the same alteration may not be present in the metastatic disease after ≥1 line of chemotherapy or immunotherapy.

The frequency of FGFR alterations can shift throughout the treatment time course. We recently published a study on the frequency of FGFR alterations in bladder cancer and upper tract disease. There were differences among metastatic sites, primary tumor, and liquid biopsies that may have arisen over time. We clearly show that a difference of >180 days between the liquid biopsy and the tumor biopsy results in a difference in the frequency of FGFR alterations. We advise treating physicians to do a tumor or liquid biopsy just before deciding on starting treatment with erdafitinib. Otherwise, the risk of losing the target is substantial, and this may affect responses and expose the patient to unnecessary toxicity.

Sequencing Therapy With Erdafitinib
Currently, we are trying to figure out how erdafitinib, and potentially any other pan‑FGFR inhibitors, fit into the current treatment landscape of evolving drugs and new approvals for bladder cancer. For instance, it has not been fully decided on whether it is better to use an ADC or erdafitinib in the postimmunotherapy metastatic setting. In general, we should consider that we are treating a select patient population and failing erdafitinib does not preclude the possibility of receiving an ADC. However, at the same time, using an ADC after immunotherapy failure and before erdafitinib may select for molecular alterations and lead to a loss of the target for erdafitinib. In that case, it would be best to retest the tumor before starting erdafitinib therapy. My preference would be to provide erdafitinib first and then use any other postimmunotherapy drugs in a salvage setting.

Ongoing Clinical Trials With Erdafitinib
Before moving to combination therapy, we still have to confirm the reliability of the results obtained with erdafitinib in the BLC2001 study. The randomized, 2-cohort phase III THOR study (NCT03390504) is comparing the efficacy of erdafitinib with the standard of care in patients (estimate enrollment N = 631) with metastatic or unresectable urothelial carcinoma and selected FGFR alterations after failure of 1 line of chemotherapy. Patients in the first cohort received previous treatment with an anti–PD-1/PD-L1 agent and chemotherapy and were randomized to receive either erdafitinib or chemotherapy. Patients in the second cohort received previous chemotherapy without anti–PD-1/PD-L1  treatment and were randomized to receive erdafitinib or pembrolizumab. The THOR study will help determine how erdafitinib will ultimately be used in clinical practice.

Many trials are testing FGFR inhibitors with immunotherapy compounds throughout the different stages of disease. There are trials in non‑muscle‑invasive disease, muscle‑invasive disease, and metastatic disease, and trials that are investigating these combinations as first‑line therapy for cisplatin‑ineligible patients and as second‑line therapy. There is a potential issue with toxicity with combination therapies, so physicians should be well instructed on managing, in parallel, the adverse events related to immunotherapy and the FGFR inhibitors.

Differences in the European Union Treatment Landscape
Of importance, erdafitinib, sacituzumab govitecan, and most of the immunotherapy drugs available to treat bladder cancer are still unavailable in the European Union (EU). For instance, pembrolizumab is not yet approved in the EU for non‑muscle‑invasive disease, and we are still far from getting approval of some drugs in the perioperative space for muscle‑invasive disease. The European Medicines Agency has been more conservative than the FDA and does not allow approval based on single-arm, single-agent phase II data. In the non-muscle-invasive disease setting, there may be chances of getting FDA approvals with single-arm trials like the KEYNOTE-057 with pembrolizumab, but this is not the case in the EU.

There is an increasing concern surrounding patient access to new drugs and the disparities that are emerging among countries and among continents, mainly between the US and the EU. These disparities can be discouraging and concerning from the patient standpoint. More and more, patients in the EU who have already received chemotherapy and immunotherapy are asking for erdafitinib and an ADC, which are not available in most of the EU countries. In some cases, patients are migrating to other countries to get access to specific drugs. This creates a disparity in patient access to new drugs that have already demonstrated robust activity and are already registered and approved in other countries because those who can afford to migrate and pay for drugs have increased access to treatments. This can be very frustrating from a physician standpoint. Physicians, patient representatives and advocates, stakeholders, and regulatory bodies need to come together to address these concerns.

Conclusions
To use FGFR inhibitors optimally we must test tumors for FGFR alterations early and use personalized therapies, like erdafitinib, as soon as possible because alterations may change throughout the disease course. In the postimmunotherapy space, erdafitinib should be the first option for biomarker‑selected patients. Combination therapies that overcome the limitations of single‑agent therapy are still under evaluation in phase II and III trials, but there is hope that we may provide further improvement in the data presented with erdafitinib as a single agent.

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Are you using next-generation sequencing to identify FGFR alterations in your patients with bladder cancer? I encourage you to answer the polling question and post your thoughts and questions in the discussion box below.

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