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Targeted Therapies for Bladder Cancer and Beyond: Overview and Current Status of FGFR Inhibitors

Ignacio Duran, MD, PhD
Released: June 14, 2021

Erdafitinib in Urothelial Cancer

Erdafitinib in FGFR-Altered Urothelial Carcinoma (BLC2001): Background

We know that FGFR is altered in approximately 15% to 20% of advanced UC and even higher in 54% of upper tract UC.[35,36] These data along with the need for treatments beyond cisplatin/gemcitabine chemotherapy, resulted in erdafitinib being tested in those patient populations. Because of the interesting signal detected in the phase I study mentioned previously, a pivotal phase II study of erdafitinib was launched.

Pivotal Phase II Erdafitinib Study in FGFR-Positive Metastatic UC After ≥1 Line of Platinum-Based Chemotherapy

At ASCO 2018, Siefker-Radtke and colleagues[37] presented the results of the phase II BLC2001 trial assessing the efficacy and safety of erdafitinib in patients with FGFR‑positive metastatic UC (N = 99) after ≥1 line of platinum‑based chemotherapy. Patients were tested for FGFR fusions or mutations and were then randomized initially to 2 different regimens. Regimen 1 was erdafitinib 10 mg/day, 7 days on and 7 days off. Regimen 2 was erdafitinib 6 mg once daily. After an analysis of AEs and pharmacokinetic and pharmacodynamic data, the optimal dose of erdafitinib was determined to be 8 mg/day and a third regimen of erdafitinib 8 mg once daily was made. The primary endpoint of this study was objective response rate and secondary endpoints were progression-free survival (PFS), OS, safety, duration of response (DoR), pharmacokinetics, and predictive biomarker evaluation.[21,37]

Phase II Erdafitinib Study: Results

The overall response rate to erdafitinib in patients metastatic UC and FGFR mutation or fusion and with a poor prognosis was 40%. The median OS was 13.8 months (95% CI: 9.8-not reached).[37]

Phase II Erdafitinib Study: Results

However, the OS for the whole study population was updated to 11.3 months at ASCO 2020 by Siefker-Radtke and colleagues.[24] Erdafitinib showed consistent results in patients who have progressed on platinum (OS: 10.6 months) and/or PD-L1 inhibitors (OS: 10.9 months).

Erdafitinib

Although only 99 patients participated in the phase II study, the data were quite striking in a context where we did not have very good treatment options. As a result, in April 2019 the FDA granted accelerated approval of erdafitinib for patients with locally advanced or metastatic bladder cancer with susceptible FGFR2 or FGFR3 genetic alterations after platinum chemotherapy (including within 12 months of neoadjuvant or adjuvant chemotherapy).

The approval was based on FGFR genetic alterations, making erdafitinib the first precision medicine treatment approved in bladder cancer. Along with the drug approval, the FDA also approved, a companion diagnostic therascreen FGFR RGQ RT PCR Kit.

Considerations of Current Use of These Newer Agents in Clinical Practice

How do we address the questions that arise now that we have the option of using new agents in our clinical practice? First, does the patient have any alterations in FGFR3 or FGFR2? If so, we may consider the use of erdafitinib. Second, what previous therapies has the patient received and what were their responses? Does the patient have any residual toxicity (eg, neuropathy)? It is also important to consider patient comorbidities as these patients can be more frail.

Management of FGFR Inhibitor Treatment-Emergent AEs of Interest

This table highlights 3 important points. First, using erdafitinib will most likely help your patient, but there will be some AEs, such as hyperphosphatemia, stomatitis, nail toxicity, skin toxicity, and central serous retinopathy (CSR) (a form of ocular toxicity). Second, the incidences of these AEs can be quite high. Third, fortunately, grade 3 AEs are infrequent and rarely lead to treatment discontinuation.[38]

Pivotal Phase II Erdafitinib Study: TRAEs of Special Interest or Clinical Importance

CSR is a class AE of MAPK pathway inhibitors that cause ocular toxicity.[39,40] In the pivotal phase II erdafitinib study, treatment was discontinued due to CSR in 3 patients, but no retinal vein or artery occlusion was observed. The most common non-CSR AEs are dry eye (19%), blurry vision (16%), increased lacrimation (11%), and conjunctivitis (9%).[37] All AEs of special interest were manageable with supportive treatment and dose interruption or modification.[38] 

Common AEs Associated With Erdafitinib

Tyrosine kinase inhibitors can have particular AEs and I mentioned earlier that FGF regulates calcium and vitamin D metabolism. This is this important to know as one common AE is hyperphosphatemia, which is a result of FGFR inhibition in the kidneys. FGFR inhibition counteracts renal FGF-23/Klotho signaling, resulting in CYP27B1 and CYP24A1 deregulation and the induction of hypervitaminosis D and hyperphosphatemia.[41]  Normally the median time to hyperphosphatemia is approximately 20 days (range: 8-116) so vigilance in monitoring phosphate levels is required. Also, patients must be informed that they should avoid agents that will increase serum phosphate levels, such as phosphate enemas and other laxatives, antacids, and vitamin D supplements before initiating erdafitinib. 

Ocular Toxicity Associated With Erdafitinib

Ocular toxicity, as mentioned previously, is another AE to be aware of. If managed properly, it should not be a problem. There are different eye toxicities. For example, 1 in 3 patients will present with dry eye symptoms, but 1 in 4 patients may have CSR. Patients should be assessed by an ophthalmologist before starting erdafitinib. Ocular toxicity may require therapy interruption, dosage adjustment, and/or therapy discontinuation.

Managing Patients on Erdafitinib

The good news is that the AEs are well described and their management is well defined. Although monitoring for hyperphosphatemia and ocular toxicity is very important, stomatitis and nail changes are also commonly seen in the clinic and must be addressed. For stomatitis, for instance, patients are advised to rinse with specific mouthwashes, such as salt and soda, and for nail changes, podiatry care can prevent infection. 

Erdafitinib Dose and Administration

The recommended starting dose of erdafitinib is 8 mg/day orally. In some cases, the starting dose can be up titrated to 9 mg/day in patients with a serum phosphate level <5.5 mg/dL and if there are no ocular disorders or grade ≥2 AEs after 14-21 days after treatment initiation. Erdafitinib is available as tablets of 3 mg, 4 mg, and 5 mg, making it easy to adjust the dose if required. It can be taken with or without food. But patients should be told to restrict their phosphate intake to 600-800 mg/day. 

Patient Monitoring Parameters While Receiving Erdafitinib

Ideally, patient serum phosphate level should be evaluated at baseline, then at Day 14 and at Day 21 after initiation of treatment and then, if everything is fine, a monthly assessment should be sufficient. The patient should also have a baseline ophthalmologic examination before starting treatment and then monthly for the first 4 months and then every 3 months if there are no issues.

Erdafitinib Dose Modifications for AEs

If a patient requires a dose modification for AEs, the erdafitinib dose should be titrated down until the AE resolves. Dose modifications are shown in this table. If a patient started erdafitinib at 9 mg, decrease the dose to 8 mg, then to 6 mg, then to 5 mg, and finally to 4 mg. If the patient started at 8 mg, reduce the dose to 6 mg, then to 5 mg, and then down to 4 mg. If the dose needs to be reduced to <4 mg, treatment should be stopped as there is evidence that erdafitinib is not effective below the 4-mg/day dose.

Erdafitinib Dose Modifications for Specific AEs

Even with dietary restriction of phosphate intake to 600-800 mg/day, patients may have their serum phosphate level increase to ≥7 mg/dL. In this case, the use of an oral phosphate binder (eg, sevelamer or acetazolamide) should be considered.[19]

Erdafitinib Dose Modifications for CSR

The dose modifications for erdafitinib for CSR include holding treatment for grade 1 until it resolves, and if it resolves within 4 weeks, the drug can be restarted at the next dose level down. If CSR does not recur, re‑escalation can be considered. If it is stable for 2 consecutive eye examinations but has not resolved, resume erdafitinib at the next lower dose.

For grade 2 CSR with some decrease in visual acuity, withhold the drug until the CSR is resolved. If it resolves within 4 weeks, resume treatment at the next dose level down. For grade 3, withhold until resolution, and if it resolves within 4 weeks, resume 2 dose levels down. If CSR recurs, treatment should be permanently discontinued. Treatment should also be discontinued permanently for a grade 4 visual acuity change.

For other AEs, if they are grade 3, withhold treatment until they resolve to grade 1 or baseline, and then resume treatment at 1 dose level down. For grade 4 AEs, permanently discontinue treatment. 

Patient Education With Erdafitinib

Erdafitinib is a powerful drug that can greatly benefit the patient, but patient education and communication is critical for the healthcare professional to prevent and manage any significant issues with AEs. Communication should include details about dosing, common AEs and what to watch for, and required monitoring (eg, serum phosphate levels, eye examinations with an ophthalmologist).

Patient education should also include a discussion about drug–drug interactions. Erdafitinib metabolism is via CYP2C9 and CYP3A4, so moderate CYP2C9 or strong CYP3A4 inhibitors should be avoided. Strong CYP2C9 or strong CYP3A4 inducers will reduce erdafitinib efficacy and should be avoided. If inhibitors or inducers are not avoidable, then monitor for AEs and determine whether dosing should be titrated up or down to achieve optimal dosing.

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