Balversa (Erdafitinib), First-in-Class FGFR Kinase Inhibitor, Approved for Patients with Metastatic Urothelial Carcinoma and FGFR Mutations

Bladder cancer, the sixth most common cancer in the United States, affects approximately 699,450 people and accounts for nearly 5% of all new cancer cases.¹ It is estimated that 80,470 new cases of bladder cancer will be diagnosed in 2019, and 17,670 deaths will be attributable to the disease. Bladder cancer is 4 times more common in men than in women. The relative 5-year survival is 7% for patients with locally advanced bladder cancer and 5% for patients with metastatic disease.¹

More than 90% of bladder cancer cases are urothelial carcinomas (also called transitional-cell carcinoma), a type of bladder cancer that forms in the cells and tissues lining the urothelium along the renal pelvis, ureters, bladder, and proximal urethra.²

Fibroblast growth factor–signaling—specifically, genetic mutations in fibroblast growth factor receptors (FGFRs)—plays a role in the pathogenesis of certain cancers, including urothelial carcinoma, and is linked to tumor growth, metastasis, and overall prognosis.³ In fact, FGFR alterations or mutations are present in up to 32% of patients with urothelial cancer.⁴

Treatments for patients with locally advanced or metastatic urothelial carcinoma may include 1 or more of the current therapies, including chemotherapy; immunotherapy, such as checkpoint inhibitors with anti–programmed cell death-1 (PD-1) or anti-PD ligand 1 (PD-L1) activity; radiation therapy; and urinary diversion surgery or cystectomy.² The poor prognosis associated with advanced or metastatic urothelial cancer signals the need for additional therapeutic options.

Erdafitinib New Oral Treatment for Urothelial Cancer

On April 12, 2019, the US Food and Drug Administration (FDA) accelerated the approval of erdafitinib (Balversa; Janssen) for the treatment of adults with locally advanced or metastatic urothelial carcinoma and susceptible FGFR3 or FGFR2 genetic alterations that progressed during or after ≥1 lines of platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.^5,6 At the same time, the FDA approved the companion diagnostic therascreen FGFR RGO RT-PCR Kit for the identification of patients with FGFR alterations who are eligible for erdafitinib therapy.^5,6

“We’re in an era of more personalized or precision medicine, and the ability to target cancer treatment to a patient’s specific genetic mutation or biomarker is becoming the standard, with advances being made in new disease types,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence. “Today’s approval represents the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer. FGFRs regulate important biological processes including cell growth and division during development and tissue repair. This drug works by targeting genetic alterations in FGFRs.”⁵

Erdafitinib is the first FGFR kinase inhibitor to receive FDA approval; the approval was accelerated based on tumor response rate; the FDA granted erdafitinib breakthrough therapy designation.^5,7 Final approval by the FDA is contingent on additional clinical data to confirm the clinical benefit of erdafitinib.^5,6

Mechanism of Action

Erdafitinib is a targeted kinase inhibitor that exerts its action by binding to and blocking the enzymatic activity of several cell proteins, including FGFR1, FGFR2, FGFR3, and FGFR4. In addition, erdafitinib binds to other proteins, including FLT4, KIT, VEGFR2, RET, CSF1R, and PDGFRA.⁶

In preclinical studies, erdafitinib showed antitumor activity in FGFR-expressing cell lines and bladder cancer xenograft models.⁶

Dosing and Administration

Erdafitinib is available as a 3-mg, 4-mg, and 5-mg tablet.⁶

Before initiating treatment with erdafitinib, the presence of FGFR genetic alterations in tumor specimens should be confirmed by the FDA-approved therascreen companion diagnostic.⁶

The recommended initial dosage of erdafitinib is 8 mg orally once daily, with a dose increase to 9 mg daily if appropriate. Erdafitinib tablets should be swallowed whole and can be taken with or without food.⁶

Pivotal Clinical Trial

The efficacy and safety of erdafitinib were evaluated in Study BLC2001,⁸ an open-label, single-arm phase 2 clinical trial with 87 patients (median age, 67 years) included in the blinded Independent Review Committee; all patients had locally advanced or metastatic urothelial carcinoma.^5,6

Eligible patients had disease progression during or after at least 1 chemotherapy. All patients had ≥1 FGFR3 gene mutations (including exons R248C, S249C, G370C, Y373C) or FGFR2 gene fusions ­(FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7) as confirmed by laboratory screening. Treatment with erdafitinib was continued until disease progression or until unacceptable toxicity.⁶

Erdafitinib demonstrated antitumor activity in patients with measurable lesions, with an objective response rate of 32.2% (Table). The response to erdafitinib treatment was sustained for a median of 5.4 months. Responders included patients who had not responded to previous treatment with a PD-1 or PD-L1 inhibitor.⁶

Adverse Reactions

The most common (incidence ≥20%) adverse events associated with erdafitinib, including laboratory abnormalities, were increased phosphate level (76%), stomatitis (56%), fatigue (54%), increased creatinine (52%), diarrhea (47%), dry mouth (45%), onycholysis (41%), increased creatinine alanine aminotransferase and alkaline phosphatase levels (41% each), low sodium (40%), reduced appetite (38%), decreased albumin (37%), dysgeusia (37%), low hemoglobin (35%), dry skin (34%), increased aspartate aminotransferase (30%), decreased magnesium (30%), constipation (28%), dry eye (28%), alopecia (26%), palmar-plantar erythrodysesthesia syndrome (26%), decreased phosphate (24%), abdominal pain (23%), increased calcium (22%), nausea (21%), and musculoskeletal pain (20%).⁶

Serious adverse events occurred in 41% of patients, including serious eye disorders (10%). Overall, 13% of patients permanently discontinued treatment because of adverse events, including eye disorders (6%).⁶

Erdafitinib has no contraindications.⁶

Use in Specific Populations

Erdafitinib can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should use effective contraception during treatment with erdafitinib and for 1 month after the last dose. Male patients with female partners of reproductive potential should use effective contraception during treatment with erdafitinib and for 1 month after the last dose. Erdafitinib may impair fertility in female patients.⁶

Data are not available on the presence of erdafitinib in human milk, its effects on the breastfed child, or on milk production. Lactating women should not breastfeed during treatment with erdafitinib and for 1 month after the last dose.⁶

Erdafitinib plasma concentrations may be higher in patients with the cytochrome (CY)P2C9*3/*3 genotype. Patients with a known or suspected CYP2C9*3/*3 genotype should be monitored for increased adverse reactions.⁶

No overall differences in efficacy or safety were observed between patients aged ≥65 years and younger patients.⁶

Drug Interactions

Coadministration of erdafitinib with strong inhibitors of CYP2C9 or CYP3A4 increases erdafitinib plasma concentrations. Alternative therapies that are not strong CYP2C9 or CYP3A4 inhibitors should be considered, or patients should be monitored closely for adverse reactions.⁶

Coadministration of erdafitinib with strong inducers of CYP2C9 or CYP3A4 may decrease erdafitinib plasma concentrations significantly. Coadministration of strong inducers of CYP2C9 or CYP3A4 with erdafitinib should be avoided.⁶

When erdafitinib is coadministered with moderate CYP2C9 or CYP3A4 inducers, erdafitinib plasma concentrations are decreased, and the dose of erdafitinib may require an increase to 9 mg.⁶

Concomitant use of serum phosphate level-altering agents with erdafitinib should be avoided before the initial dose increase period based on serum phosphate levels (days 14-21).⁶

Concomitant use of erdafitinib with sensitive CYP3A4 substrates with narrow therapeutic indices should be avoided.⁶

When erdafitinib is coadministered with organic cation transporter 2 (OCT2) substrates, the plasma concentrations of OCT2 substrates may increase. Using alternative therapies or reducing the dose of OCT2 substrates (eg, metformin) should be considered, based on the patient’s tolerability.⁶

Concomitant use of erdafitinib with P-glycoprotein (P-gp) substrates may increase the plasma concentrations of P-gp substrates, potentially leading to adverse events. If coadministration of erdafitinib with P-gp substrates is unavoidable, allow at least 6 hours before or after administering P-gp substrates with narrow therapeutic indices.⁶

Warnings and Precautions

Erdafitinib can cause serious eye disorders, including central serous retinopathy (CSR) or retinal pigment ­epithelial detachment (RPED). Patients should receive monthly ophthalmologic examinations to monitor visual symptoms during the first 4 months of erdafitinib treatment, every 3 months thereafter, and at any time visual symptoms occur. If CSR or RPED occurs, erdafitinib should be withheld; if CSR or RPED does not resolve within 4 weeks, or if the condition is grade 4 severity, erdafitinib should be discontinued permanently.⁶

Hyperphosphatemia can occur as a pharmacodynamic effect of erdafitinib. Patients should be monitored for hyperphosphatemia and dose modifications should be followed when required.⁶

Erdafitinib can cause fetal harm when used by pregnant women. Patients of reproductive potential should be cautioned about the potential risk to the fetus and should use effective contraception. Male patients with female partners of reproductive potential should use effective contraception during erdafitinib treatment and for 1 month after the last dose.⁶

Conclusion

Erdafitinib, a once-daily oral therapy and the first FGFR kinase inhibitor to receive FDA approval, may improve outcomes for patients with urothelial carcinoma and FGFR genetic alterations. The approval of erdafitinib provides a new treatment option and the first targeted therapy for patients with locally advanced or metastatic urothelial carcinoma and susceptible FGFR3 or FGFR2 genetic alterations, or for those whose disease progressed during or after ≥1 lines of platinum-containing chemotherapy.

References

1. National Cancer Institute. SEER cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed May 23, 2019.
2. National Cancer Institute. Bladder cancer treatment (PDQ) – health professional version. Updated February 6, 2019. www.cancer.gov/types/bladder/hp/bladder-treatment-pdq#_4. Accessed May 28, 2019.
3. Perera TPS, Jovcheva E, Mevellec L, et al. Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mol Cancer Ther. 2017;16:1010-1020.
4. Helsten T, Elkin S, Arthur E, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22:259-267.
5. US Food and Drug Administration. FDA approves first targeted therapy for metastatic bladder cancer. April 12, 2019. Accessed May 22, 2019.
6. Balversa (erdafitinib) tablets, for oral use [prescribing information]. Horsham, PA: Janssen Products; April 2019.
7. Janssen. Balversa (erdafitinib) receives U.S. FDA approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma with certain FGFR genetic alterations. April 12, 2019. www.janssen.com/balversa-erdafitinib-receives-us-fda-approval-treatment-patients-locally-advanced-or-metastatic. Accessed May 24, 2019.
8. Loriot Y, Necchi A, Park SH, et al; for the BLC2001 study group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381:338-348.