European Approval Sought for Erdafitinib in Locally Advanced or Metastatic FGFR3+ Urothelial Carcinoma

A marketing authorization application (MAA) has been submitted to the European Medicines Agency (EMA) seeking the approval of erdafitinib (Balversa) for the treatment of adult patients with locally advanced, unresectable or metastatic urothelial carcinoma harboring susceptible FGFR3 alterations who experienced disease progression during or following at least 1 line of therapy containing a PD-1/PD-L1 inhibitor.¹

The MAA is based on data from cohort 1 of the phase 3 THOR trial (NCT03390504), where findings showed that treatment with erdafitinib reduced the risk of death by 36% vs chemotherapy (HR, 0.64; 95% CI, 0.47-0.88; P = .005).² At a median follow-up of 15.9 months, patients in the erdafitinib arm (n = 136) experienced a median overall survival (OS) of 12.1 months compared with 7.8 months for those in the chemotherapy arm (n = 130).

“This submission, and Janssen’s ongoing study of erdafitinib, reinforces our commitment to deliver much-needed targeted therapies in the areas of high unmet need, including for devastating diseases like metastatic urothelial carcinoma,” Kiran Patel, MD, vice president of Clinical Development, Solid Tumors, at Janssen Research & Development, stated in a news release. “Erdafitinib has demonstrated promising results in advanced, FGFR-altered urothelial carcinoma, making this submission a vital step towards improving outcomes for patients in the future. The OS benefit we’ve seen with erdafitinib also supports the need for biomarker testing for FGFR alterations in all patients with metastatic urothelial carcinoma.”

In April 2019, the FDA granted accelerated approval to erdafitinib for the treatment of adult patients with locally advanced or metastatic bladder cancer with an FGFR3 or FGFR2 alteration that has progressed on platinum-containing chemotherapy.³

On August 29, 2023, a supplemental new drug application was submitted to the FDA, seeking the full approval of erdafitinib for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma harboring susceptible FGFR3 alterations who progressed during or following at least 1 line of a PD-1/PD-L1 inhibitor in the locally advanced or metastatic setting or within 12 months of neoadjuvant or adjuvant therapy, was submitted to the FDA.⁴ That submission was also supported by data from THOR.

During the randomized, controlled, open-label, multicenter trial, cohort 1 included patients at least 18 years of age with metastatic or unresectable urothelial carcinoma who experienced confirmed disease progression.2 Other key inclusion criteria consisted of 1 to 2 lines of prior systemic therapy, including prior treatment with an anti–PD-1 or –PD-L1 therapy; an ECOG performance status of 0 to 2; and an FGFR2/3 mutation or fusion.

Investigators randomly assigned patients 1:1 to receive 8 mg of oral erdafitinib once per day with pharmacodynamically guided up-titration to 9 mg, or physician’s choice of chemotherapy (docetaxel or vinflunine) once every 3 weeks.

Along with the primary end point of OS, key secondary end points included progression-free survival (PFS), overall response rate (ORR), and safety.

Additional data showed that patients treated with erdafitinib achieved a median PFS of 5.6 months vs 2.7 months for those given chemotherapy (HR, 0.58; 95% CI, 0.44-0.78; P = .0002). Patients in the experimental arm experienced an ORR of 45.6%, and the complete response (CR) and partial response (PR) rates were 6.6% and 39.0%, respectively. In the chemotherapy arm, the ORR was 11.5% with a CR rate of 0.8% and a PR rate of 10.8% (relative risk, 3.94; 95% CI, 2.37-6.57; P < .001).

Regarding safety, serious treatment-related adverse effects (TRAEs) were reported in 13.3% of patients treated with erdafitinib who experienced any AEs (n = 135). That rate was 24.1% for evaluable patients treated with chemotherapy (n = 112). One treatment-related death was reported in the erdafitinib arm compared with 6 in the chemotherapy arm. Any-grade TRAEs occurred in 97.0% of patients in the erdafitinib arm vs 86.6% of patients in the chemotherapy arm. The rates of grade 3/4 TRAEs were 45.9% and 46.4%, respectively.

The most common TRAEs in the erdafitinib group included hyperphosphatemia (any grade, 78.5%; grade 3/4, 5.2%), diarrhea (54.8%; 3.0%), stomatitis (45.9%, 8.1%), dry mouth (38.5%; 0%), palmar-plantar erythrodysesthesia syndrome (30.4%; 9.6%), and onycholysis (23.0%; 5.9%).

The most common TRAEs in the chemotherapy arm included anemia (any grade, 27.7%; grade 3/4, 6.3%), alopecia (21.4%; 0%), nausea (19.6%; 1.8%), neutropenia (18.8%; 13.4%), leukopenia (11.6%; 8.0%), and febrile neutropenia (8.0%; 8.9%).

In the erdafitinib arm, 8.1% of patients discontinued treatment due to AEs vs 13.4% in the chemotherapy arm.

Any-grade AEs of interest included nail disorders (66.7% for erdafitinib vs 5.4% for chemotherapy), skin disorders (54.8% vs 12.5%), central serous retinopathy (17.0% vs 0%), and other eye disorders (42.2% vs 5.4%).

“For patients with advanced urothelial carcinoma, including FGFR-driven tumors, outcomes remain poor and treatment options are limited; therefore, there is a need for novel, targeted therapies,” Martin Vogel, EMEA Therapeutic Area Lead Oncology at Janssen-Cilag GmbH, said. “We are excited by the prospect of bringing innovative, personalized approaches to market for patients as we work towards our wider goal of making this complex disease a more manageable and ultimately curable condition.”

References

1. Janssen submits marketing authorisation application to the European Medicines Agency seeking approval of erdafitinib for the treatment of patients with locally advanced or metastatic urothelial cancer with susceptible FGFR alterations. News release. Janssen. September 8, 2023. Accessed September 12, 2023. https://www.janssen.com/janssen-submits-marketing-authorisation-application-european-medicines-agency-seeking-approval
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. doi:10.1200/JCO.2023.41.17_suppl.LBA4619
3. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. News release. FDA. April 12, 2019. Accessed September 12, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma
4. Janssen submits supplemental new drug application to the U.S. Food and Drug Administration seeking full approval of Balversa (erdafitinib) for the treatment of patients with locally advanced or metastatic urothelial carcinoma and selected fibroblast grow. News release. Janssen. August 28, 2023. Accessed September 12, 2023. https://www.janssen.com/janssen-submits-supplemental-new-drug-application-us-food-and-drug-administration-seeking-ful