Erdafitinib nears EU approval for FGFR3-positive urothelial carcinoma

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending approval of erdafitinib (Balversa) as a monotherapy in the treatment of adult patients with unresectable or metastatic urothelial carcinoma harboring susceptible FGFR3 genetic alterations who have received at least 1 prior line of therapy containing a PD-1 or PD-L1 inhibitor in the unresectable or metastatic treatment setting.¹

Erdafitinib received full US FDA approval in January 2024.

“FGFR alterations are important oncogenic drivers in urothelial carcinoma and can be associated with adverse clinical outcomes,” said Yohann Loriot, MD, PhD, Institut Gustave Roussy and University of Paris-Saclay, France, in a news release.¹ “As we aim to optimize treatment outcomes for patients, there is a significant unmet need for novel, targeted therapies that enable treatment decisions tailored according to a patient’s individual genetic and disease characteristics.”

Erdafitinib received full US FDA approval in January 2024 for patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least 1 line of prior systemic therapy. This indication excludes patients who, despite being eligible, have not received treatment with PD-1/PD-L1 checkpoint inhibitors.²

The positive CHMP opinion, as well as the US FDA approval, are supported by findings from cohort 1 of the phase 3 THOR trial, (NCT03390504), which showed that erdafitinib significantly improved overall survival (OS) compared with investigator’s choice of chemotherapy in patients with FGFR2/3-altered metastatic urothelial cancer who had previously received an anti–PD-(L)1 therapy.³

At a median follow-up of 15.9 months, the median OS was 12.1 months with erdafitinib (n = 136) vs 7.8 months with investigator’s choice of chemotherapy (n = 130), translating to a 36% reduction in the rate of death (HR, 0.64; 95% CI, 0.47-0.88; P = .005). Based on the interim analysis, the independent monitoring committee recommended stopping the study, unblinding the data, and having patients cross over from chemotherapy to erdafitinib.

Further, the median progression-free survival (PFS) was 5.6 months with erdafitinib vs 2.7 months with chemotherapy, translating to a 42% reduction in the rate of disease progression or death (HR, 0.58; 95% CI, 0.44-0.78; P = .0002). The overall response rate (ORR) was 35.3% in the erdafitinib arm vs 8.5% in the chemotherapy arm.

In terms of safety, 45.9% of patients in the erdafitinib safety cohort (n = 135) and 46.4% of patients in the chemotherapy arm experienced at least 1 treatment-related adverse effect (TRAE) of grade 3 or higher. The rate of treatment discontinuation due to TRAEs was 8.1% in the erdafitinib arm and 13.4% in the chemotherapy arm.

Serious AEs were reported in 13.3% of patients in the erdafitinib arm, and 1 treatment-related death occurred and was cited by investigators as being sudden death. AEs in the erdafitinib arm were mostly manageable with dose modifications and supportive care. In the chemotherapy arm, 24.1% of patients had serious AEs, and 6 treatment-related deaths occurred and were due to febrile bone marrow aplasia (n = 2), febrile neutropenia (n = 1), septic shock (n = 2), and atypical pneumonia (n = 1).

Overall, THOR is a phase 3, randomized, open-label, multicenter study, open to patients with stage IV metastatic or unresectable urothelial cancer. Patients were screened for selected FGFR alterations and were assigned to 2 cohorts based on prior anti–PD-(L)1 treatment. Those with prior anti–PD-(L)1 therapy (cohort 1 for this analysis) were randomly assigned to erdafitinib or investigator’s choice of chemotherapy. Erdafitinib was given at a dose of 8 mg once daily, with up-titration to 9 mg once daily if the serum phosphate level was 9.0 mg/dL or less and there were no associated adverse events at day 14. Chemotherapy was docetaxel 75 mg/m2 or vinflunine 320 mg/m2 every 3 weeks.

Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point for the trial was OS, with secondary end points of PFS, ORR, patient-reported outcomes, safety, and pharmacokinetics.

In the prior anti–PD-(L)1 cohort, 33.1% of patients in the erdafitinib arm had received 1 line of prior systemic therapy, with 24.3% having received chemotherapy plus anti–PD-(L)1 treatment, and 8.1% receiving anti–PD-(L)1 treatment alone. In the chemotherapy arm, 25.4% of patients received 1 line of prior systemic therapy, with 11.5% receiving combination treatment and 12.3% receiving an anti–PD-(L)1 inhibitor alone.

Other baseline characteristics between the arms were well balanced. The median age in the erdafitinib arm was 66 years (range, 32-85). Most were men (70.6%), White (59.6%), and had the presence of visceral metastases (74.3%), with 22.8% being in the liver. Nearly all patients had an ECOG performance status of 0 or 1 (91.2%).

Primary tumors were present in the upper tract for 30.1% of patients in the erdafitinib arm and 36.9% of patients in the chemotherapy arm. PD-L1 low expression (combined positive score less than 10) was detected in 92.7% of patients in the erdafitinib arm (among 96 evaluable patients) and 86.1% of patients in the chemotherapy arm (among 79 evaluable patients).

In terms of FGFR alterations, at baseline these were reported as mutations in 79.4% and 82.3%, fusions in 18.4% and 14.6%, and mutations and fusions in 1.5% and 2.3% of patients in the erdafitinib and chemotherapy arms, respectively.

According to the news release, the THOR trial currently includes a long-term extension period following the clinical cut-off date of the final analysis in each cohort.¹

“Today’s recommendation from the CHMP marks important progress towards transforming outcomes for patients diagnosed with bladder cancer with FGFR alterations,” concluded Henar Hevia, PhD, senior director and EMEA therapeutic area lead in oncology at Johnson & Johnson Innovative Medicine, in the news release.¹ “There is a critical need for a multidisciplinary care team approach to identify patients who may benefit from erdafitinib through biomarker testing, ensuring the right treatment reaches the right patient at the right time. Pending approval, we look forward to providing eligible patients across the region with a new treatment option as soon as possible.”

References

1. CHMP adopts positive opinion for BALVERSA (erdafitinib) for the treatment of adult patients with unresectable or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations. News release. Janssen Cilag International NV. Published online and accessed June 28, 2024. https://www.globenewswire.com/news-release/2024/06/28/2905783/0/en/CHMP-adopts-positive-opinion-for-BALVERSA-erdafitinib-for-the-treatment-of-adult-patients-with-unresectable-or-metastatic-urothelial-carcinoma-with-susceptible-FGFR3-genetic-altera.html

2. FDA approves erdafitinib for locally advanced or metastatic urothelial carcinoma. FDA. January 19, 2024. Accessed June 28, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-erdafitinib-locally-advanced-or-metastatic-urothelial-carcinoma

3. 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