Full FDA approval sought for erdafitinib for urothelial carcinoma

A supplemental New Drug Application (sNDA) has been filed with the FDA for the full approval of erdafitinib (Balversa) for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma harboring a susceptible FGFR3 alteration and disease progression after ≥1 PD-1/PD-L1 inhibitor in the locally advanced or metastatic setting or within 12 months of neoadjuvant or adjuvant therapy.¹

The confirmatory THOR trial (NCT03390504) is a randomized, open-label, multicenter study enrolling patients with stage IV metastatic or unresectable urothelial cancer. Patients were screened for selected FGFR alterations and assigned to 1 of 2 cohorts based on prior anti–PD-(L)1 treatment. The key cohort for the erdafitinib sNDA is cohort 1, which included those patients with prior anti–PD-(L)1 therapy.

Erdafitinib previously received an accelerated approved for the treatment of adult patients with FGFR2/3-positive locally advanced or metastatic urothelial carcinoma that has progressed on or after ≥1 line of platinum-containing chemotherapy, including ≤12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.¹

Transitioning an accelerated FDA approval into a full approval requires verification of the treatment’s clinical benefit in a confirmatory trial. The confirmatory trial supporting the sNDA for erdafitinib is the phase 3 THOR trial (NCT03390504), which showed that erdafitinib significantly improved overall survival 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.²

At a median follow-up of 15.9 months, the median overall survival (OS) was 12.1 months with erdafitinib (n = 136) vs 7.8 months with investigator’s of choice chemotherapy (n = 130), translating to a 36% reduction in the risk 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.

The median progression-free survival (PFS) was 5.6 months with erdafitinib vs 2.7 months with chemotherapy, translating to a reduction in the risk of disease progression of death of 42% (HR, 0.58; 95% CI, 0.44-0.78; P = .0002). The overall response rate (ORR) was 45.6% with a complete response (CR) rate of 6.6% and a partial response (PR) rate of 39.0% in the erdafitinib arm. The ORR in the chemotherapy arm was 11.5% with 1 CR (0.8%) and a PR rate of 10.8%.²

"Balversa continues to generate promising clinical findings for patients with FGFR-altered metastatic urothelial cancer, who often face poor disease outcomes," Peter Lebowitz, MD, PhD, global therapeutic area head, Oncology, Janssen Research & Development, LLC, stated in a press release.1 "Through the ongoing development of this targeted therapy, we are committed to transforming bladder cancer treatment to positively impact the lives of patients."

THOR is a 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 uptitration to 9 mg once daily if serum phosphate level is 9.0 mg/dL or less and there are no associated adverse events are observed at day 14. Chemotherapy was docetaxel 75 mg/m² or vinflunine 320 mg/m2 every 3 weeks.²

Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. Assessments via CT or MRI were performed every 6 weeks for 6 months, every 12 weeks for the following 6 months, then as clinically indicated. The primary end point was OS, with secondary end points of PFS, ORR, and safety.

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.²

Among patients who received 2 prior lines of systemic therapy in the erdafitinib arm (66.2%), the first line of therapy was chemotherapy alone in 56.6%, chemotherapy plus anti–PD-(L)1 in 4.4%, and other in 5.1%. These rates in patients who received chemotherapy (74.6%) were 58.5%, 7.7%. and 8.5%, respectively. Second line of therapy for patients in the erdafitinib and chemotherapy arms were anti–PD-(L)1 alone (55.9% vs 58.5%), chemotherapy alone (7.4% vs 10.8%), and other (2.9% vs 5.4%).

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 < 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).²

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.

In terms of safety, in the erdafitinib safety cohort (n = 135), 45.9% of patients had at least 1 treatment-related adverse effect (TRAE) of grade 3 or 4. The most common TRAEs of any-grade or grade 3/4 in this arm were hyperphosphatemia (78.5% and 5.2%), diarrhea (54.8% and 3.0%), stomatitis (45.9% and 8.1%), dry mouth (38.5% and 0%), palmar-plantar erythrodysesthesia (30.4% and 9.6%), and onycholysis (23.0% and 5.9%).²

Treatment discontinuation rates were 8.1% and 13.4% in the erdafitinib and chemotherapy arms, respectively. 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 because of febrile bone marrow aplasia (n = 2), febrile neutropenia (n = 1), septic shock (n = 2), and atypical pneumonia (n = 1).²

The FDA will now review the safety and efficacy data from the THOR trial and decide whether or not to accept the sNDA and if accepted, designate the application for a priority or standard review.

References

1. 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 Growth Factor Receptor Gene Alterations. Accessed August 29, 2023. https://finance.yahoo.com/news/janssen-submits-supplemental-drug-application-201500611.html

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.