Targeted treatment with the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib significantly improved overall survival, progression-free survival, and objective response rates compared with investigator’s choice of chemotherapy in patients with advanced urothelial cancers and FGFR2/3 aberrations, according to the results of the phase III randomized THOR trial presented at the 2023 ASCO Annual Meeting.¹ Patients enrolled in the trial had not responded to one or two prior lines of treatment, including anti–PD-L1 therapy, and the benefits of erdafitinib were observed across subgroups.

Erdafitinib achieved a 36% reduction in mortality compared with chemotherapy. At a median follow-up of 15.9 months, the median overall survival was 12.1 months with erdafitinib (n = 136) vs 7.8 months with investigator’s choice chemotherapy (n = 130, P = .005).

The median progression-free survival was 5.6 months with erdafitinib vs 2.7 months with chemotherapy, reflecting a 42% reduction in the risk of disease progression or death (P = .0002). The overall response rate was 45.6% with erdafitinib vs 11.5% with chemotherapy (P < .001). Complete response rate was 6.6% vs 0.8%, respectively, and partial response rate was 39% vs 10.8%, respectively.

Yohann ­Loriot, MD, PhD

“The phase III THOR study supports the clinical efficacy of erdafitinib as the standard-of-care option for patients with metastatic urothelial cancer with FGFR alteration after immune checkpoint inhibitor treatment,” said initial author Yohann ­Loriot, MD, PhD, of Gustave Roussy Institute, University Paris-Saclay, Villejuif, France. “The overall survival benefit of erdafitinib supports molecular testing of FGFR in all patients with metastatic urothelial carcinoma,” he added.

“We anticipate that this effect [from the study results] will be significant,” Dr. Loriot continued. “The results of the THOR trial provide level 1 evidence and will change the current guidelines.”

Background

Metastatic urothelial carcinoma has a poor prognosis. First-line treatment is platinum-containing chemotherapy, and in responders, avelumab maintenance therapy achieves a median survival of 21 months. Improved, more efficacious treatments are needed.

Although there is no cure for metastatic urothelial cancer, selective FGFR inhibition is an important area of investigation for patients who harbor these aberrations, which account for 10% to 20% of these patients. Erdafitinib is a tyrosine kinase inhibitor that inhibits all five FGFR proteins in urothelial tumors, and it is the only U.S. Food and Drug Administration–approved FGFR inhibitor for patients with urothelial carcinoma and select FGFR aberrations.

Erdafitinib was approved based on a phase II single-arm trial in patients with unresectable or metastatic urothelial cancer and FGFR2/3 alterations, which showed a complete or partial response in 40%. Thus far, several single-arm or phase II studies support the safety and efficacy of erdafitinib in metastatic urothelial cancer. However, THOR is the first phase III trial to compare erdafitinib vs the standard of care in patients previously treated with platinum-containing chemotherapy (docetaxel or vinflunine) and immune checkpoint inhibitor therapy.

Study Design

The multicenter, open-label, randomized THOR trial included 266 patients with advanced urothelial cancer that harbored FGFR2/3 aberrations and whose disease did not respond to one or two prior lines of treatment. All patients had received anti–PD-1 treatment in the first- or second-line setting.

Patients were screened for selected FGFR alterations and were assigned to two cohorts based on prior anti–PD-1 treatment. Patients were randomly assigned to receive erdafitinib or investigator’s choice of chemotherapy. Erdafitinib was given at 8 mg once daily and titrated up to 9 mg, based on serum phosphate level and adverse events at day 14. Chemotherapy was given as docetaxel at 75 mg/m² or vinflunine at 320 mg/m² every 3 weeks.

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, and then as clinically indicated. The primary endpoint was overall survival, with secondary endpoints of progression-free survival, objective response rate, and safety.

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

Among patients who received two prior lines of systemic therapy in the erdafitinib arm (66.2%), the first line of therapy was chemotherapy alone in 56.6% and chemotherapy plus anti–PD-1 inhibition in 4.4%. These rates in patients who received chemotherapy (74.9%) were 58.5% and 7.7%, respectively. The second line of therapy for patients in the erdafitinib and chemotherapy arms included anti–PD-1 inhibition alone (55.9% vs 58.5%) and chemotherapy alone (7.4% vs 10.8%).

Other baseline characteristics were well balanced between the two arms, including patient age (about 66 years), sex (about 70% were male), and race (about 60% were White). About 75% had visceral metastases (about 23% in the liver). Nearly all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The site of the primary tumor was the upper tract for 30.1% of patients in the erdafitinib arm and 36.9% of patients in the chemotherapy arm. Low PD-L1 expression (Combined Positive Score < 10) was observed in 92.7% of patients in the erdafitinib arm and 86.1% of those in the chemotherapy arm. Baseline FGFR alterations included mutations, fusions, and both.

Key Outcomes

Results were consistent across all subgroups. The greatest magnitude of benefit was seen in those with translocations and those with primary tumors in the upper tract. Median overall survival in patients with FGFR translocations was 16.4 months with erdafitinib vs 8.0 months with chemotherapy. Median overall survival in patients with upper tract tumors was 23.3 months vs 7.2 months with erdafitinib and chemotherapy, respectively.

In the erdafitinib safety cohort (n = 135), 45.9% of patients had at least one treatment-related grade 3 or 4 adverse event. The most common treatment-related adverse events of any grade or grade 3 or 4 in this arm were hyperphosphatemia, diarrhea, stomatitis, dry mouth, palmar-plantar erythrodysesthesia, and onycholysis.

In the chemotherapy arm (n = 112), 46.4% of patients experienced a grade 3 or 4 treatment-related adverse event. The most common any-grade and grade 3 or 4 events were anemia, alopecia, nausea, neutropenia, leukopenia, and febrile neutropenia.

Treatment discontinuation rates were 8.1% and 13.4% in the erdafitinib and chemotherapy arms, respectively. Serious adverse events were reported in 13.3% of patients given erdafitinib, including one treatment-related death. Adverse events in the erdafitinib arm were mostly manageable with dose modifications and supportive care, according to the investigators. In the chemotherapy arm, 24.1% of patients had serious adverse events, and six treatment-related deaths were reported. 

DISCLOSURE: Dr. Loriot has received honoraria from Pfizer and Sanofi; has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Janssen, MSD Oncology, Roche, and Seattle Genetics; has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, CureVac, Exelixis, Incyte, Janssen Oncology, Medivation, MSD Oncology, Nektar, OncoGenex, Pfizer, and Sanofi; and has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, AstraZeneca, Janssen Oncology, MSD Oncology, Roche, and Seattle Genetics.

REFERENCE

1. Loriot Y, Matsubara N, Park SH, et al: Phase 3 THOR study: Results of erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor alterations. 2023 ASCO Annual Meeting. Abstract LBA4619. Presented June 5, 2023.