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Erdafitinib Prolongs Survival in Patients with Metastatic Urothelial Carcinoma and FGFR Alterations After Previous Anti–PD1(-L1) Treatment

Findings from the THOR Cohort 1 study
03 Nov 2023
Targeted Therapy;  Molecular Oncology;  Cytotoxic Therapy
Urothelial Cancer

In a Cohort 1 of the phase III THOR study, treatment with erdafitinib resulted in significantly longer median overall survival (OS) than chemotherapy among patients with locally advanced or metastatic urothelial carcinoma with FGFR alterations after previous treatment with anti–PD1 or anti–PD-L1 therapy. Erdafitinib was also associated with a significantly longer median progression-free survival (PFS) and a greater likelihood of objective response than chemotherapy. Side effects that were observed during erdafitinib therapy were occasionally serious and fatal in a few patients.

These data further support the recommendation for molecular testing in patients with metastatic urothelial carcinoma to identify those with FGFR alterations who may benefit from erdafitinib. The findings are published by Dr. Arlene O. Siefker-Radtke of the University of Texas M.D. Anderson Cancer Center in Houston, TX, US, and colleagues on 21 October 2023 in the NEJM. The subgroup findings were presented at ESMO Congress 2023 in Madrid, Spain by Dr. Yohann Loriot of the Gustave Roussy and Université Paris-Saclay in Villejuif, France.   

The authors wrote in the background that more than 50% of patients with metastatic urothelial carcinoma are ineligible for cisplatin treatment, and those who receive chemotherapy typically have progression within a few months. PD1 and PD-L1 inhibitors are often used in patients who are ineligible for cisplatin, as maintenance therapy after platinum-based chemotherapy, or as second-line therapy for relapsed or refractory disease. However, only approximately 30% of patients with metastatic urothelial cancer have a response to PD1 or PD-L1 inhibitors. Coexisting conditions and residual side effects of previous therapy often prevent patients from receiving later-line treatments. 

FGFR alterations are observed in approximately 20% of advanced or metastatic urothelial cancers and in approximately 36% of upper tract urothelial cancers and may function as oncogenic drivers. Erdafitinib is an oral selective pan-FGFR tyrosine kinase inhibitor. In a phase II, single-group study BLC2001 involving patients with locally advanced or metastatic urothelial cancer with susceptible FGFR3/2 alterations who had progression after platinum-containing chemotherapy, 40% of the patients who received erdafitinib had an objective response; the median PFS was 5.5 months, and the median OS was 11.3 months. Based on this study, erdafitinib was approved to treat locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy.

THOR is a confirmatory, phase III, randomised study involving patients with previously treated metastatic urothelial carcinoma who were divided into two cohorts. In Cohort 1, the study investigators assessed whether erdafitinib would improve survival over chemotherapy among patients with FGFR-altered metastatic urothelial carcinoma whose disease progressed after one or two previous treatments that included an anti–PD1 or anti–PD-L1 agent. In Cohort 2, they are examining erdafitinib as compared with pembrolizumab in patients who had not previously received an anti–PD1 or anti–PD-L1 agent. In the article published in the NEJM, the investigators present the results from the Cohort 1.

In Cohort 1, patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator’s choice of chemotherapy (docetaxel or vinflunine). The primary endpoint was OS. A total of 266 patients underwent randomisation: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months.

The median OS was significantly longer with erdafitinib than with chemotherapy, 12.1 months versus 7.8 months with hazard ratio for death of 0.64 (95% confidence interval [CI] 0.47 to 0.88; p = 0.005). The median PFS was also longer with erdafitinib than with chemotherapy, 5.6 months versus 2.7 months with hazard ratio for progression or death of 0.58 (95% CI 0.44 to 0.78; p < 0.001).

OS appeared to be longer with erdafitinib than with chemotherapy in a variety of subgroups, including those defined according to previous lines of therapy, the presence or absence of previous platinum-based therapy, primary tumour location (lower or upper tract), the presence or absence of liver or lung metastases, chemotherapy type, and FGFR alteration type.

The analysis of subgroups defined according to FGFR alteration is limited by the absence of FGFR2 alterations in the study population, but is reflective of the fact that FGFR2 alterations are rare in urothelial carcinoma. FGFR3 mutations and fusions are early events in the oncogenesis of urothelial carcinoma. The testing of samples from the primary tumour should be sufficient to detect FGFR3 alterations.

The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups, 45.9% in the erdafitinib group and 46.4% in the chemotherapy group. Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (0.7% versus 5.4% of patients).

The study was presented in part at the ASCO 2023 Annual Meeting (2-6 June, Chicago, IL, US).

The study was supported by Janssen Research and Development.


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