A phase 3 randomized clinical trial published on November 23, 2023 in The New England Journal of Medicine has demonstrated that erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor, significantly improves overall survival compared to chemotherapy in patients with advanced urothelial carcinoma harboring FGFR alterations who had previously received immunotherapy.
The THOR trial was a global, multicenter study conducted across 121 sites in 23 countries. It was funded by Janssen Research and Development. The study aimed to evaluate the efficacy and safety of erdafitinib versus chemotherapy in patients with metastatic urothelial carcinoma with FGFR3/2 alterations who had disease progression during or after treatment with immune checkpoint inhibitors.
A total of 266 patients were enrolled and randomized 1:1 to receive either erdafitinib (n=136) or investigator's choice of chemotherapy with docetaxel or vinflunine (n=130). Key inclusion criteria were adults with metastatic or surgically unresectable urothelial cancer, select FGFR3/2 alterations (mutations or fusions), ECOG performance status 0-2, adequate organ function, and disease progression during or after previous systemic therapy that included an anti-PD-1 or anti-PD-L1 agent. Patients could have received up to two previous lines of therapy.
The study population was predominantly male (71.4%) with a median age of 66-69 years. Most patients had visceral metastases (74.4%) and had received one (29.3%) or two (70.3%) previous lines of therapy. The majority (89.1%) had received prior chemotherapy. Notably, 89.7% of patients with available PD-L1 data had low PD-L1 expression (combined positive score <10).
The primary endpoint was overall survival. At a median follow-up of 15.9 months, erdafitinib demonstrated a statistically significant improvement in overall survival compared to chemotherapy. The median overall survival was 12.1 months with erdafitinib versus 7.8 months with chemotherapy (hazard ratio for death 0.64; 95% CI 0.47-0.88; p=0.005). The estimated 12-month survival rate was 51% with erdafitinib compared to 38% with chemotherapy.
Secondary endpoints also favored erdafitinib. Median progression-free survival was 5.6 months with erdafitinib versus 2.7 months with chemotherapy (HR 0.58; 95% CI 0.44-0.78; p<0.001). The objective response rate was significantly higher with erdafitinib (45.6% vs 11.5%; relative benefit 3.94; 95% CI 2.37-6.57; p<0.001), including complete responses in 6.6% of erdafitinib-treated patients versus 0.8% with chemotherapy.
The safety profile of erdafitinib was consistent with previous studies. The incidence of grade 3-4 treatment-related adverse events was similar between erdafitinib (45.9%) and chemotherapy (46.4%). However, treatment-related adverse events leading to death were less common with erdafitinib (0.7% vs 5.4%). The most common grade 3-4 treatment-related adverse events with erdafitinib were palmar-plantar erythrodysesthesia syndrome (9.6%), stomatitis (8.1%), onycholysis (5.9%), and hyperphosphatemia (5.2%).
Adverse events of special interest with erdafitinib included skin disorders (11.9% grade 3-4), nail disorders (11.1% grade 3-4), central serous retinopathy (2.2% grade 3-4), and other eye disorders (2.2% grade 3-4). Most cases of central serous retinopathy resolved by the end of the study.
The study had some limitations. The open-label design could potentially introduce bias in the assessment of progression-free survival and adverse events. The trial excluded patients with ECOG performance status >2, limiting generalizability to patients with poorer performance status. Additionally, the study population lacked racial diversity, with only one Black patient enrolled, complicating extrapolation of results to this subgroup.
The authors concluded that erdafitinib resulted in significantly longer overall survival than chemotherapy in patients with FGFR-altered metastatic urothelial carcinoma who had progressed on prior anti-PD-1/PD-L1 therapy. They noted that the survival benefit was observed across various subgroups, including those defined by previous lines of therapy, presence of prior platinum-based therapy, primary tumor location, metastatic sites, and type of FGFR alteration.
These results have important clinical implications for the management of advanced urothelial carcinoma. The findings support the use of molecular testing for FGFR alterations in patients with metastatic urothelial cancer to identify those who may benefit from erdafitinib therapy. Given that approximately 20% of advanced urothelial cancers harbor FGFR alterations, this represents a significant subset of patients who may derive benefit from targeted therapy.
The study positions erdafitinib as an effective treatment option for patients with FGFR-altered urothelial carcinoma who have progressed on immunotherapy. This is particularly relevant given the limited options and poor outcomes typically seen in this setting. The safety profile of erdafitinib, while requiring monitoring and management, appears distinct from and potentially more favorable than that of chemotherapy or antibody-drug conjugates in terms of myelosuppression and neuropathy.
The results also highlight the potential for precision medicine approaches in urothelial cancer. By targeting a specific molecular alteration, erdafitinib demonstrated efficacy in a biomarker-selected population. This underscores the importance of comprehensive genomic profiling in advanced urothelial cancer to identify actionable alterations and guide treatment selection.
Furthermore, the study provides valuable data on the efficacy of FGFR inhibition following immunotherapy in urothelial cancer. Given that FGFR-altered tumors are often associated with low PD-L1 expression and limited T-cell infiltration, targeting FGFR may be a particularly effective strategy in this molecularly defined subgroup.
While the results are promising, several questions remain. The optimal sequencing of erdafitinib in relation to other available therapies, including enfortumab vedotin, still needs to be determined. Additionally, strategies to overcome resistance to FGFR inhibition and potential combination approaches warrant further investigation.
In conclusion, this phase 3 trial provides robust evidence supporting the use of erdafitinib in FGFR-altered metastatic urothelial carcinoma after progression on immunotherapy. The significant improvement in overall survival, coupled with a manageable safety profile, establishes erdafitinib as an important treatment option in this setting. These findings reinforce the value of molecular profiling in guiding treatment decisions for patients with advanced urothelial cancer and highlight the potential of targeted therapies to improve outcomes in biomarker-selected populations.
References
Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023;389(21):1961-1971. doi:10.1056/NEJMoa2308849
