Episode 6: The THOR-2 trial

Prof Emmanuel Seront from UCL Louvain and Prof Vulsteke from Maria Middelares Gent are engaged in a discussion centred on the THOR-2 trial, which investigates targeted therapy for high-risk non–muscle-invasive bladder cancer (HR NMIBC).

In cohort 1 of the study, patients develop papillary disease following unsuccessful BCG treatment. This cohort encompasses both unresponsive patients and those with prior BCG exposure. BCG unresponsiveness is defined as treatment failure within six months post-adequate maintenance and induction courses. Patients experiencing failure after six months are also eligible for the trial and THOR-2 equally allocated both cohorts. Moreover, inclusion in the trial required biomarker positivity. Thus, only papillary patients with positive FGFR alterations, fusions, or mutations were eligible, constituting an estimated 30% of the patient pool—a challenging demographic to identify.

Given the absence of effective standard treatment, establishing a control arm proved challenging. Consequently, randomization favoured a 2:1 allocation for erdafitinib versus control. Unlike CIS-eligible patients, whose endpoint is a complete response, the focus for this patient subset is RFS, evaluated at 6 and 12 months. Results indicate that erdafitinib significantly improves RFS at both 6 and 12 months compared to gemcitabine or mitomycin C. At 6 and 12 months, RFS rates were 96% and 77% for erdafitinib versus 73% and 41% for chemotherapy, respectively, with a hazard ratio of 0.28 and median RFS not reached for erdafitinib.

However, erdafitinib’s success in the trial is tempered by limitations. The trial prematurely closed due to slow enrollment, resulting in only 73 participants, far fewer than the intended 200. Erdafitinib’s selectivity, requiring biomarker positivity, contributed to the low enrollment rate. When no therapeutic options are available, reimbursement implications need to be considered in assessing FGFR alterations. Despite the efficacy of erdafitinib, concerns persist regarding its toxicity, notably central retinopathy, which may not be reversible. Consequently, intravesical administration using TAR210 emerges as a potential solution to mitigate systemic toxicity.

The trial’s findings advocate for reevaluating erdafitinib delivery methods, prioritizing intravesical approaches to enhance patient outcomes and potentially obviating the need for radical cystectomy.