Trial in progress: A phase II switch maintenance study of live biotherapeutic MRx0518 and avelumab in patients with unresectable locally advanced or metastatic urothelial carcinoma (UC) who did not progress on first-line platinum-containing chemotherapy.

TPS4610 Background: Efficacy of avelumab for maintenance treatment of UC was investigated in the JAVELIN Bladder 100 study (NCT02603432), which led to the FDA approval of avelumab for maintenance treatment as the current standard of care for patients with locally advanced or metastatic UC that have not progressed with first-line platinum-based chemotherapy. Outcomes included median overall survival (OS) of 21.4 months (95% CI 0.56-0.86), median progression-free survival (PFS) of 3.7 months (95% CI 3.5-5.5) and objective response rate (ORR) of 9.7% (95% CI 6.8-13). MRx0518 is a novel, human gut microbiome-derived, single-strain, live biotherapeutic. It is a bacterium of the Enterococcus genus that was selected for development in solid tumor treatment for its strong in vitro and in vivo immunostimulatory activity. In vivo studies have shown that MRx0518 can inhibit tumor growth in different syngeneic cancer models as both monotherapy and in combination with immune checkpoint inhibitors. MRx0518 has been shown to reduce Treg and increase Th1 and Tc1 lymphocyte differentiation in vitro and increase intratumoral CD4+ and CD8+ T cells and NK cells in vivo. In clinical studies, preliminary data shows that MRx0518 monotherapy can increase anti-tumor TILs and systemic pro-inflammatory immune signaling molecules. This is a pilot study evaluating whether the addition of MRx0518 to avelumab in the maintenance setting of metastatic platinum-treated UC may improve outcomes. Methods: The study will enroll 30 patients with unresectable locally advanced or metastatic UC at multiple US centers. Patients must have measurable disease after a partial response or stable disease on 4-6 cycles of platinum-containing induction chemotherapy. Patients will receive 800 mg avelumab IV infusion every 2 weeks in combination with 1 oral capsule (10x1010 – 10x1011 CFU) MRx0518 twice daily until disease progression, patient withdrawal or unacceptable toxicity. Primary objectives are to assess safety of the combination, and effect on PFS at 6 months. Secondary objectives are to assess other efficacy measures including PFS, ORR, OS, duration of response, time to response, and disease control rate. Collection of paired research biopsies at baseline (after chemotherapy) and on treatment (after 8 weeks of MRx0518 + avelumab), plus longitudinal blood sampling, will allow investigation of immunological changes systemically both in the tumor and as potential predictive markers of response. Stool and urine samples collected before, during and after treatment will allow investigation of changes to the microbiome and metabolome. Recruitment is open, awaiting accrual. Clinical trial information: NCT05107427.