Phase 1 results of Oncobax-AK in combination with ipilimumab/nivolumab in advanced clear cell renal cell carcinoma (ccRCC; NCT05865730).

4529 Background: Patients with advanced solid tumors who respond to immunotherapy are more likely to have Akkermansia spp (Akk) in their stools, whereas its absence (45%) is associated with worse outcome, regardless of other prognostic factors. Here, we report the safety and efficacy findings from a Phase I trial evaluating Oncobax-AK live biotherapeutics in combination with nivolumab/ipilimumab in intermediate- and poor-risk IMDC ccRCC patients who tested negative for stool Akk . We report first results of cohort 1. Methods: Intermediate- and poor-risk IMDC advanced ccRCC patients were screened across 4 centers in France for Akk using a qPCR stool test designed to detect specific Akk strains (SGB9226/SGB9228). Patients who tested negative for stool Akk received either 1X (cohort 1) or 6X oral capsules (cohort 2) of Oncobax-AK (a specific strain of SGB9228, p2261) for one week as monotherapy, followed by a combination treatment with nivolumab/ipilimumab administered continuously until progression in cohorts 1 and 2, respectively. The primary endpoints were safety, pharmacodynamics of Oncobax-AK, and overall response rate (ORR) according to RECIST 1.1. Blood and stool samples were collected at multiple time points for multi-omics analyses. Results: Among the 29 patients screened for Akk , 11 (38%) did not harbor gut Akk and were eligible . Two patients declined to continue. Ultimately, 9 patients (8 intermediate and 1 poor IMDC risk group) were enrolled in cohort 1, with a median age of 57 years (n = 9: 1 female and 8 males). No serious adverse events related to Oncobax-AK was observed. Only one patient experienced a serious immunotherapy-related adverse event that led to treatment withdrawal. After a median follow-up of 14.9 months, all patients are still alive, with 4 showing a partial response (PR) for more than 6 months (including 2 patients with ongoing PR for over 15 months, continuing the intervention). One patient had stable disease (SD), 3 had progressive disease (PD), and 1 was not evaluable (NE). Among evaluable patients, the ORR was 50%. Multi-omics analyses revealed that Oncobax-AK remains detectable over time and induced changes in the microbiome, leaky gut markers, and immune and metabolite profiles. These changes suggest potential pharmacodynamic biomarkers, reflecting the biological effects of Oncobax-AK. Conclusions: This is the first trial targeting patients lacking Akkermansia spp. in their stools. Oncobax-AK, combined with Ipilimuab/Nivolumab in intermediate- and poor-risk IMDC ccRCC, appears safe and may modulate gut microbiota, inflammation, metabolites, and immune profiles. This potentially mimics a responder's profile and leads to clinical and radiological benefits in some patients. Based on these promising results, enrollment in cohort 2 (6X) is ongoing and has now been expanded to include non-small cell lung cancer patients. Clinical trial information: NCT05865730 .