Phase 1 study of gotistobart (BNT316/ONC-392) in combination with lutetium Lu 177 vipivotide tetraxetan (Lu 177) in patients with metastatic castration-resistant prostate cancer (mCRPC).

5067 Background: When used in combination with physician’s choice of care, Lu 177 showed significant PFS and OS improvements in mCRPC. Combinations with novel agents are being explored to extend the therapeutic benefit. Preclinical models have demonstrated that radiotherapy selectively expands and functionally activates regulatory T cells (Tregs) in the tumor microenvironment (TME). Given the role of gotistobart (a unique pH-sensitive anti-CTLA-4 antibody that preserves CTLA-4 recycling and avoids lysosomal degradation) in selective depletion of Tregs in the TME, this study will initially test the safety and toxicity of gotistobart plus Lu 177 in mCRPC. Methods: PRESERVE-006 (NCT05682443) is an open-label, randomized, active control, multi-center, phase 1/2 study of gotistobart in combination with Lu 177 in patients with mCRPC who have progressed after androgen receptor pathway inhibition. Patients were randomized to receive gotistobart at 3 mg/kg, Q4W, 6 mg/kg Q6W, or 10 mg/kg Q6W for up to 13 doses plus Lu 177 7.4 GBq (200 mCi) Q6W for up to 6 doses, or to the control arm to receive Lu 177 7.4 GBq (200 mCi), Q6W for up to 6 doses. Here we report results from the dose escalation phase (Phase 1) that aims to assess safety and select two dose regimens for the Phase 2 dose optimization study. Results: As of December 20, 2024, 24 patients received at least 1 drug dose with a median 6.21 (range 1.2–11.3) months on study. Median age was 70.5 (range 52–86) years, and 62.5%, 25.0% and 4.2% were White, Black, and Asian, respectively. Median follow-up was 10.9, 2.6 and 5.4 months for the 3 mg/kg Q4W (N = 6), 6 mg/kg Q6W (N = 5) and 10 mg/kg Q6W (N = 6) combination regimens, respectively, and 6.5 months for Arm B Lu 177 (N = 7). No deaths, dose-limiting toxicity, or Gr 4–5 treatment-related AEs (TRAEs) were observed at any gotistobart dose. TRAEs related to gotistobart or Lu 177 were Gr 1–2 at 3 mg/kg Q4W and 6 mg/kg Q6W; one patient (16.7%) in the 3 mg/kg regimen had Gr 2 colitis leading to treatment discontinuation. At 10 mg/kg Q6W, two patients (33%) had Gr 3 colitis (both of whom discontinued treatment) and one patient (16.7%) had Gr 3 fatigue. Infusion-related reactions (Gr 1–2) were seen in 6 mg/kg (40.0%) and 10 mg/kg (66.7%) regimens. In the efficacy-evaluable population, confirmed PSA50 (a key secondary endpoint for Phase 2) was observed in 4 of 6 patients and 3 of 6 patients in 3 and 10 mg/kg regimens, respectively versus 1 of 6 patients in the Lu 177 control group. Conclusions: With known limitations in sample size during dose escalation,gotistobart in combination with Lu 177 demonstrated a manageable safety profile and promising preliminary PSA50 rates in patients with mCRPC during the dose escalation phase. Overall findings support combination regimens with gotistobart doses less than 10 mg/kg in the ongoing Phase 2 randomized dose optimization study. Clinical trial information: NCT05682443 .