CLTR-06 RESPECT-LM: PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT OF RHENIUM OBISBEMEDA IN LEPTOMENINGEAL METASTASES WITH EMERGING DATA FROM REPEATED DOSING (RESPECT-LMM)
Andrew Brenner, Henriette Balinda, Priya Kumthekar, Michael Schulder, Eva Galvan, Ande Bao, Joel Michalek, Fatema Ataei, Penny Vroman, William Phillips, John Floyd, Jonathan Yang, Marc Hedrick, Michael YoussefAbstract
Background
Rhenium obisbemeda (186RNL, REYOBIQ) is a liposomal nanoparticle encapsulating β-emitting rhenium-186 designed for intracavitary delivery. Results demonstrated favorable safety and encouraging activity in leptomeningeal metastases (LM), with a recommended phase 2 single dose of 44 mCi (MTD 66 mCi). We report pharmacokinetic (PK) and pharmacodynamic (PD) findings and emerging data from an ongoing repeated-dosing study (ReSPECT-LMM, NCT07098806).
Methods
Planar imaging was performed post-dose and at 24–168 hours. Target and organ dosimetry were calculated using OLINDA/EXM. CSF was collected at baseline, 8, 24, and 48 hours, and days 14 and 28 for RNA sequencing. Immunologic effects were evaluated in an ID8agg/C57BL6 model. Preliminary clinical data from the repeated-dosing cohort were summarized descriptively.
Results
A linear dose–response relationship was observed, with mean absorbed doses of 28–272 Gy and 7–205 Gy to cranial and spinal subarachnoid spaces, respectively. Normal organ exposure remained low (liver 1–3 Gy, spleen 2–6 Gy, blood 0–3 Gy). RNA sequencing of CSF (n = 60 samples, 11 patients) identified two temporal gene expression patterns: an early innate inflammatory response followed by a proliferation/DNA repair program. Immune deconvolution demonstrated delayed adaptive immune activation, predominantly CD8+ T-cell–driven. In the ID8agg model, combination therapy with 186RNL and anti–PD-1 enhanced CD8+ activation, increased NK populations, and improved tumor control (p = 0.008). In the ongoing repeated-dosing study, Cohort 1A (n = 3) completed three doses of 13.2 mCi without dose-limiting toxicities. Three patients in Cohort 2A and one in Cohort 1B have received at least one dose and remain on study, with no new safety signals observed to date.
Conclusions
186RNL delivers tumoricidal radiation doses to LM exceeding conventional EBRT by > 8-fold while maintaining low systemic exposure. Treatment induces temporally coordinated immune remodeling with delayed CD8+ engagement, supporting combination immunotherapy and repeated dosing strategies under active investigation.