PI-035 - PHARMACOKINETICS OF TARLATAMAB, A DELTA LIKE LIGAND-3 (DLL3) TARGETED HALF-LIFE EXTENDED BISPECIFIC T-CELL ENGAGER (BITE) IMMUNOTHERAPY IN PATIENTS WITH PREVIOUSLY TREATED NEUROENDROCRINE PROSTATE CANCER (NEPC)

C. Thompson¹, M. Minocha², A. Murphy², Y. Zhou³, A. Parkes⁴, B. Yu⁴, P. Martinez⁵, B. Houk⁶; ¹Amgen, Inc., Thousand Oaks, CA, USA, ²Clinical Pharmacology Modeling and Simulation, Amgen, Thousand Oaks, CA, USA, ³Clinical Immunology, Amgen, Thousand Oaks, CA, USA, ⁴Early Development Oncology, Amgen, Thousand Oaks, CA, USA, ⁵Global Development Oncology, Amgen, Thousand Oaks, CA, USA, ⁶Amgen Inc., Thousand Oaks, CA, USA.

Background: Tarlatamab binds to both DLL3 on cancer cells and cluster of differentiation-3 (CD3) on T cells leading to T cell-mediated tumor lysis. Tarlatamab was approved by the FDA under an accelerated approval pathway in May of 2024 for the treatment of patients with previously treated small cell lung cancer (SCLC). Tarlatamab is also being evaluated in a Phase 1b study in NEPC patients. Here the pharmacokinetics and immunogenicity data in NEPC patients are presented.

Methods: DeLLpro-300 (ClinicalTrials.gov identifier: NCT04702737) is an ongoing, international, open-label study in previously treated adult patients with de novo or treatment-emergent NEPC. Patients were administered a 1 mg step dose of tarlatamab on cycle 1 day 1 (C1D1) followed by 100 mg on C1D8, C1D15 and Q2W thereafter in a 28-day cycle; the 100 mg dose being the highest safe and tolerable dose evaluated from the phase 1 SCLC trial (DeLLphi-300; NCT03319040). Intensive pharmacokinetic (PK) samples were collected during the first 2 cycles, and additional sparse samples for PK and immunogenicity were collected at regular intervals in subsequent cycles. PK data were analyzed using non-compartmental analysis and summarized. Anti-drug antibody (ADA) data and its effect on PK was summarized.

Results: PK data were available from all 40 patients treated with tarlatamab. Following IV infusion, serum concentrations declined with time in a biphasic manner. After Q2W dosing, steady-state in serum exposures was achieved by C2D15. The steady-state geometric mean (%CV) peak serum concentrations (Cmax) and pre-dose (Ctrough) were 27.6 (30) µg/mL and 4.27 (49) µg/mL, respectively, consistent with exposures observed in patients with SCLC at the same evaluated dose. Two subjects had treatment emergent ADA which is also consistent with the ADA incidence in patients with SCLC. Tarlatamab Ctrough was comparable between subjects who were ADA positive and those who were negative over time. Geometric mean (%CV) terminal half-life was 6.8 (36) days, consistent with observations in SCLC patients.

Conclusion: In patients with de novo or treatment emergent NEPC, tarlatamab exhibited comparable pharmacokinetics relative to patients with SCLC. Treatment emergent ADA incidence was low and did not have a clinically relevant impact on exposures. Terminal half-life supports Q2W dosing.