Amgen Research (Munich) GmbH

Tarlatamab binds to delta-like ligand 3 on cancer cells and cluster of differentiation-3 on T cells, leading to T-cell-mediated tumor lysis, and has demonstrated a promising safety and efficacy profile in patients with previously treated small-cell lung cancer (SCLC). Here, we present pharmacokinetic results from DeLLphi-300 (NCT03319940), an ongoing international, open-label, first-in-human study in previously treated adult patients with SCLC.

Multiple escalating doses of tarlatamab were administered every 2 weeks (Q2W; 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mg) in a 28-day cycle. To reduce the risk of cytokine-release syndrome, starting at the 3 mg dose level, a step dose regimen was employed consisting of a 1 mg infusion on cycle 1 day 1 (C1D1), followed by the target dose on C1D8, C1D15, and Q2W thereafter. All doses were infused over 1 h. Other tarlatamab dosing regimens were also explored, either for patient convenience (every 3 weeks) or to mitigate cytokine-release syndrome (extended intravenous infusion over a period of 3 days). Intensive pharmacokinetic samples were collected during cycles 1 and 2, and additional samples for pharmacokinetic and immunogenicity measurement were collected at regular intervals in later cycles. Pharmacokinetic data were analyzed using noncompartmental analysis, and antidrug antibody (ADA) incidence, including any effect on tarlatamab pharmacokinetic parameters, was summarized.

Pharmacokinetic data were available from 203 patients. The median age was 62 years (range 32-80), and 55.7% (n = 113) of patients were male, 78.3% (n = 159) were white, and 8.3% (n = 17) were of Japanese descent. Following intravenous infusion, serum tarlatamab concentrations declined with time in a biphasic manner. Serum exposures increased in an approximately dose-proportional manner across the evaluated target dose range with a mean (standard deviation) estimated terminal phase elimination half-life of 5.8 (1.6) days, and steady state achieved by approximately C2D15. Of the 183 evaluable patients, 12 (6.6%) developed treatment-emergent ADAs; the distribution of dose-normalized serum concentrations were similar between patients who were ADA positive and ADA negative. In addition, the distribution of exposures was comparable in Japanese and non-Japanese patients.

In patients with previously treated SCLC, tarlatamab demonstrated dose-proportional pharmacokinetic and extended half-life characteristics that support a Q2W dosing interval. Neither Japanese race nor ADA had a clinically relevant impact on exposures.

We assessed BM T cells of AML patients at initial diagnosis (ID), complete remission (CR), and first relapse (RL).We next measured the expression of inhibitory receptors within the CD4⁺ and CD8⁺ T cell compartments during AML progression and compared them to HD T cells.Taken together, our study provides insights into the dysfunctional state of BM T cells and the mol. determinants of their function during AML progression.It is of high importance that clin. trials evaluating these therapies incorporate thorough biomarker studies, including BM biopsies to obtain a T-cell signature associated with response to treatment.

The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell–dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment.

Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer.See related commentary by Hage Chehade et al., p. 20.See related article by Kelly et al., p. 76.This article is featured in Selected Articles from This Issue, p. 5