Minocha Mukul, Thompson Corbin G, Murphy Alexis, Zhou Yanchen, Brandl Christian, Parkes Amanda, Chen Xi, Yu Brian, Martinez Pablo, Houk Brett E
Clinical Pharmacology Modeling & Simulation, Amgen, Thousand Oaks, CA, USA.
Clinical Immunology, Amgen, South San Francisco, CA, USA.
Clin Pharmacokinet. 2024 Dec;63(12):1757-1768. doi: 10.1007/s40262-024-01451-7. Epub 2024 Nov 26.
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.
塔勒妥单抗可与癌细胞上的δ样配体3及T细胞上的分化簇3结合，从而导致T细胞介导的肿瘤溶解，并且在先前接受过治疗的小细胞肺癌（SCLC）患者中已显示出有前景的安全性和疗效。在此，我们展示了DeLLphi - 300（NCT03319940）的药代动力学结果，这是一项正在进行的针对先前接受过治疗的成年SCLC患者的国际、开放标签、首次人体研究。
在28天的周期内，每2周（Q2W；0.003、0.01、0.03、0.1、0.3、1、3、10、30和100 mg）给予多剂量递增的塔勒妥单抗。为降低细胞因子释放综合征的风险，从3 mg剂量水平开始，采用逐步给药方案，即在第1周期第1天（C1D1）输注1 mg，随后在C1D8、C1D15以及此后的Q2W给予目标剂量。所有剂量均在1小时内输注完毕。还探索了其他塔勒妥单抗给药方案，要么是为了方便患者（每3周一次），要么是为了减轻细胞因子释放综合征（在3天内进行延长静脉输注）。在第1和第2周期收集密集的药代动力学样本，并在后续周期定期收集用于药代动力学和免疫原性测量的额外样本。使用非房室分析对药代动力学数据进行分析，并总结抗药抗体（ADA）发生率，包括其对塔勒妥单抗药代动力学参数的任何影响。
有203例患者的药代动力学数据可用。中位年龄为62岁（范围32 - 80岁），55.7%（n = 113）的患者为男性，78.3%（n = 159）为白人，8.3%（n = 17）为日本血统。静脉输注后，血清塔勒妥单抗浓度随时间呈双相下降。在所评估的目标剂量范围内，血清暴露量以近似剂量比例的方式增加，平均（标准差）估计终末相消除半衰期为5.8（1.6）天，大约在C2D15时达到稳态。在183例可评估患者中，12例（6.6%）出现治疗中出现的ADA；ADA阳性和阴性患者的剂量标准化血清浓度分布相似。此外，日本患者和非日本患者的暴露分布具有可比性。
在先前接受过治疗的SCLC患者中，塔勒妥单抗显示出剂量比例性药代动力学和延长的半衰期特征，支持每2周一次的给药间隔。日本种族和ADA对暴露量均无临床相关影响。
