Teclistamab Dosing in Responders: Modeling and Simulation Results from the MajesTEC-1 Study in Relapsed/Refractory Multiple Myeloma.

IF 4.4 3区医学 Q2 ONCOLOGY

Targeted Oncology Pub Date : 2025-05-07 DOI:10.1007/s11523-025-01149-1

Yue Guo, Jin Niu, Natalia A Quijano Cardé, Liviawati Wu, Xin Miao, Shalla Hanson, Yaming Su, Carlos Pérez Ruixo, Deeksha Vishwamitra, Katherine Chastain, Mahesh N Samtani, Weirong Wang, Nahor Haddish-Berhane

{"title":"Teclistamab Dosing in Responders: Modeling and Simulation Results from the MajesTEC-1 Study in Relapsed/Refractory Multiple Myeloma.","authors":"Yue Guo, Jin Niu, Natalia A Quijano Cardé, Liviawati Wu, Xin Miao, Shalla Hanson, Yaming Su, Carlos Pérez Ruixo, Deeksha Vishwamitra, Katherine Chastain, Mahesh N Samtani, Weirong Wang, Nahor Haddish-Berhane","doi":"10.1007/s11523-025-01149-1","DOIUrl":null,"url":null,"abstract":"Background: Based on the phase I/II MajesTEC-1 study, the B-cell maturation antigen (BCMA) and cluster of differentiation (CD)3 bispecific antibody, teclistamab, is approved for relapsed/refractory multiple myeloma (RRMM) at a dose of 1.5 mg/kg weekly (QW), with the option to switch to 1.5 mg/kg every other week (Q2W) in patients maintaining complete response (CR) or better for ≥ 6 months on the QW schedule.Objective: We report the pharmacokinetics (PK), pharmacodynamics, and anticancer activity of teclistamab 1.5 mg/kg Q2W, and the PK of teclistamab 3 mg/kg every 4 weeks (Q4W), on the basis of modeling and simulation results from MajesTEC-1.Methods: Teclistamab PK was assessed using a population PK approach. Exposure-response analysis was based on individual estimated teclistamab serum trough concentration (Ctrough). The impact of responders switching to Q2W teclistamab dosing on the formation of the key pharmacological species that drive the mechanism of action of teclistamab (i.e., the trimer formed by simultaneous engagement of teclistamab with BCMA on target multiple myeloma cells and CD3 on effector T cells) was estimated using a quantitative systems pharmacology (QSP) model. Additionally, steady-state teclistamab PK and trimer was simulated for the 1.5 mg/kg Q2W and Q4W (3 mg/kg or 1.5 mg/kg) doses.Results: Median estimated teclistamab serum Ctrough was lower after the first and fourth Q2W doses (14.4 and 11.7 µg/mL, respectively) than after QW doses (20.4 µg/mL) but remained above the 90% maximal effective concentration. No statistically significant exposure-response trend was observed for duration of response (DOR), progression-free survival, or overall survival in responders who switched to teclistamab 1.5 mg/kg Q2W dosing. Despite the lower teclistamab serum Ctrough, the QSP model estimated comparable target cell-biologics-effector cell (TBE) trimer formation, tumor volume reduction, and DOR for responders switching to 1.5 mg/kg Q2W dosing versus not switching. Steady-state exposure metrics and trimer formation with teclistamab 3 mg/kg Q4W were estimated to be comparable with those at 1.5 mg/kg Q2W.Conclusions: MajesTEC-1 modeling and simulation results, which contributed to the teclistamab label update, support the approved switch to teclistamab 1.5 mg/kg Q2W in patients maintaining ≥ CR for ≥ 6 months on the QW dose, without negatively impacting clinical efficacy. In addition, it is estimated that the 3 mg/kg Q4W schedule will provide maintenance of response comparable with the 1.5 mg/kg Q2W schedule. Teclistamab 3 mg/kg Q4W dosing will be evaluated in > 800 patients in three phase III studies in early line RRMM (MajesTEC-3, MajesTEC-9, and MonumenTAL-6) and in 100 patients in RRMM in the phase I MajesTEC-10 study.Clinical trial registration: NCT03145181 (phase I, 9 May 2017); NCT04557098 (phase II, 21 September 2020).","PeriodicalId":22195,"journal":{"name":"Targeted Oncology","volume":" ","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Targeted Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11523-025-01149-1","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Based on the phase I/II MajesTEC-1 study, the B-cell maturation antigen (BCMA) and cluster of differentiation (CD)3 bispecific antibody, teclistamab, is approved for relapsed/refractory multiple myeloma (RRMM) at a dose of 1.5 mg/kg weekly (QW), with the option to switch to 1.5 mg/kg every other week (Q2W) in patients maintaining complete response (CR) or better for ≥ 6 months on the QW schedule.

Objective: We report the pharmacokinetics (PK), pharmacodynamics, and anticancer activity of teclistamab 1.5 mg/kg Q2W, and the PK of teclistamab 3 mg/kg every 4 weeks (Q4W), on the basis of modeling and simulation results from MajesTEC-1.

Methods: Teclistamab PK was assessed using a population PK approach. Exposure-response analysis was based on individual estimated teclistamab serum trough concentration (C_trough). The impact of responders switching to Q2W teclistamab dosing on the formation of the key pharmacological species that drive the mechanism of action of teclistamab (i.e., the trimer formed by simultaneous engagement of teclistamab with BCMA on target multiple myeloma cells and CD3 on effector T cells) was estimated using a quantitative systems pharmacology (QSP) model. Additionally, steady-state teclistamab PK and trimer was simulated for the 1.5 mg/kg Q2W and Q4W (3 mg/kg or 1.5 mg/kg) doses.

Results: Median estimated teclistamab serum C_trough was lower after the first and fourth Q2W doses (14.4 and 11.7 µg/mL, respectively) than after QW doses (20.4 µg/mL) but remained above the 90% maximal effective concentration. No statistically significant exposure-response trend was observed for duration of response (DOR), progression-free survival, or overall survival in responders who switched to teclistamab 1.5 mg/kg Q2W dosing. Despite the lower teclistamab serum C_trough, the QSP model estimated comparable target cell-biologics-effector cell (TBE) trimer formation, tumor volume reduction, and DOR for responders switching to 1.5 mg/kg Q2W dosing versus not switching. Steady-state exposure metrics and trimer formation with teclistamab 3 mg/kg Q4W were estimated to be comparable with those at 1.5 mg/kg Q2W.

Conclusions: MajesTEC-1 modeling and simulation results, which contributed to the teclistamab label update, support the approved switch to teclistamab 1.5 mg/kg Q2W in patients maintaining ≥ CR for ≥ 6 months on the QW dose, without negatively impacting clinical efficacy. In addition, it is estimated that the 3 mg/kg Q4W schedule will provide maintenance of response comparable with the 1.5 mg/kg Q2W schedule. Teclistamab 3 mg/kg Q4W dosing will be evaluated in > 800 patients in three phase III studies in early line RRMM (MajesTEC-3, MajesTEC-9, and MonumenTAL-6) and in 100 patients in RRMM in the phase I MajesTEC-10 study.

Clinical trial registration: NCT03145181 (phase I, 9 May 2017); NCT04557098 (phase II, 21 September 2020).

查看原文本刊更多论文

泰克司他抗给药：MajesTEC-1研究中复发/难治性多发性骨髓瘤的建模和模拟结果

背景：基于I/II期MajesTEC-1研究，b细胞成熟抗原（BCMA）和分化集群（CD）3双特异性抗体teclistamab被批准用于治疗复发/难治性多发性骨髓瘤（RRMM），剂量为每周1.5 mg/kg (QW)，在QW计划中保持完全缓解（CR）或更好≥6个月的患者可选择切换到每隔一周1.5 mg/kg （Q2W）。目的：基于MajesTEC-1的建模和模拟结果，报告teclistamab 1.5 mg/kg Q2W和teclistamab 3mg /kg每4周（Q4W）的药代动力学（PK）、药效学和抗癌活性。方法：采用群体PK法评估Teclistamab的PK。暴露-反应分析基于个体估计的特司他单抗血清谷浓度（Ctrough）。使用定量系统药理学（QSP）模型估计应答者切换到Q2W teclistamab剂量对驱动teclistamab作用机制的关键药理学物质形成的影响（即teclistamab与BCMA同时作用于靶多发性骨髓瘤细胞和CD3同时作用于效应T细胞形成的三聚体）。此外，模拟了1.5 mg/kg Q2W和Q4W （3 mg/kg或1.5 mg/kg）剂量下teclistamab PK和三聚体的稳态。结果：第一次和第四次Q2W剂量（分别为14.4和11.7µg/mL）比QW剂量（20.4µg/mL）后的中位估计teclistamab血清穿透率低，但仍高于90%最大有效浓度。在转向替司他抗1.5 mg/kg Q2W剂量的应答者中，在反应持续时间（DOR）、无进展生存期或总生存期方面没有观察到统计学上显著的暴露-反应趋势。尽管teclistamab血清穿透率较低，但QSP模型估计，切换到1.5 mg/kg Q2W剂量与不切换时，应答者的靶细胞生物制剂-效应细胞（TBE）三聚体形成、肿瘤体积缩小和DOR相当。据估计，泰司他抗3mg /kg Q4W的稳态暴露指标和三聚体形成与1.5 mg/kg Q2W的相当。结论：MajesTEC-1建模和模拟结果促进了teclistamab标签的更新，支持在QW剂量维持≥CR≥6个月的患者中切换到teclistamab 1.5 mg/kg Q2W，而不会对临床疗效产生负面影响。此外，据估计，3mg /kg Q4W方案将提供与1.5 mg/kg Q2W方案相当的反应维持。Teclistamab 3mg /kg Q4W剂量将在3个早期RRMM III期研究（MajesTEC-3、MajesTEC-9和MonumenTAL-6）的800名患者和MajesTEC-10 I期研究的100名RRMM患者中进行评估。临床试验注册：NCT03145181 （I期，2017年5月9日）；NCT04557098（第二阶段，2020年9月21日）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Targeted Oncology 医学-肿瘤学

CiteScore

8.40

自引率

3.70%

发文量

审稿时长

>12 weeks

期刊介绍： Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.