Wermke Martin, Gambardella Valentina, Kuboki Yasutoshi, Felip Enriqueta, Sanmamed Miguel F, Alese Olatunji B, Sayehli Cyrus M, Arriola Edurne, Wolf Jürgen, Villaruz Liza C, Bertulis Julia, Studeny Matus, Bouzaggou Mohamed, Fang Xiaoyan, Morgensztern Daniel
TU Dresden University of Technology, NCT/UCC Early Clinical Trial Unit, Dresden, Germany.
Department of Medical Oncology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain.
J Clin Oncol. 2025 Sep 20;43(27):3021-3031. doi: 10.1200/JCO-25-00363. Epub 2025 Jul 24.
We report phase I results for obrixtamig (BI 764532), a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager, in patients with previously treated DLL3-positive small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (epNECs), or large cell neuroendocrine carcinoma of the lung (LCNEC-L).
Patients received escalating intravenous obrixtamig doses using four regimens: a fixed dose once every 3 weeks (A); a fixed dose once weekly (B1); a step-up dose once weekly for two weeks and target dose once weekly (B2); and a step-up dose once weekly for 3 weeks, target dose once weekly for 3 weeks, and once every 3 weeks thereafter (B3). The primary objective was maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics, and tumor response (RECIST v1.1).
As of February 21, 2024, 168 patients received obrixtamig, 72% received ≥2 lines of previous anticancer therapy, and 51% received previous anti-PD-1/PD-L1 therapy. Seven dose-limiting toxicities occurred during MTD evaluation (Regimen A, n = 1; Regimen B2, n = 6). MTD was not reached. The most common treatment-related adverse event was cytokine release syndrome (any grade: 57%; grade ≥3: 3%); most cases occurred early and were reversible. Across all doses, regimens, and tumor types, the overall response rate (ORR) was 23% (95% CI, 17.4% to 30.2%), the median duration of response (DoR) was 8.5 months (95% CI, 6.2 to not reached), and the 6-month DoR rate was 70% (95% CI, 53% to 88%). All patients in Regimens B2/B3 received the minimum effective dose (≥90 μg/kg once weekly or once every 3 weeks), achieving an ORR of 28% (95% CI, 20.7% to 35.9%). With Regimens B2/B3, ORRs were 21% (95% CI, 12.9% to 33.1%), 27% (95% CI, 17.4% to 39.6%), and 70% (95% CI, 39.7% to 89.2%) for SCLC, epNECs, and LCNEC-L, respectively.
The demonstrated tolerability and efficacy of obrixtamig regimens, administered as step-up followed by target doses of 90-1,080 μg/kg (once weekly or once every 3 weeks), in patients with heavily pretreated DLL3-positive tumors support further exploration in SCLC, epNEC, and LCNEC-L.
我们报告了obrixtamig（BI 764532）的I期试验结果，它是一种δ样配体3（DLL3）/CD3 IgG样T细胞衔接器，用于治疗既往接受过治疗的DLL3阳性小细胞肺癌（SCLC）、肺外神经内分泌癌（epNECs）或肺大细胞神经内分泌癌（LCNEC-L）患者。
患者使用四种方案接受递增静脉注射obrixtamig剂量：每3周一次固定剂量（A）；每周一次固定剂量（B1）；每周一次递增剂量持续两周，然后每周一次目标剂量（B2）；每周一次递增剂量持续3周，每周一次目标剂量持续3周，此后每3周一次（B3）。主要目标是最大耐受剂量（MTD）。次要目标包括安全性、药代动力学和肿瘤反应（RECIST v1.1）。
截至2024年2月21日，168例患者接受了obrixtamig治疗，72%的患者接受过≥2线既往抗癌治疗，51%的患者接受过既往抗PD-1/PD-L1治疗。在MTD评估期间发生了7例剂量限制性毒性反应（方案A，n = 1；方案B2，n = 6）。未达到MTD。最常见的治疗相关不良事件是细胞因子释放综合征（任何级别：57%；≥3级：3%）；大多数病例发生在早期且可逆转。在所有剂量组、方案和肿瘤类型中，总体缓解率（ORR）为23%（95%CI，17.4%至30.2%），中位缓解持续时间（DoR）为8.5个月（95%CI，6.2至未达到），6个月DoR率为70%（95%CI，53%至88%）。方案B2/B3中的所有患者均接受了最小有效剂量（≥90μg/kg每周一次或每3周一次），ORR为28%（95%CI，20.7%至35.9%）。采用方案B2/B3时，SCLC、epNECs和LCNEC-L的ORR分别为21%（95%CI，12.9%至33.1%）、27%（95%CI，17.4%至39.6%）和70%（95%CI，39.7%至89.2%）。
在既往接受过大量治疗的DLL3阳性肿瘤患者中，以递增剂量随后给予90 - 1080μg/kg（每周一次或每3周一次）目标剂量的obrixtamig方案所显示出的耐受性和疗效，支持在SCLC、epNEC和LCNEC-L中进一步探索。
