Fiedler Walter, Cresta Sara, Schulze-Bergkamen Henning, De Dosso Sara, Weidmann Jens, Tessari Anna, Baumeister Hans, Danielczyk Antje, Dietrich Bruno, Goletz Steffen, Zurlo Alfredo, Salzberg Marc, Sessa Cristiana, Gianni Luca
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus-Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano, Italy.
ESMO Open. 2018 Feb 1;3(2):e000303. doi: 10.1136/esmoopen-2017-000303. eCollection 2018.
Changes in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).
Forty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12-1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.
A maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55-113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71-414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.
Tomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.
单克隆抗体（mAb）恒定区（Fc）糖基化的改变可增强抗体依赖的细胞介导的细胞毒性，而不依赖于抗体阻断受体后的下游效应，从而扩展了其适应症。我们在一项I期剂量递增研究（NTC01222637）中研究了托木珠单抗（一种针对表皮生长因子受体的IgG1糖工程化单克隆抗体，具有增强的肿瘤细胞毒性）的安全性、药代动力学、药效学和抗肿瘤活性。
41例对标准治疗难治的晚期实体瘤患者，采用3+3剂量递增设计，每周（12 - 1370 mg）或每两周（990 mg）接受托木珠单抗治疗。
未达到最大耐受剂量。最常见的治疗相关不良事件为31例（76%）患者发生的输注相关反应（3级，12%），主要局限于首剂，以及30例（73%）患者出现的皮肤毒性（1级或2级）。23例可评估患者中有9例（39%）出现低镁血症。与西妥昔单抗相似，托木珠单抗浓度在剂量≥480 mg时与剂量成比例增加，中位终末半衰期（t½）为82小时，范围为55 - 113小时。抗肿瘤活性包括1例非小细胞肺癌患者持续超过4.5年的完全缓解，以及1例结直肠癌患者持续353天的部分缓解。12例患者病情稳定（中位，166天，范围，71 - 414天），2例患者对不可测量疾病的控制时间延长（>1年）。
托木珠单抗在晚期转移性疾病的经大量预处理患者中安全且显示出有前景的抗肿瘤活性。一项针对复发或转移性头颈部鳞状细胞癌患者的化疗联合每周一次托木珠单抗或西妥昔单抗随后用相应单克隆抗体维持治疗的IIb期试验正在进行。
