Aroldi Francesca, Elez Elena, André Thierry, Perkins Geraldine, Prenen Hans, Popovici Vlad, Gallagher Peter, Houlden Jennifer, Collins Linda, Roberts Corran, Rolfo Christian, Di Nicolantonio Federica, Grayson Margaret, Boyd Ruth, Bettens Karolien, Delfavero Jurgen, Coyle Victoria, Lawler Mark, Khawaja Hajrah, Laurent-Puig Pierre, Salto-Tellez Manuel, Maughan Tim S, Tabernero Josep, Adams Richard, Jones Robert, Hennessy Bryan T, Bardelli Alberto, Peeters Marc, Middleton Mark R, Wilson Richard H, Van Schaeybroeck Sandra
Department of Oncology, University of Oxford, Old Road Campus Research Building Roosevelt Drive, Oxford, OX3 7DQ, UK.
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), 08035, Barcelona, Spain.
BMC Cancer. 2025 Apr 10;25(1):658. doi: 10.1186/s12885-025-14068-1.
Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients.
In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected.
Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1-21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency.
Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients. EudraCT-Number: 2014-000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).
靶向RAS突变（MT）的结直肠癌（CRC）仍然是一项艰巨的挑战，主要是由于RAS/MEK介导的反馈回路普遍存在。临床前研究确定MET/STAT3是RAS MT CRC中对KRAS-MEK1/2阻断耐药的重要介质。这项剂量递增/扩展研究评估了MEK1/2抑制剂比美替尼与MET抑制剂克唑替尼联合用于RAS MT晚期CRC患者的安全性和初步疗效。
在剂量递增阶段，晚期实体瘤患者接受比美替尼与克唑替尼联合治疗，采用滚动6设计来确定最大耐受剂量（MTD）以及安全性/耐受性。随后在RAS MT CRC患者中进行剂量扩展，以评估治疗反应。收集用于药代动力学、MET生物标志物和ctDNA分析的血样，以及用于药效学、c-MET免疫组织化学（IHC）、MET原位杂交（ISH）和MET DNA-ISH分析的皮肤/肿瘤活检样本。
在剂量递增阶段的3个队列中招募了20名患者。MTD为比美替尼30mg每日两次，第1 - 21天，每28天一个周期，克唑替尼250mg每日一次持续给药。剂量限制性毒性包括≥3级转氨酶升高、肌酐磷酸激酶升高和疲劳。36名RAS MT转移性CRC患者进入剂量扩展阶段。药代动力学和药效学参数显示有靶点作用的证据。在整个研究中，最常见的治疗相关不良事件（TR-AE）为皮疹（80.4%）、疲劳（53.4%）和腹泻（51.8%），≥3级TR-AE发生率为44.6%。RAS MT CRC队列中的最佳临床反应是7名患者病情稳定（24%）。7名患者（24.1%）观察到肿瘤MET过表达（IHC H评分>180且MET ISH +3），其中只有1名患者存在MET扩增。该患者在第1周期因毒性反应提前停药。与低基线RAS MT等位基因频率的患者相比，高基线RAS MT等位基因频率的患者中位总生存期显著缩短。
比美替尼/克唑替尼联合方案耐受性较差，在RAS MT晚期CRC患者中未观察到客观反应。欧洲临床试验注册号：2014-000463 - 40（2014年6月20日：MEK1/2抑制剂PD-0325901或比美替尼与cMET抑制剂克唑替尼联合用于RAS突变和RAS野生型伴异常c-MET的序贯I期研究）
