Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

中文翻译：

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MET 抑制剂卡马替尼联合西妥昔单抗治疗 MET 阳性结直肠癌患者的 1b 期研究，这些患者在接受抗 EGFR 单克隆抗体治疗后出现进展。

背景 克服 KRAS 野生型 (WT) 转移性结直肠癌 (mCRC) 患者抗表皮生长因子受体 (EGFR) 单克隆抗体 (mAb) 的耐药性有助于满足治疗选择有限的患者的需求。方法 在这项 1b 期研究中，抗 EGFR mAb 治疗后进展的 N/KRAS WT、MET 阳性 mCRC 患者每天两次口服剂量递增的卡马替尼（150、300 和 400 mg）加每周静脉注射西妥昔单抗（在批准的剂量）。主要目标是确定卡马替尼联合西妥昔单抗的推荐扩展剂量 (RDE)。还探讨了安全性、初步活性、药代动力学和药效学。结果 13 名患者入组。在所研究的剂量下，没有患者出现剂量限制性毒性；RDE 被确定为卡马替尼 400 mg 每天两次加西妥昔单抗。所有患者都经历了疑似与研究治疗相关的不良事件 (AE)。五名患者 (38.5%) 报告了严重程度为 3/4 级的研究药物相关 AE。根据 RECIST v1.1，没有患者达到完全或部分反应；然而，在 4 名患者中观察到 29-44% 的肿瘤缩小。结论 卡马替尼加西妥昔单抗耐受性良好。观察到初步的活动迹象。需要进一步调查以获得疗效数据并改进反应的预测性生物标志物。临床试验注册号NCT02205398。5%) 报告了严重程度为 3/4 级的研究药物相关 AE。根据 RECIST v1.1，没有患者达到完全或部分反应；然而，在 4 名患者中观察到 29-44% 的肿瘤缩小。结论 卡马替尼加西妥昔单抗耐受性良好。观察到初步的活动迹象。需要进一步调查以获得疗效数据并改进反应的预测性生物标志物。临床试验注册号NCT02205398。5%) 报告了严重程度为 3/4 级的研究药物相关 AE。根据 RECIST v1.1，没有患者达到完全或部分反应；然而，在 4 名患者中观察到 29-44% 的肿瘤缩小。结论 卡马替尼加西妥昔单抗耐受性良好。观察到初步的活动迹象。需要进一步调查以获得疗效数据并改进反应的预测性生物标志物。临床试验注册号NCT02205398。