Dual Targeting of the Epidermal Growth Factor Receptor Using the Combination of Cetuximab and Erlotinib: Preclinical Evaluation and Results of the Phase II DUX Study in Chemotherapy-Refractory, Advanced Colorectal Cancer
Dual Targeting of the Epidermal Growth Factor Receptor Using the Combination of Cetuximab and Erlotinib: Preclinical Evaluation and Results of the Phase II DUX Study in Chemotherapy-Refractory, Advanced Colorectal Cancer
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DOI：
10.1200/jco.2011.38.6599
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发表时间：
2012-05-01
影响因子：
45.3
通讯作者：
Tebbutt, Niall C.
中科院分区：
文献类型：
--
作者：
Weickhardt, Andrew J.;Price, Tim J.;Tebbutt, Niall C.
目的：本临床前和II期研究评估西妥昔单抗和厄洛替尼联合治疗转移性结直肠癌（mCRC）的有效性和安全性。患者与方法体外研究西妥昔单抗联合厄洛替尼对结直肠癌细胞株的活性及作用机制。在临床研究中，化疗难治性mCRC患者使用西妥昔单抗400mg /m(2)作为负荷剂量，然后每周使用西妥昔单抗250mg /m2联合厄洛替尼100mg每日口服。主要终点是缓解率（RR），分别在KRAS野生型（WT）和KRAS突变型肿瘤中进行评估。次要终点包括毒性、无进展生存期（PFS）和总生存期。目标累积为50例患者，采用一期设计。结果前期临床研究表明，西妥昔单抗和厄洛替尼共同治疗结肠癌细胞系的生长抑制具有协同作用，这是由于对表皮生长因子受体途径的抑制增强和对STAT3的不同作用。在临床研究中，50名患者入组，其中48名患者可评估反应。总RR为31% (95% CI， 26%至57%)，中位PFS为4.6个月（95% CI， 2.8至5.6个月）。KRAS WT肿瘤的RR为41% (95% CI， 26%至57%)，中位PFS为5.6个月（95% CI， 2.9至5.6个月）。11例KRAS突变患者无应答。常见的3级和4级毒性是皮疹（48%）、低镁血症（18%）和疲劳（10%）。结论西妥昔单抗联合厄洛替尼协同抑制结肠癌细胞系的生长，对KRAS WT mCRC患者具有良好的疗效，值得进一步的随机研究进行评价。
PurposeThis preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC).Patients and MethodsThe activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m2 with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design.ResultsPreclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI, 2.8 to 5.6 months). RR was 41% (95% CI, 26% to 57%) in KRAS WT tumors, with a median PFS of 5.6 months (95% CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48%), hypomagnesaemia (18%), and fatigue (10%).ConclusionThe combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.