A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naive Patients with Advanced Non-Small Cell Lung Cancer
A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naive Patients with Advanced Non-Small Cell Lung Cancer
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DOI：
10.1158/1078-0432.ccr-09-3033
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发表时间：
2010-06-01
影响因子：
11.5
通讯作者：
Smit, Egbert F.
中科院分区：
文献类型：
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作者：
Lind, Joline S. W.;Dingemans, Anne-Marie C.;Smit, Egbert F.
目的：这项多中心、II期研究评估了厄洛替尼（一种表皮生长因子受体（EGFR）抑制剂）联合索拉非尼（一种针对血管内皮生长因子受体的多酪氨酸激酶抑制剂）治疗既往未经治疗的晚期非小细胞肺癌（NSCLC）患者的疗效和安全性。未经化疗的IIIB/IV期NSCLC患者接受厄洛替尼（150 mg，每日一次）和索拉非尼（400 mg，每日两次）治疗，直至疾病进展或出现不可接受的毒性。主要终点是6周时的无进展率。次要终点包括客观缓解率（ORR）、进展时间、总生存期和不良事件。探索性终点包括治疗前EGFR和KRAS突变状态、药代动力学和细胞色素P450多态性。6周时的非进展率为74%：12例（24%）部分缓解，25例（50%）疾病稳定。最终，ORR为28%。中位至进展时间为5.0个月[95%置信区间（95% CI），3.2-6.8个月]。中位总生存期为10.9个月（95% CI，3.8-18.1个月）。3/4级不良事件包括疲劳（16%）、手足皮肤反应（16%）、皮疹（16%）、腹泻（14%）和低磷血症（42%）。有1例治疗相关致死性肺出血。携带野生型EGFR的患者的ORR（19%）高于之前报道的厄洛替尼/索拉非尼单药治疗的ORR。厄洛替尼水平降低。这是与CYP 3A 4多态性，可能是由于索拉非尼。结论：尽管可能的药物相互作用，索拉非尼加厄洛替尼具有良好的临床活性在IIIB/IV期NSCLC患者，并具有可接受的安全性。需要进一步评估该联合治疗作为EGFR突变阴性患者的潜在挽救治疗以及可能的药物相互作用。临床癌症研究; 16（11）; 3078-87。(C)2010年AACR。
Purpose: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC).Experimental Design: Chemotherapy-naive patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms.Results: Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib.Conclusion: Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted. Clin Cancer Res; 16(11); 3078-87. (C) 2010 AACR.