Reckamp Karen L, Krysan Kostyantyn, Morrow Jason D, Milne Ginger L, Newman Robert A, Tucker Christopher, Elashoff Robert M, Dubinett Steven M, Figlin Robert A
Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at University of California at Los Angeles, 90095, USA.
Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3381-8. doi: 10.1158/1078-0432.CCR-06-0112.
Overexpression of cyclooxygenase-2 (COX-2) activates extracellular signal-regulated kinase/mitogen-activated protein kinase signaling in an epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI)-resistant manner. Because preclinical data indicated that tumor COX-2 expression caused resistance to EGFR TKI, a phase I trial to establish the optimal biological dose (OBD), defined as the maximal decrease in urinary prostaglandin E-M (PGE-M), and toxicity profile of the combination of celecoxib and erlotinib in advanced non-small cell lung cancer was done.
Twenty-two subjects with stage IIIB and/or IV non-small cell lung cancer received increasing doses of celecoxib from 200 to 800 mg twice daily (bid) and a fixed dose of erlotinib. Primary end points included evaluation of toxicity and determination of the OBD of celecoxib when combined with erlotinib. Secondary end points investigate exploratory biological markers and clinical response.
Twenty-two subjects were enrolled, and 21 were evaluable for the determination of the OBD, toxicity, and response. Rash and skin-related effects were the most commonly reported toxicities and occurred in 86%. There were no dose-limiting toxicities and no cardiovascular toxicities related to study treatment. All subjects were evaluated on intent to treat. Seven patients showed partial responses (33%), and five patients developed stable disease (24%). Responses were seen in patients both with and without EGFR-activating mutations. A significant decline in urinary PGE-M was shown after 8 weeks of treatment, with an OBD of celecoxib of 600 mg bid.
This study defines the OBD of celecoxib when combined with a fixed dose of EGFR TKI. These results show objective responses with an acceptable toxicity profile. Future trials using COX-2 inhibition strategies should use the OBD of celecoxib at 600 mg bid.
环氧合酶-2（COX-2）的过表达以一种对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）耐药的方式激活细胞外信号调节激酶/丝裂原活化蛋白激酶信号传导。由于临床前数据表明肿瘤COX-2表达会导致对EGFR TKI耐药，因此开展了一项I期试验，以确定塞来昔布与厄洛替尼联合用于晚期非小细胞肺癌时的最佳生物学剂量（OBD）（定义为尿前列腺素E-M（PGE-M）的最大降幅）及毒性特征。
22例IIIB期和/或IV期非小细胞肺癌患者接受了剂量递增的塞来昔布，剂量为每日两次（bid），从200mg至800mg，同时接受固定剂量的厄洛替尼。主要终点包括毒性评估以及确定塞来昔布与厄洛替尼联合使用时的OBD。次要终点研究探索性生物学标志物和临床反应。
入组22例患者，其中21例可评估OBD、毒性和反应。皮疹及皮肤相关效应是最常报告的毒性反应，发生率为86%。未出现剂量限制性毒性，也未出现与研究治疗相关的心血管毒性。所有受试者均按意向性治疗进行评估。7例患者出现部分缓解（33%），5例患者病情稳定（24%）。有EGFR激活突变和无EGFR激活突变的患者均出现了反应。治疗8周后尿PGE-M显著下降，塞来昔布的OBD为每日两次600mg。
本研究确定了塞来昔布与固定剂量EGFR TKI联合使用时的OBD。这些结果显示出客观反应且毒性特征可接受。未来使用COX-2抑制策略的试验应采用每日两次600mg的塞来昔布OBD。
