Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer.
Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer.
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DOI：
10.1158/1078-0432.ccr-11-3090
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发表时间：
2012-06-01
期刊：
影响因子：
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通讯作者：
Gandhi L
中科院分区：
文献类型：
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作者：
Rudin CM;Hann CL;Garon EB;Ribeiro de Oliveira M;Bonomi PD;Camidge DR;Chu Q;Giaccone G;Khaira D;Ramalingam SS;Ranson MR;Dive C;McKeegan EM;Chyla BJ;Dowell BL;Chakravartty A;Nolan CE;Rudersdorf N;Busman TA;Mabry MH;Krivoshik AP;Humerickhouse RA;Shapiro GI;Gandhi L
Bcl-2是细胞凋亡的关键调节因子，在大多数小细胞肺癌（SCLC）中过表达。Nativoclax（ABT-263）是一种有效的选择性Bcl-2和Bcl-xL抑制剂。这项IIa期研究的主要目的包括在至少接受过一次既往治疗后复发性和进展性SCLC患者中使用推荐的II期剂量的安全性和初步探索性疗效评估。39例患者在初始导入期每日150 mg，持续7天后接受了navitoclax 325 mg每日一次。研究终点包括安全性和毒性评估、缓解率、无进展生存期和总生存期（PFS和OS）以及探索性药效学相关性。与navitoclax相关的最常见毒性是血小板减少症，41%的患者达到III-IV级。在1例（2.6%）患者中观察到部分缓解，在9例（23%）患者中观察到疾病稳定。中位PFS为1.5个月，中位OS为3.2个月。血浆前胃泌素释放肽（pro-GRP）水平与肿瘤Bcl-2拷贝数之间存在强相关性（R = 0.93）。探索性分析显示细胞角蛋白19片段抗原21-1、神经元特异性烯醇化酶、前GRP和循环肿瘤细胞数的基线水平与临床获益相关。navitoclax靶向Bcl-2显示出对晚期和复发性SCLC的有限单药活性。相关分析表明了几种推定的临床益处生物标志物。临床前模型支持navitoclax可增强SCLC和其他实体瘤对标准细胞毒素的敏感性。未来的研究将集中在联合疗法上。
Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III–IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro–gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.