ASCO 2012： 难治性SCLC:阿柏西普有潜力（SWOG 0802研究）

一项Ⅱ期临床试验表明，一种新型血管内皮生长因子（VEGF）阻滞剂可延缓铂类耐药小细胞肺癌（SCLC）的进展速度。

美国田纳西大学的Jeffrey Warren Allen博士和同事们发现，与单纯托泊替康治疗相比，联合阿柏西普可提高患者3个月无进展生存（PFS）率（27% 对 10%，P=0.01）。

他们在2012年美国临床肿瘤学会年会（ASCO 2012）上报告，患者总生存和缓解率未得到提高，但毒性反应小。

“有必要在该患者群体中进一步研究托泊替康和阿柏西普的效果，”Allen说。

作为研究者之一的美国加利福尼亚大学戴维斯综合肿瘤中心的David R. Gandara博士指出，托泊替康是唯一获准用于SCLC二线治疗的药物，主要对仍对铂类敏感的患者有效。

“在二线治疗中，如果患者仍对铂类敏感，则许多化疗药物有效，但是若患者对铂类耐药则疗效较差，”他解释说。

为对铂类为基础化疗耐药的SCLC患者探索新的治疗选择迫在眉睫，但很多靶向药物都失败了，他指出。

阿柏西普是一种重组人融合蛋白，与循环VEGF紧密结合，使其不能与细胞表面受体相互作用。

Allen等共报告了98例可评估的铂类耐药、广泛期或局限期SCLC患者，随机给予其单纯托泊替康（4 mg/m2静脉注射，第1、8和15日给药）或联合阿柏西普（6 mg/kg静脉注射，第1日给药）治疗。

该研究还纳入了铂类敏感队列，但本次报告时尚未分析该队列。

托泊替康标准给药方案是每个周期连续5日每日给药，但研究者选择了每周给药方案以减轻毒性反应。

联合阿柏西普治疗组3个月无进展生存率显著高于单纯托泊替康治疗组，但两组的中位PFS均为1.4个月。

联合治疗组和单纯托泊替康组的总生存期也无显著差异（4.6个月 对 4.2个月，P=0.35）。

研究中罕见肿瘤缩小。单纯托泊替康组未出现客观缓解，阿柏西普组客观缓解率仅为2%。

但是，“抗血管生成药物可能会在实体瘤疗效评价标准（RECIST）未显示缓解的情况下已经显示生物学活性，”Gandara指出。

阿柏西普和托泊替康联合治疗组毒性反应主要为血液学毒性。联合治疗组和单纯治疗组出现3级毒性事件的患者例数分别为20和15例，出现4级毒性事件的例数分别为8和5例。


标题：SWOG 0802: A randomized phase II trial of weekly topotecan with and without AVE0005 (aflibercept) in patients with platinum-treated extensive-stage small cell lung cancer (E-SCLC).(Abstract 7005)

作者：Jeffrey Warren Allen, James Moon, Shirish M. Gadgeel, Karen Kelly,et al.

英文摘要：

Background: Topotecan (T) (oral and IV) is the only FDA-approved second-line chemotherapy for patients with SCLC. Weekly T is associated with less toxicity than the daily x 5 regimen. AVE0005 (aflibercept) (A) is a novel recombinant human fusion protein which binds to circulating VEGF, thereby inhibiting its interaction with cell surface receptors. We sought to evaluate the efficacy and toxicity of weekly IV T (4 mg/m2) with or without A (6 mg/kg Q21D) in patients with relapsed SCLC following one line of platinum-based chemotherapy for E or limited-stage (L) SCLC.

Methods: Patients were randomized 1:1 to T or A+T. Eligible patients had adequate organ function, ECOG PS 0-1, and no recent bleeding or cardiac events. Patients with brain metastases stable for ≥ 3 months prior to study entry were allowed. Primary endpoint was 3-month PFS. Patients were stratified as platinum-sensitive (PS) or platinum-refractory (PR). PR patients had progressed within 90 days of last chemotherapy for E and 6 months for L. This report is limited to the PR stratum.

Results: 98 patients were registered. 1 was ineligible and 1 withdrew consent, leaving 96 evaluable for the primary endpoint (91 for toxicity (see Table for characteristics)). 3-month PFS was 26% for A+T versus 9% for T (P=0.01). Overall survival was similar in each arm (4.6 mos (A+T) versus 3.9 mos (T) (P=0.25)). There was 1 partial response with A+T. Disease control rate (DCR) was 28% with A+T and 12% with T. Toxicity was mainly hematologic with 14% and 19% of patients experiencing a Grade 4 event with T and A+T, respectively. There was one treatment-related death with T (renal failure).

Conclusions: This study met its primary endpoint of improved 3-month PFS with A+T (p=0.01), warranting further study in the PR setting. Clinical benefit with A+T was achieved primarily through improved DCR. Toxicity was manageable and less than is seen with standard dose T. Accrual to the PS cohort is ongoing.