一项评估尼拉帕利联合吉西他滨和顺铂作为转移性非小细胞肺癌一线治疗方案添加物的 II 期随机研究。
A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small-cell lung cancer.
机构信息
Department of Oncology, University of Turin, AOU San Luigi, Orbassano, Italy.
Thoracic Cancer Unit, Department of Medicine, Gustave-Roussy, Villejuif, France.
出版信息
Ann Oncol. 2014 Nov;25(11):2156-2162. doi: 10.1093/annonc/mdu384. Epub 2014 Aug 19.
BACKGROUND
Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine-cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients.
PATIENTS AND METHODS
Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m(2), days 1/8) and cisplatin (75 mg/m(2), day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature.
RESULTS
One hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%-42.1%] with GC versus 20.0% (95% CI 11.9%-30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8-5.6) months with GC and 5.7 (95% CI 4.6-6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56-1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9-17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48-1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3-4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each).
CONCLUSIONS
Addition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS.
TRIAL REGISTRATION
ClinicalTrial.gov Identifier NCT01086254.
背景
依匹哌唑是一种新型抗癌药物，最初被认为是一种多聚（ADP-核糖）聚合酶（PARP）抑制剂，但随后被证明通过半胱氨酸加合物非选择性地作用于蛋白质修饰。这项随机的 II 期研究调查了在转移性非小细胞肺癌（NSCLC）患者中添加依匹哌唑与吉西他滨联合顺铂的效果。
患者和方法
经组织学证实为 IV 期 NSCLC 的患者被随机分为 2:1 组，分别接受吉西他滨（1250 mg/m2，第 1/8 天）和顺铂（75 mg/m2，第 1 天）联合[吉西他滨/顺铂/依匹哌唑（GCI）]或不联合[吉西他滨/顺铂（GC）]依匹哌唑（5.6 mg/kg，第 1/4/8/11 天），每 3 周为一个周期，共 6 个周期。主要终点是总缓解率（ORR）。次要目标包括无进展生存期（PFS）、总生存期（OS）和安全性。该研究的设计并非为了进行正式的疗效比较，而是将对照组的结果与文献进行基准比较。
结果
共有 119 名患者被随机分为 GC 组（39 名）和 GCI 组（80 名）。更多的 GCI 患者为男性（80% GCI 和 67% GC），且 PS 0（61% GCI 和 49% GC）。GC 组的 ORR 为 25.6%（95%CI 13.0%-42.1%），GCI 组为 20.0%（95%CI 11.9%-30.4%），这不能排除无效假设（GCI 的 ORR ≤20%；P=0.545）。GC 组的中位 PFS 为 4.3（95%CI 2.8-5.6）个月，GCI 组为 5.7（95%CI 4.6-6.6）个月（风险比 0.89，95%CI 0.56-1.40）。GC 组的中位 OS 为 8.5（95%CI 5.5-未达到）个月，GCI 组为 12.0（95%CI 8.9-17.1）个月（风险比 0.78，95%CI 0.48-1.27）。更多的 GCI 患者接受了二线治疗（51% GC 和 68% GCI）。两组的毒性相似。3-4 级毒性包括乏力（28% GC 和 8% GCI）、恶心（3% GC 和 14% GCI）和食欲下降（各 10%）。
结论
与 GC 组相比，添加依匹哌唑并未提高 ORR。GCI 的安全性与 GC 组相当。PS 和性别分布的不平衡可能影响了 PFS 和 OS 的研究结果。
试验注册
ClinicalTrials.gov 标识符 NCT01086254。
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