Instituto de Biomedicina de Sevilla, University Hospital Virgen del Rocío, Seville, Spain.
Lancet Oncol. 2012 Mar;13(3):247-55. doi: 10.1016/S1470-2045(12)70063-3. Epub 2012 Feb 16.
Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, non-pemetrexed doublet. The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin.
In this double-blind, multicentre, phase 3, randomised placebo-controlled trial, patients with advanced non-squamous NSCLC aged 18 years or older, with no previous systemic chemotherapy for lung cancer, with at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 participated. Before randomisation, patients entered an induction phase which consisted of four cycles of induction pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) on day 1 of a 21-day cycle. Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage (IIIB or IV), ECOG performance status (0 or 1), and induction response (complete or partial response, or stable disease), and randomly assigned (2:1 ratio) to receive maintenance therapy with either pemetrexed (500 mg/m(2) every 21 days) plus best supportive care or placebo plus best supportive care until disease progression. Randomisation was done with the Pocock and Simon minimisation method. Patients and investigators were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00789373.
Of the 1022 patients enrolled, 939 participated in the induction phase. Of these, 539 patients were randomly assigned to receive continuation maintenance with pemetrexed plus best supportive care (n=359) or with placebo plus best supportive care (n=180). Among the 359 patients randomised to continuation maintenance with pemetrexed, there was a significant reduction in the risk of disease progression over the placebo group (HR 0·62, 95% CI 0·49-0·79; p<0·0001). The median progression-free survival, measured from randomisation, was 4·1 months (95% CI 3·2-4·6) for pemetrexed and 2·8 months (2·6-3·1) for placebo. Possibly treatment-related laboratory grade 3-4 adverse events were more common in the pemetrexed group (33 [9%] of 359 patients) than in the placebo group (one [<1%] of 180 patients; p<0·0001), as were non-laboratory grade 3-5 adverse events (32 [9%] of 359 patients in the pemetrexed group; eight [4%] of 180 patients in the placebo group; p=0·080); one possibly treatment-related death was reported in each group. The most common adverse events of grade 3-4 in the pemetrexed group were anaemia (16 [4%] of 359 patients), neutropenia (13 [4%]), and fatigue (15 [4%]). In the placebo group, these adverse events were less common: anaemia (one [<1%] of 180 patients), neutropenia (none), and fatigue (one <1%]). The most frequent serious adverse events were anaemia (eight [2%] of 359 patients in the pemetrexed group vs none in the placebo group) and febrile neutropenia (five [1%] vs none). Discontinuations due to drug-related adverse events occurred in 19 (5%) patients in the pemetrexed group and six (3%) patients in the placebo group.
Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin.
Eli Lilly and Company.
接受含铂类而非培美曲塞的双药诱导化疗后，晚期非鳞状非小细胞肺癌（NSCLC）患者可从培美曲塞维持治疗中获益。PARAMOUNT 试验旨在评估培美曲塞维持治疗是否能改善培美曲塞联合顺铂诱导化疗后的无进展生存期。
在这项双盲、多中心、随机、安慰剂对照的 3 期临床试验中，纳入年龄为 18 岁及以上、无既往全身化疗史、至少有一个可测量病灶、东部肿瘤协作组（ECOG）体能状态为 0 或 1 的晚期非鳞状 NSCLC 患者。在随机分组前，患者进入诱导期，包括培美曲塞（500mg/m2）联合顺铂（75mg/m2），每 21 天为一个周期，共 4 个周期。完成 4 个周期诱导治疗后未进展且 ECOG 体能状态为 0 或 1 的患者，根据疾病分期（IIIB 或 IV 期）、ECOG 体能状态（0 或 1）和诱导反应（完全或部分缓解或疾病稳定）进行分层，随机接受培美曲塞（500mg/m2，每 21 天）联合最佳支持治疗或安慰剂联合最佳支持治疗维持治疗，直至疾病进展。随机分组采用 Pocock 和 Simon 最小化法。患者和研究者对治疗分配均设盲。主要终点为在意向治疗人群中的无进展生存期。本研究在 ClinicalTrials.gov 登记，NCT00789373。
在纳入的 1022 例患者中，939 例患者参加了诱导期。其中，539 例患者随机接受培美曲塞联合最佳支持治疗（n=359）或安慰剂联合最佳支持治疗（n=180）的维持治疗。在随机接受培美曲塞维持治疗的 359 例患者中，与安慰剂组相比，疾病进展风险显著降低（HR 0.62，95%CI 0.49-0.79；p<0.0001）。从随机分组开始，培美曲塞组的中位无进展生存期为 4.1 个月（95%CI 3.2-4.6），安慰剂组为 2.8 个月（2.6-3.1）。培美曲塞组（33 [9%]例）与安慰剂组（1 [<1%]例）相比，可能与治疗相关的实验室 3-4 级不良事件更常见（p<0.0001），非实验室 3-5 级不良事件也更常见（培美曲塞组 32 [9%]例，安慰剂组 8 [4%]例；p=0.080）。两组各有 1 例可能与治疗相关的死亡事件报告。培美曲塞组最常见的 3-4 级不良事件为贫血（359 例患者中有 16 [4%]例）、中性粒细胞减少症（13 [4%]例）和疲劳（15 [4%]例）。在安慰剂组，这些不良事件较少见：贫血（180 例患者中 1 [<1%]例）、中性粒细胞减少症（无）和疲劳（1 [<1%]例）。最常见的严重不良事件为贫血（培美曲塞组 359 例患者中有 8 [2%]例，安慰剂组无）和发热性中性粒细胞减少症（培美曲塞组 5 [1%]例，安慰剂组无）。因药物相关不良事件而停药的患者分别为培美曲塞组 19 例（5%）和安慰剂组 6 例（3%）。
对于体能状态良好、在接受培美曲塞联合顺铂诱导化疗后未进展的晚期非鳞状 NSCLC 患者，培美曲塞维持治疗是一种有效且耐受良好的治疗选择。
礼来公司。
