一线帕尼单抗联合 FOLFOX4 或 FOLFIRI 方案治疗结直肠癌伴多发或不可切除肝转移：一项随机、II 期临床试验（PLANET-TTD）。
First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised, phase II trial (PLANET-TTD).
机构信息
Ramon y Cajal University Hospital, Ramon y Cajal Institute for Health Research - IRYCIS, Alcala University, CIBERONC, Carretera de Colmenar Viejo, km 9.100, ES-28034 Madrid, Spain.
Germans Trias i Pujol Hospital-ICO, Carretera de Canyet s/n, ES-08916 Badalona, Spain.
出版信息
Eur J Cancer. 2017 Aug;81:191-202. doi: 10.1016/j.ejca.2017.04.024. Epub 2017 Jun 19.
BACKGROUND
In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations.
METHODS
Multicentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients.
RESULTS
Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6-1.5]; WT-RAS:13/15; HR: 0.7 [0.4-1.3]). Median OS was 37/41 months (HR:1.0 [0.6-1.8]; WT-RAS: 39/49; HR:0.9 [0.4-1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm.
CONCLUSIONS
In patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov:NCT00885885).
背景
在野生型（WT）-Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）转移性结直肠癌（mCRC）的一线治疗中，帕尼单抗（Pmab）联合 FOLFOX[亚叶酸钙、5-氟尿嘧啶和奥沙利铂]或 FOLFIRI[亚叶酸钙、5-氟尿嘧啶和伊立替康]可改善结局。然而，尚无试验直接比较这两种联合方案。
方法
这项多中心、开放性标签研究纳入了未经治疗的年龄≥18 岁的（WT）-KRAS mCRC 患者，这些患者有多个或无法切除的肝局限性疾病（LLD），随机接受 Pmab-FOLFOX4 或 Pmab-FOLFIRI 治疗。主要终点为客观缓解率（ORR）。次要终点包括肝转移灶切除率（R0+R1）、无进展生存期（PFS）、总生存期（OS）、不良事件和围手术期安全性。探索性终点为：RAS 状态的反应、早期肿瘤退缩（ETS）和 WT-RAS 患者的深度缓解（DpR）。
结果
对 77 例患者的数据进行了分析（Pmab-FOLFOX4 组 38 例，Pmab-FOLFIRI 组 39 例；WT-RAS 患者分别为 27 例/26 例）。Pmab-FOLFOX4 和 Pmab-FOLFIRI 的 ORR 分别为 74%和 67%（WT-RAS 患者分别为 78%和 73%）。在上述患者中，分别有 45%和 59%接受了手术切除（WT-RAS 患者分别为 37%和 69%）。R0-R1 切除率分别为 34%和 46%（WT-RAS 患者分别为 26%和 54%）。中位 PFS 为 13/14 个月（Pmab-FOLFIRI 与 Pmab-FOLFOX4 相比，HR：0.9；95%CI：0.6-1.5；WT-RAS：HR：0.7；0.4-1.3）。中位 OS 为 37/41 个月（HR：1.0；0.6-1.8；WT-RAS：HR：0.9；0.4-1.9）。在 WT-RAS 患者中，确认有反应的患者中位 DpR 分别为 71%和 66%，并且在第 8 周时，分别有 65%和 77%的患者出现 ETS≥30%和≥20%，两组之间无显著差异；这些患者的中位 PFS 和 OS 更长，切除率更高。手术与更长的生存时间相关。围手术期和总体安全性相似，但 Pmab-FOLFOX4 组中 3/4 级中性粒细胞减少症（40%/10%；p=0.003）和周围神经病（13%/0%；p=0.025）的发生率更高。
结论
在 WT-KRAS mCRC 伴 LLD 的患者中，一线 Pmab-FOLFOX4 和 Pmab-FOLFIRI 均能产生较高的 ORR 和 ETS，从而可能实现潜在的治愈性切除。两种方案之间的疗效无显著差异。（临床试验.gov：NCT00885885）
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