Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan.
Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
Nat Commun. 2024 Nov 25;15(1):10217. doi: 10.1038/s41467-024-54460-2.
The clinical significance of FOLFOXIRI (5-FU, leucovorin, oxaliplatin, and irinotecan) plus anti-EGFR monoclonal antibody using cetuximab for metastatic colorectal cancer (mCRC) remains controversial. We report results from a randomized phase 2 DEEPER trial (UMIN000018217, jRCTs061180022) to test the superiority of modified (m)-FOLFOXIRI plus weekly cetuximab over bevacizumab in patients with RAS wild-type (wt) mCRC. Primary endpoint was depth of response (DpR). Secondary endpoints included objective response rate (ORR), early tumor shrinkage (ETS) at week 8, progression-free survival (PFS), overall survival (OS), time to tumor growth (TTG), time to treatment failure (TTF), association between tumor shrinkage and prognosis, association between TTG and prognosis, R0 resection rate, and safety. In 359 enrolled patients with RAS wt mCRC, median DpR was significantly better in cetuximab (57.3% vs 46.0%, p = 0.0029); however, ORR, ETS, R0 resection rate, TTG, TTF, PFS and OS were similar between 2 treatments. There was a weak association between DpR and survival time in both treatments. The correlation between TTG and OS was slightly stronger in cetuximab. The post-hoc exploratory analysis showed that cetuximab produced greater PFS (15.3 vs 11.7 months; HR 0.68) and OS (53.6 vs 40.2 months; HR 0.54) in patients with left-sided and RAS/BRAF wt tumors. m-FOLFOXIRI plus cetuximab has clinical benefit for tumor shrinkage in RAS wt mCRC. The survival benefit for RAS/BRAF wt and left-sided mCRC needs further investigation.
FOLFOXIRI（5-FU、亚叶酸钙、奥沙利铂和伊立替康）联合抗 EGFR 单克隆抗体西妥昔单抗治疗转移性结直肠癌（mCRC）的临床意义仍存在争议。我们报告了一项随机 2 期 DEEPER 试验（UMIN000018217，jRCTs061180022）的结果，该试验旨在检验改良 FOLFOXIRI（m）联合每周西妥昔单抗对比贝伐珠单抗在 RAS 野生型（wt）mCRC 患者中的优势。主要终点为深度缓解（DpR）。次要终点包括客观缓解率（ORR）、第 8 周时的早期肿瘤退缩（ETS）、无进展生存期（PFS）、总生存期（OS）、肿瘤进展时间（TTG）、治疗失败时间（TTF）、肿瘤退缩与预后的关系、TTG 与预后的关系、R0 切除率和安全性。在 359 名 RAS wt mCRC 入组患者中，西妥昔单抗组的中位 DpR 显著优于贝伐珠单抗组（57.3% vs 46.0%，p=0.0029）；然而，两种治疗方法的 ORR、ETS、R0 切除率、TTG、TTF、PFS 和 OS 相似。两种治疗方法中，DpR 与生存时间均存在弱相关性。在西妥昔单抗组中，TTG 与 OS 的相关性略强。事后探索性分析显示，在左半结肠癌和 RAS/BRAF wt 肿瘤患者中，西妥昔单抗可带来更优的 PFS（15.3 个月 vs 11.7 个月；HR 0.68）和 OS（53.6 个月 vs 40.2 个月；HR 0.54）。m-FOLFOXIRI 联合西妥昔单抗在 RAS wt mCRC 患者中具有肿瘤缩小的临床获益。RAS/BRAF wt 和左半结肠癌患者的生存获益尚需进一步研究。
