背景:在 RAS 野生型转移性结直肠癌(mCRC)患者中，三联疗法、FOLFOXIRI、联合贝伐单抗(bev)或帕尼单抗(panitumumab)在早期肿瘤收缩(ETS)和反应深度(DpR)方面优于双联疗法。在 TRIBE 试验(N EnglJ Med 2014)或 VOLFI 试验(J Clin Oncol 2019)中分别进行。对于西妥昔单抗(cet)与 bev 联合三组治疗方案进行直接比较的研究较少。因此，我们研究了 bev 与 cet 联合 FOLFOXIRI 治疗既往未经治疗的 RAS 野生型肿瘤 mCRC 患者的有效性和安全性。

Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial (N Engl J Med 2014) or the VOLFI trial (J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors.

方法：该试验是一项随机 II 期试验，以 360 例 RAS 野生型 mCRC 患者为主要终点，评价改良(m) FOLFOXIRI(伊立替康 150mg/m2，奥沙利铂 85mg/m2, 5-FU 2400mg/m2)联合 cet / bev 作为一线治疗 DpR 的整个疗程。试验的目的是为了表明 cet 组的中位数 DpR 比 bev 组高 12.5% 以上，在 0.05 的显著性水平下幂为 85%。中的次要终点包括第 8 周的 ETS 率、总缓解率(ORR)、无进展生存期(PFS)、总生存期(OS)、二次切除率和毒性。

Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150mg/m2, oxaliplatin 85mg/m2, 5-FU 2400mg/m2) plus cet vs. bev as first-line treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05. Secondary endpoints included ETS rate at week 8, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), secondary resection rate, and toxicity.

结果：2015 年 7 月至 2019 年 6 月期间，共有 359 名患者入组。对于完整的分析集（中位年龄65 岁，男性 64％，PS0 / 1：91％/ 9％，左/右原发性：83％/ 17％），分别将 173 例和 175例患者随机分配到 cet 和 bev 组。在 2020 年 9 月的截止日期，cet 组的平均周期数为 10（范围 1-51），bev 组的平均周期数为 12（范围 1-51）。 ASCO GI 专题讨论会 2021（《临床研究杂志》 39,2021，增刊 3；摘要 86）。达到主要终点（p = 0.001）； CET 组为 57.4％（-15.0〜100），BEV 组为 46.0％（-0.6〜100）。至于主要肿瘤方面，左侧的中位 DpR 分别为 60.3％对 46.1％（p = .0007）和右侧的 50.0％对 41.2％（p = .46）。次要终点的 ETS 发生率和 ORR 分别为 77.8％和 69.1％，而 bev 组分别为 74.6％和 71.7％，无统计学意义。尽管存活数据不成熟，但两组的 PFS 和 OS 分别为 12.7 个月（95％CI 11.5-14.0）和 37.6 个月（95％CI 30.8 至 43.0）。

Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. On the cutoff date of September 2020, the median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. Safety data was already reported at the ASCO GI symposium 2021 (J Clin Oncol 39, 2021 suppl 3; abstr 86). The primary endpoint was met (p =.001); 57.4%（-15.0̃100）for the cet arm versus 46.0% （-0.6̃100）for the bev arm. As for primary tumor sidedness, median DpR were 60.3% versus 46.1% (p =.0007) in the left-side and 50.0% versus 41.2% (p =.46) in the right-side. The ETS rate and ORR as the secondary endpoints were 77.8% and 69.1% in the cet arm versus 74.6% and 71.7% in the bev arm, respectively, with no statistical significance. Although the survival data were immature, PFS and OS of both arms were 12.7 months (95%CI 11.5-14.0) and 37.6 months (95%CI 30.8 to 43.0), respectively.

结论:作为 RAS 野生型 mCRC 一线治疗的主要终点，mFOLFOXIRI + cet 被证明明显优于 mFOLFOXIRI + bev。

Conclusion: The mFOLFOXIRI plus cet has been shown to be significantly superior to the mFOLFOXIRI plus bev in terms of DpR as the primary endpoint in first-line treatment for RAS wild-type mCRC.