讨论RAS野生型转移性结直肠癌（mCRC）诱导化疗后使用抗表皮生长因子受体抗体的最佳维护策略仍然存在争议。评估FOLFIRI（亮酸葉酸，氟尿嘧啶和伊立替康）加奎托昔单药维持治疗的疗效和安全性，作为诱导治疗后的维持治疗。TIME（以厄洛替昔为维持治疗的伊立替昔为基础的一线治疗：PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]）是一个第2期非比较性多中心随机临床试验，于2014年1月15日至2018年11月23日期间在139名不可手术的RAS野生型mCRC患者中进行。分析的截止日期为2022年7月21日。在8个周期的FOLFIRI加奎托昔诱导治疗后，没有疾病进展的患者被随机分为每两周一次的奎托昔单药维持治疗组或观察组。在疾病进展时，建议使用相同的诱导方案进行16周，然后继续使用奎托昔维持治疗组或观察组，直到疾病进展，使用完整的诱导方案。主要终点是从随机化后的6个月无进展率。基于意向治疗的分析进行。利用下一代测序的探索性生物分子分析，调查了肿瘤突变谱的潜在预测价值。共有214名患者参与研究（男性141人[65.9%]；中位年龄67岁[范围23-85岁]），其中139名患者随机分为接受奎托昔（n = 67，男性45人[67.2%]，中位年龄64岁[范围34-85岁]）或观察（n = 72，男性50人[69.4%]，中位年龄68岁[23-85岁]）的组。奎托昔组的6个月无进展率为38.8%（[67中的26人] 95% CI，27.1%-51.5%），观察组的6个月无进展率为5.6%（[72中的4人] 95% CI，1.5%-13.6%）。在中位随访时间为40.5个月（95% CI，33.6-47.5个月）后，奎托昔组的中位无进展生存期（PFS）为5.3个月（95% CI，3.7-7.4个月），观察组为2.0个月（95% CI，1.8-2.7个月）。奎托昔组的中位总生存期（OS）为24.8个月（95% CI，18.7-30.4个月），观察组为19.7个月（95% CI，13.3-24.4个月）。在探索性多变量分析中，不论治疗组，线粒体激酶激活的突变在短期无进展生存期方面均与较短的随机化期相关（风险比1.63[95% CI，1.01-2.62]; P = .04）。在维持治疗期间，奎托昔组中最常见的3级或4级治疗相关毒性效应是皮疹（67中的8人[11.9%]）。这项随机临床试验未达到主要终点，但表明奎托昔维持治疗与临床意义上的PFS和OS益处相关。然而，对于具有MAPK突变而不考虑原发性肿瘤的一侧的患者来说，在一线联合FOLFIRI-奎托昔治疗后进行奎托昔维持治疗或治疗间歇似乎不合适。对MAPK信号通路突变的更全面的评估需要进一步研究，以完善RAS野生型mCRC患者的治疗策略。 ClinicalTrials.gov识别号：NCT02404935。

The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated.To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy.The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022.After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen.The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile.Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]).The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC.ClinicalTrials.gov Identifier: NCT02404935.