Cetuximab rechallenge in molecularly selected metastatic colorectal cancer: the randomized CAVE-2 GOIM trial.

patients_and_methods

The randomized phase II CAVE-2 GOIM trial compared two rechallenge regimens in RAS/BRAF wild-type mCRC (cetuximab monotherapy or in combination with avelumab).

随机化II期CAVE-2 GOIM试验比较了两种重新挑战方案在RAS/BRAF野生型mCRC中的效果（西妥昔单抗单药治疗或与avelumab联合使用）。

Patients were selected according to baseline plasma circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) by FoundationOne Liquid CDx.

患者根据基线血浆循环肿瘤DNA (ctDNA) 全面基因组分析 (CGP) 通过FoundationOne Liquid CDx进行选择。

Primary endpoint was overall survival(OS).

主要终点是总生存（OS）。

Results

From August 2022 to December 2024, 156 out of 328 screened patients were randomly assigned in a 2 : 1 ratio to cetuximab plus avelumab (arm A, 104 patients) or cetuximab (arm B, 52 patients).

2022年8月至2024年12月，328名筛查患者中有156名按2:1的比例随机分配至cetuximab联合avelumab治疗组（A组，104名患者）或仅cetuximab治疗组（B组，52名患者）。

Median progression-free survival(mPFS) was 5.3 months [95% confidence interval(CI) 4.3-6 months] in arm A versus 4.3 months (95% CI 3.5-5.5 months) in arm B [hazard ratio(HR) 0.78, 95% CI 0.55-1.10, P = 0.158].

A组的中位无进展生存期（mPFS）为5.3个月[95%置信区间（CI）4.3-6个月]，而B组为4.3个月（95% CI 3.5-5.5个月）[风险比（HR）0.78，95% CI 0.55-1.10，P = 0.158]。

Median OS (mOS) was 14.8 months (95% CI 12.1-18.3 months) in arm A versus 12.9 months (95% CI 11 months-not evaluable) in arm B (HR 1.00, 95% CI 0.65-1.52, P = 0.983).

在A组中，中位总生存期（mOS）为14.8个月（95%置信区间12.1-18.3个月），而在B组中为12.9个月（95%置信区间11个月-未评估）（HR 1.00，95%置信区间0.65-1.52，P = 0.983）。

A pre-planned exploratory analysis evaluated the impact of genomic pathogenic variants on therapeutic efficacy in the EGFR pathway.

一项预先计划的探索性分析评估了基因组致病变异对EGFR通路治疗效果的影响。

In the whole study population, 124/156 patients had tumors without any genomic alteration in KRAS, NRAS, BRAF, EGFR extracellular domain, PIK3CA exon 20, MAP2K1, AKT1, MET, PTEN, and ERBB2 ('negative hyperselection').

在整体研究人群中，156名患者中有124名患者的肿瘤在KRAS、NRAS、BRAF、EGFR胞外域、PIK3CA外显子20、MAP2K1、AKT1、MET、PTEN和ERBB2基因上没有检测到任何基因组改变（'阴性超选择'）。

These patients had significantly improved mPFS [5.35 months (95% CI 4.4-5.9 months) versus 3.65 months (95% CI 2.8-4.8 months); HR 0.62, 95% CI 0.42-0.92, P = 0.017] and mOS [15.0 months (95% CI 12.6-19.9 months) versus 11.1 months (95% CI 8.6-15.6 months); HR 0.61, 95% CI 0.39-0.97, P = 0.037] compared with patients having at least one pathogenic variant ('positive hyperselection').

这些患者与至少携带一种致病性变异的患者（'阳性超选择'）相比，mPFS显著改善[5.35个月（95% CI 4.4-5.9个月）对比3.65个月（95% CI 2.8-4.8个月）；HR 0.62，95% CI 0.42-0.92，P = 0.017]，mOS也显著改善[15.0个月（95% CI 12.6-19.9个月）对比11.1个月（95% CI 8.6-15.6个月）；HR 0.61，95% CI 0.39-0.97，P = 0.037]。

Similarly, improved objective response rate, mPFS, and OS were observed for each treatment arm in patients with 'negative hyperselection'.

同样，在'负向超选择'患者中，每个治疗组的客观缓解率、无进展生存期（mPFS）和总生存期（OS）都有所改善。

Conclusions

Addition of avelumab does not increase efficacy of cetuximab rechallenge.

添加avelumab并未增加cetuximab再挑战的疗效。

Liquid biopsy CGP identifies patients who benefit from anti-EGFR rechallenge supporting its implementation in the continuum of care of mCRC.

液态活检CGP能够识别出从抗EGFR重挑战中获益的患者，支持其在转移性结直肠癌(mCRC)连续护理中的应用。