Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan A Phase 2 Single-Arm Clinical Trial
Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan A Phase 2 Single-Arm Clinical Trial
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DOI：
10.1001/jamaoncol.2018.5080
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发表时间：
2019-03-01
期刊：
影响因子：
28.4
通讯作者：
Santini, Daniele
中科院分区：
文献类型：
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作者：
Cremolini, Chiara;Rossini, Daniele;Santini, Daniele
重要性基于一项小型回顾性研究，对于既往接受过相同的基于抗表皮生长因子受体的方案治疗的KRAS野生型转移性结直肠癌（mCRC）患者，使用基于西妥昔单抗的治疗进行再激发可能有效。最近的数据表明，液体活检作为一种工具，以跟踪循环肿瘤DNA（ctDNA）中的分子事件的作用。目的前瞻性评估西妥昔单抗联合伊立替康作为三线治疗RAS和BRAF野生型mCRC患者的活性，这些患者最初对伊立替康和西妥昔单抗一线治疗敏感，然后耐药。和参与者2015年1月7日至2017年6月19日进行的多中心II期单组试验。在基线时收集用于ctDNA分析的液体活组织检查。主要合格性标准包括组织样本的RAS和BRAF野生型状态;既往一线伊立替康和西妥昔单抗方案至少部分缓解，一线治疗无进展生存期至少6个月，西妥昔单抗末次给药后4周内进展;干预西妥昔单抗，500 mg/m2，每两周一次，加伊立替康，180 mg/m2。主要结果和指标根据实体瘤疗效评价标准1.1版的总体缓解率。次要终点包括无进展生存期和总生存期，并作为探索性分析，RAS突变ctDNA.Results 28例患者（9名女性和19名男性;中位年龄，69岁[范围，45-79岁]）入组。报告了6例部分缓解（4例确认）和9例疾病稳定（缓解率，21%; 95% CI，10%-40%;疾病控制率，54%; 95% CI，36%-70%）。由于缓解率的95%CI下限高于5%，因此满足主要终点。在25例可评价患者中的12例（48%）中，在再激发基线时收集的ctDNA中发现RAS突变。在获得确认部分缓解的患者样本中未检测到RAS突变。RAS野生型ctDNA患者的无进展生存期显著长于RAS突变型ctDNA患者（中位无进展生存期，4.0 vs 1.9个月;风险比，0.44; 95% CI，0.18-0.98; P = 0.03）的患者结论和相关性这是首次前瞻性证明西妥昔单抗和伊立替康的再激发策略在RAS患者中可能有效。和对基于伊立替康和西妥昔单抗的一线治疗具有获得性耐药性的BRAF野生型mCRC。ctDNA上RAS突变状态的评估可能有助于选择候选患者。
IMPORTANCE Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA).OBJECTIVE To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy.DESIGN, SETTING, AND PARTICIPANTS Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment.INTERVENTIONS Biweekly cetuximab, 500 mg/m(2), plus irinotecan, 180 mg/m(2).MAIN OUTCOMES AND MEASURES Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA.RESULTS Twenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% Cl of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P =.03).CONCLUSIONS AND RELEVANCE This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients.