超高选择性转移性结直肠癌患者帕尼单抗联合 FOLFIRI 治疗的 KRAS、NRAS、BRAF 和 PIK3CA 高敏基因分型的 II 期研究：ULTRA 试验。
Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial.
机构信息
Translational Research Laboratory, Institut Català d'Oncologia Oncobell Program-IDIBELL, L'Hospitalet de Llobregat; Department of Medical Oncology, Institut Català d'Oncologia Oncobell Program-IDIBELL, CIBERONC, L'Hospitalet de Llobregat.
Translational Research Laboratory, Institut Català d'Oncologia Oncobell Program-IDIBELL, L'Hospitalet de Llobregat.
出版信息
Ann Oncol. 2019 May 1;30(5):796-803. doi: 10.1093/annonc/mdz082.
BACKGROUND
Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI.
PATIENTS AND METHODS
This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed.
RESULTS
Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR.
CONCLUSIONS
High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations.
CLINICALTRIALS.GOV NUMBER: NCT01704703.
EUDRACT NUMBER
2012-001955-38.
背景
多项研究表明，准确量化不仅 KRAS 和其他低丰度突变的重要性，因为抗 EGFR 治疗的益处可能取决于某些敏感性阈值。我们评估了使用高灵敏度数字 PCR（dPCR）来确定 KRAS、NRAS、BRAF 和 PIK3CA 状态是否可以选择超患者，以改善 panitumumab 联合 FOLFIRI 的临床结果。
患者和方法
这是一项单臂 II 期试验，分析了接受 panitumumab 联合 FOLFIRI 治疗至疾病进展或早期退出的伊立替康耐药转移性结直肠癌患者肿瘤组织中 38 个 KRAS、NRAS、BRAF 和 PIK3CA 热点的突变谱。突变谱通过纳流控 dPCR 确定，并通过 0%至 5%的截止值与临床结果（ORR、总缓解率；PFS、无进展生存期；OS、总生存期）相关联。还进行了定量 PCR（qPCR）分析。
结果
共纳入 72 例可评估患者。dPCR 检测到 RAS（KRAS/NRAS）突变 23 例（32%），RAS/BRAF 突变 25 例（35%），而 qPCR 分别检测到 7 例（10%）和 11 例（15%）。PIK3CA 突变未纳入分析，因为仅在 2 例（3%）患者的 dPCR 和 1 例（1%）患者的 qPCR 中检测到突变。不同 dPCR 截止值用于 RAS（KRAS/NRAS）和 RAS/BRAF 分析转化为不同的临床结果。野生型患者的最高 ORR、PFS 和 OS 值和突变患者的最低值用 5%的截止值获得。我们在 qPCR 定义的 RAS/BRAF 野生型和突变型患者中观察到类似的结果。
结论
高灵敏度 dPCR 准确鉴定了 KRAS、NRAS、BRAF 和 PIK3CA 突变患者。用于预测结果的最佳 RAS/BRAF 突变截止值为 5%，这解释了 dPCR 并未提高 qPCR 的预测性能。低频率突变等位基因的生物学和临床意义需要进一步研究。
临床试验.gov 编号：NCT01704703。
EudraCT 编号：2012-001955-38。
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